6 - Topnotch Pharma Supertable Updated April 2017 By Yns Pereyra

SUPER PHARMA TABLE Maria Yña Eluisia T. Pereyra RPh, MD, MBA DRUG

MOA and INDICATION

ADVERSE EFFECTS

NOTABLE PROPERTIES

1. AUTONOMIC DRUGS Cholinomimetics A. Direct Acting Choline Esters i. Acetylcholine

ii.Betanechol

iii. Carbachol

Muscarinic agonist; activates M1 through M3 receptors in all peripheral tissues. Results to increased secretion, smooth muscle contraction (except in vascular smooth muscles where it causes relaxation) and changes in heart rate Muscarinic agonist; activates M1 through M3 receptors in all peripheral tissues (same as Ach) ; for Bladder and bowel atony

CNS stimulation, miosis, cyclospasm, brochoconstriction, excessive GI and GU smooth muscle contraction, increased secretory activity of sweat gland, airways etc, vasodilation

very short lived DOA: 5-30sec, apidly hydrolyzed by AChE; acts on both M and N receptors

Cylospasm, diarrhea, urinary urgency, vasodilation, reflex tachycardia, sweating

Nonselective muscarinic and nicotinic agonist; similar to betanechol; used topically for glaucoma treatment

Cylospasm, diarrhea, urinary urgency, vasodilation, reflex tachycardia, sweating

Results in smooth muscle contraction except in vascular smooth muscles where it causes relaxation; resistant to AChE, orally active, act on M receptors only acts on both M and N receptors, DOA: 30mins-2hrs

B. Direct Acting Muscarinic Alkaloids i. Pilocarpine

Partial muscarinic agonist; used for treatment of Glaucoma, Sjogren's syndrome and Sicca syndrome

Miosis, blurring of vision

good lipid solubility compared to choline esters

Agonist at both NN and NM receptos; activates autonomic post ganglionic neurons (both sympathetic and parasympathetic) and skeletal muscle neuromuscular end plates ; for Smoking Cessation Selective partial agonist at nicotinic receptors; used exclusively for smoking cessation

Generalized ganglionic stimulation (hypertension, Able to enter the CNS and activates tachycardia, nausea, vomiting, diarrhea) NN receptors ; DOA: 1-6h only

C. Direct Acting Nicotinic Agonists i. Nicotine

ii. Varenicline

D. Short Acting Cholinesterase Inhibitor (Alcohol)

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Generalized ganglionic stimulation (hypertension, longer DOA than nicotine: 12-24h tachycardia, nausea, vomiting, diarrhea)

i. Edrophonium

Binds briefly to active site of acetylcholinesterase (AChE) and prevents access of acetylcholine (Ach); Amplifies all actions of Ach; increases parasympathetic activity and somatic neuromuscular transmission ; for Myasthenia gravis diagnosis (Tensilon test) E. Intermediate Acting Cholinesterase Inhbitors (Carbamates) i. Neostigmine

ii. Pyridostigmine iii. Physostigmine

Miosis, salivation, nausea, vomiting, diarrhea, bradycardia

parenteral, very short lived DOA: 515min

Forms covalent bonds with AChE, but is hydrolyzed and Miosis, salivation, nausea, vomiting, diarrhea, released; Longer acting than Edrophonium ; for Myasthenia bradycardia gravis treatment; reversal of nondepolarizing muscular blockade, Ogilvie syndrome Longer acting effect compared to Neostigmine Miosis, salivation, nausea, vomiting, diarrhea, bradycardia

poor lipid solubility, oral, DOA: 30min-2h

Natural alkaloid tertiary amine, similar to neostigmine

Miosis, salivation, nausea, vomiting, diarrhea, bradycardia

good lipid solubility: able to enter the CNS, DOA: 4-8h

poor lipid solubility, oral, DOA: 4-8h

F. Long Acting Cholinesterase Inhibitors (Organophosphates) i. Echothiophate

Similar to neostigmine but with slower release

Miosis, salivation, nausea, vomiting, diarrhea, bradycardia

moderate lipid solubiliy, DOA: 27days

ii. Malathion, Parathion

malathion: scabicide, parathion: insecticide

Miosis, salivation, nausea, vomiting, diarrhea, bradycardia

high lipid solubiliy, DOA: 7-30 days

Cholinoceptor Blocking Drugs i. Scopolamine

ii. Atropine

iv. Homatropine

Competitively blocks all muscarinic receptors, antagonizes Drowsiness, blurring of vision, dry eyes, histamine and serotonin ; for motion sickness, dec. acid constipation, dry mouth, urinary retention secretion in the GIT Nonselective competitive antagonism at all muscarinic receptors in the CNS and peripheral tissues; causes mydriasis and cycloplegia; mandatory antidote for severe cholinesterase inhibitor poisoning ; Mydriatic, cycloplegic, antidote for organophosphate poisoning (DOC), for bradycardia, hypersalivation and to decrease airway secretion during general anesthesia Similar to atropine but with a shorter duration of action (12-24h) ; Mydriatic, cycloplegic in eye examinations

known as Hyoscine-N-ButylBromide (Buscopan)

Tachycardia, mydriasis, cyloplegia, skin flushing, DOC for organophosphate delirium, hallucinations, urinary retention, poisoning; notorious for causing constipation hyperthermia

Mydriatic, cycloplegic

v. Cyclopentolate

Similar to atropine but with a shorter duration of action (36h), Mydriatic, cycloplegic in eye examinations

Mydriatic, cycloplegic

vi. Tropicamide

Similar to atropine but with the shortest duration of action (15-60min); Mydriatic, cycloplegic in eye examinations

shorter DOA among cholineceptor blockers (15-60min)

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vii. Ipratropium

Competitive nonselective antagonist at muscarinic receptors ; for BA and COPD

Dry mouth, cough, nasal dryness

not as effective as SABAs but less tachycardia and arrhythmia ; few muscarinic effects outside the lungs

viii. Tiotropium

Similar to Ipratropium but with longer duration of action

Dry mouth, cough, nasal dryness

not as effective as SABAs but less tachycardia and arrhythmia ; few muscarinic effects outside the lungs

ix. Oxybutinin

Nonselective muscarinic antagonist which reduces detrussor smooth muscle tone spasms ; for decreasing urgency in mild cystitis and dec. bladder spasm after urologic surgery Regenerates active acetylcholinesterase; can relieve skeletal muscle and endplate block ; Usual antidote for early stage cholinesterase inhibitor poisoning

Tachycardia, mydriasis, cyloplegia, skin flushing, delirium, hallucinations, urinary retention, constipation

for urinary urgency and incontinence

muscle weakness

Competitively blocks all Nn nicotinic Ach receptors ; for Hypertensive emergencies (obsolete)

Postural hypotension, dry mouth, blurred vision, constipation, sexual dysfunction

Must be administered before 6-8 hours of organophosphate bond with cholinesterase occurs ; has oxime group which has high affinity for phosphorus first successful agents in treating HTN

Non-selective, direct acting sympathomimetic; activates A and B adrenergic receptors; A1 - vasoconstriction and increased BP; B1 - increased HR, conduction and contractility; B2 - bronchodilatation ; used for Cardiac arrest, anaphylaxis, asthma, COPD, Hemostasis Non-selective, direct acting sympathomimetic; activates A and B adrenergic receptors; A1 - vasoconstriction and increased BP; B1 - increased HR, conduction and contractility; B2 - bronchodilatation ; used for Neurogenic shock, cardiogenic shock

Hypertension, tachycardia, ischemia, hyperglycemia

x. Pralidoxime

xi. Hexamethonium, Mecamylamine, Trimethaptan Sympathomimetics i. Epinephrine

ii. Norepinephrine

iii. Dopamine

DOC for Anaphylaxis ; inactive per orem ; do not enter CNS significantly ; short DOA

Extreme vasospasm, tissue necrosis, excessive BP Compensatory vagal reflexes tend increase, arrhythmias, infarction, reflex to overcome the direct postive bradycardia chronotropic effects ; alpha activity > beta activity; inactive per orem ; do not enter CNS significantly ; short DOA Non-selective, direct acting sympathomimetic; activates A, Cardiovascular disturbances, arrhythmias inactive per orem ; do not enter B and D1 adrenergic receptors; A1 - vasoconstriction and CNS significantly ; short DOA; very increased BP; B1 - increased HR, conduction and effective in renal failure associated contractility; D1 - vasodilation in splanchnic and renal with shock blood vessels ; for cardiogenic Shock and heart failure

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iv. Isoproterenol

Beta nonselective sympathomimetic; nonselectively activates B adrenergic receptors; B1 - increased HR, conduction and contractility; B2- bronchodilatation ; for Asthma vi. Phenylephrine A1 agonist used for short term maintenance of BP in acute hypotension; also used intranasally to produce local vasoconstriction as a decongestant ; mydriatic, for druginduced hypotension, spinal shock vii. Clonidine A2 agonist that inhibits adenylyl cyclase and interacts with other intracellular pathways; marked vasodilation by central sympatholytic effect ; for Hypertension, Cancer pain, opioid withdrawal viii. Methyldopa, Guanfacine and Central sympatholytics analogous to clonidine ; Guanabenz Methyldopa is used for Pre-eclampsia

Cardiovascular disturbances, arrhythmias

synthetic catecholamine, not readily taken up into nerve endings

Rebound nasal congestion (Rhinitis medicamentosa), hypertension, stroke, MI

Mydriasis without cycloplegia

Sedation, rebound hypertension, dry mouth

When taken per orem, there is initial inc in BP then will go down once the drug enters the CNS

Sedation, positive Coomb's test (Hemolytic anemia)

Methyldopa - positive Coomb's test (Hemolytic anemia)

eye discomfort, hyperemia and pruritus, blurred vision

NONE

xi. Apraclonidine, Brimonidine

A2 agonist; reserved for ophthalmologic use in glaucoma for reduction of intraocular pressure

xii. Dobutamine

B1 agonist that activates adenylyl cyclase, increasing Tachyarrhythmia, Hypertension, Eosinophilic Beta1 selective myocardial contractility; with positive inotropic effect ; myocarditis, Premature ventricular beats, Angina, Clinically used for cardiogenic shock and acute heart failure Dyspnea, Fever, Headache, Nausea, Palpitation

xiii. Albuterol/Salbutamol

B2 agonist with adenylyl cyclase activation; results to bronchial smooth muscle dilation ; for Bronchial Asthma

Nausea , Fever, Bronchospasm, Vomiting, Headache, Dizziness, Cough, Allergic reactions

xiv. Fenoldopam

D1 agonist that activates adenylyl cyclase; results to vascular smooth muscle relaxation ; for Hypertension

Angina, Cardiac dysrhythmia, Dizziness, Flushing, D1 agonist Heart failure, Hypotension, Myocardial infarction, Tachycardia

xv. Bromocriptine

D2 agonist that inhibits adenylyl cyclase and interacts with Nausea, Hypotension, Headache, Dizziness other intracellular pathways; restores dopamine actions in the CNS for Parkinson's disease, prolactinemia

D2 agonist

Irreversibly blocks A1 and A2 receptors resulting to indirect baroreflex activation. Decreases blood pressure but increases heart rate due to baroreflex activation ; for Pheochromocytoma Reversible A1 and A2 receptor antagonist with low half life ; for Pheochromocytoma and Rebound hypertension

Orthostatic hypotension, Reflex tachycardia, GI irritation

Irreversible blockade

Orthostatic hypotension, Reflex tachycardia, GI irritation

Reversible blockade

Rapid development of tolerance; DOC as Asthma reliever

Sympatholytics i. Phenoxybenzamine

ii. Phentolamine

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iii. Prazosin, Doxazosin, Terazosin Blocks A1 but not A2 receptors; leads to reduction in blood Dizziness, Drowsiness, Headache, Weakness, Used in patients with HTN and BPH pressure ; for Benign Prostatic Hyperplasia, Hypertension Asthenia, Nausea, Palpitation, Edema, Orthostatic at the same time hypotension iv. Tamsulosin

Slightly selective A1a blockade causing relaxation of prostatic smooth muscles > vascular smooth muscle ; for BPH

Headache, Orthostatic hypotension, Rhinitis, Abnormal ejaculation, Dizziness, Arthralgia, Infection

vi. Labetalol

Beta blockade > A1 blockade; still with BP depressant effects and limited HR increase

Bronchospasm, cardiac depression, AV block, hypotension, dizziness, headache; Use in caution with DM Px: Masks symptoms of hypoglycemia in Propranolol has local anesthetic diabetics effect

vii. Propranolol, Nadolol, Timolol Blocks B1 and B2 receptors; lowers both HR and BP and reduces the release of renin ; for Angina prophylaxis, hypertension, arrhythmias, migraine, performance anxiety, hyperthyroidism viii. Metoprolol, Atenolol, B1 > B2 blockade; lowers both HR and BP, reduces the Alprenolol, Betaxolol, Nebivolol release of renin BUT is considered safer for patients with asthma ; for Angina prophylaxis, hypertension, arrhythmias, migraine, performance anxiety, hyperthyroidism x. Pindolol, Acebutolol, Carteolol, B1, B2 with intrinsic sympathomimetic (partial agonist) Bopindolol, Oxprenolol, Celiprolol, effect; lowers BP with modest reduction in HR Penbutolol xi. Carvedilol, Medoxalol, Bucindolol, Labetalol xii. Esmolol

Slightly selective A1a blockade causing relaxation of prostatic smooth muscles > vascular smooth muscle safe in pregnant patients

Nebivolol has vasodilating effect ; metoprolol reduce moratlity in heart failure

Pindolol is a partial agonist, therefore safer in bronchial asthma

Beta blockade > A1 blockade; still with BP depressant effects and limited HR increase ; for Heart Failure

Carvedilol reduce mortality in heart failure

B1 > B2 blockade; for rapid control of BP and arrhythmias, thyrotoxicosis and myocardial ischemia intraoperatively ; for Supraventricular tachycardia

Used in for perioperative thyroid storm

2. CARDIOVASCULAR-RENAL DRUGS Antihypertensives lower BP by decreasing volume and a direct vascular effect that is not yet fully understood Inhibit Na/Cl transporter in distal convoluted tubule. Cause i.Thiazide: Hydrochlorothiazide, moderate diuresis and reduced excretion of calcium; for Chlorthalidone, Metolazone, mild to moderate hypertension (FIRST LINE), Heart failure, Indapamide Nephrogenic Diabetes Insipidius, Renal calcium stones A. Diuretics

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Hypokalemic metabolic alkalosis, Dilutional hyponatremia, Potassium wasting, hyperlipidemia, hyperuricemia, sulfa allergy, hyperglycemia, hypercalcemia

causes hypercalcemia in contrast with loop diuretics which cause hypocalcemia ; FIRST LINE for mild to moderate hypertension

Inhibit Na/K/2Cl transporter in thick ascending limb of loop of Henle, Cause powerful diuresis and increased CA ii. Loop: Furosemide, Torsemide, excretion; for heart failure, hypertension, acute renal Bumetanide, Ethacrynic Acid failure, Pulmonary edema, hypercalcemia, Anion overdose

Hypokalemic metabolic alkalosis, Potassium wasting, ototoxicity, hyperuricemia, nephrotoxicity, dehydration, hypomagnesemia, sulfa allergy

causes hypocalcemia in contrast with thiazide diuretics which cause hypercalcemia

dry mouth, sedation, rebound hypertension, hemolytic anemia: (+) Coomb's test (methyldopa), sedation

Taper use prior to discontinuation to avoid rebound hypertension ; readily enter the CNS NONE

B. Sympathoplegics

decrease venous return, decrease HR, decrease contractile force, decrease cardiac output, decrease TPR

i.Sympathetic Outflow Blocker: Clonidine, Methyldopa

activates a2 adrenergic receptors ; for hypertensive urgency (clonidine), pre eclampsia (methyldopa)

ii. Ganglion blockers: Hexamethonium,Trimethaphan

Postural hypotension, blurred vision, constipation, dry mouth, sexual dysfunction

iii. Nerve terminal blockers: Reserpine, Guanethidine, Guanadrel

competetively blocks Nn nicotinic Ach receptors; for hypertension (obsolete), hypertensive emergencies Reserpine Irreversibly blocks the vesicular monoamine transporter (VMAT) while Guanethidine and Guanadrel inhibit the vesicular release of NE from the presynaptic neuron; for Hypertension (obsolete)

iv. Adrenergic antagonists: Prazosin,Doxazosin, Terazosin, Tamsulosin, Silodosin

selectively blocks a1 adrenergic receptors; for hypertension, benign prostatic hyperplasia

Reflex tachycardia (less chance), first dose orthostatic hypotension

Sedation, suicidal ideation, severe psychiatric depression

NONE Tamsulosin is most selective for prostatic smooth muscle ; Doxazosin and Terazosin has longer duration of action than prazosin

C. Vasodilators

i. Oral Vasolidator: Hydralazine

Minoxidil

Release NO from endothelial cells, Relaxes arteriolar combination treatment with ISDN smooth muscle, causing vasolidation. Decreases afterload ; Edema, myocardial ischemia, drug induced lupus for heart failure is more effective for pre-eclampsia, hypertension, heart failure (hydralazine), reflex tachycardia than ACEIs in blacks Opens K+ channels in vascular smooth muscle, causing hyperpolarization, muscle relaxation and vasolidation; for alopecia / male pattern baldness, hypertension

Edema, Angina, Reflex tachycardia, Pulmonary hypertension, Pericarditis, Hirsutism, salt and water retention

require concomitant use of diuretics and BBs to block compensatory responses

block voltage-gated L-type calcium channels (cardiac > vascular); for Angina, Supraventricular tachycardia, migraine, hypertension

Constipation, Nausea, flushing,gingival hyperplasia, AV block, sinus node depression, Pretibial edema, dizziness

excessive cardiac depression may occur

block voltage-gated L-type calcium channels (vascular > cardiac); for Angina, hypertension

Nausea, Flushing, dizziness, pretibial edema, constipation

greater vasodilator effect that cardiodepressant effect

ii. Calcium Channel Blockers Non-dihydropyridine calcium channel blocker: Verapamil, Diltiazem Dihydropyridine calcium channel blocker: Nifedipine, Amlodipine, Nicardipine, Nisoldipine, Isradipine, Felodipine iii. Parenteral Vasodilators

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Nitroprusside

relaxes venous and arteriolar smooth muscle; for acute heart failure, controlled hypotension, cardiogenic shock, hypertensive emergency

hypotension, headache, CN toxicity

Diazoxide

Opens K+ channels in vascular smooth muscle, causing hyperpolarization, muscle relaxation and vasolidation; for hypertension

hypotension, headache

not commonly used because it is very light sensitive, has short Duration of action ; given as continuous infusion a thiazide derivative without a diuretic effect ; also reduces insulin release (can be used to treat hypoglycemia in insulin-producing tumors)

Fenoldopam

causes arteriolar vasolidation of the afferent and efferent arterioles. Increases renal blood flow; for hypertensive emergency

hypotension, hypokalemia

short duration of action: 10mins

D. Angiotensin antagonists and renin inhibitor

i. ACE inhibitors: Captopril, Enalapril, Lisinopril, Benazepril

inhibit angiotensin converting enzyme ; for hypertension, heart failure

cough, hyperkalemia, rash, hypotension, palpitations, renal damage in patients with slows down the progression of DM preexisting renal vascular disease but is nephropathy and cardiac protective for DM nephropathy ; CI in pregnancy remodelling in heart failure

ii. Angiotensin receptor blocker: Losartan, Valsartan, Irbesartan, Candesartan

competetively blocks Angiotensin 1 receptor site ; for hypertension

fatigue / weakness, hypoglycemia, anemia, diarrhea, cough, CI in pregnancy

iii. Renin inhibitor: Aliskerin

as effective as ACEi but less cough

no reproductive toxicity but is also diarrhea, cough, rash, hyperkalemia, increase in CI because of the toxicity of ACEi inhibitor of renin's action on its substrate angiotensinogen serum creatinine, renal impairment, angioedema and ARBs

Vasodilators and anti-Angina Pectoris A. Nitrates releases nitric oxide (NO), relaxes smooth muscle, i. Ultrashort-acting nitrate: Amyl especially vascular, increases cGMP (cyclic guanosine Nitrite monophosphate); for cyanide poisoning

Reflex tachycardia, Orthostatic hypotension, methemoglobinemia

ii. Short-acting nitrate: releases nitric oxide (NO), increases cGMP (cyclic Nitroglycerin, Isosorbide Dinitrate, guanosine monophosphate) and relaxes smooth muscle Isosorbide Mononitrate especially vascular; for Angina, acute coronary syndromes

Reflex tachycardia, orthostatic hypotension, headache, tolerance (transdermal)

inhalational route, but now rarely used Dangerous hypotension with PDE inhibitors such as Sildenafil ; First Pass effect is ~90% (NTG), NTG also decrease platelet aggregation

Constipation, Nausea, flushing,gingival hyperplasia, AV block, sinus node depression, Pretibial edema, dizziness

excessive cardiac depression may occur

B. Calcium Channel Blockers i. Non-dihydropyridine calcium channel blocker: Verapamil, Diltiazem

block voltage-gated L-type calcium channels (cardiac > vascular); for Angina, Supraventricular tachycardia, migraine, hypertension

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ii. Dihydropyridine calcium channel blocker: Nifedipine, Amlodipine, Nicardipine, block voltage-gated L-type calcium channels (vascular > Nisoldipine, Isradipine, Felodipine cardiac); for Angina, hypertension

Nausea, Flushing, dizziness, pretibial edema, constipation

greater vasodilator effect that cardiodepressant effect

Drugs used in Heart Failure

A. Cardiac Glycoside

i. Digoxin

Other drugs for heart failure include Diuretics (Furosemide is the DOC for acute heart failure), Angiotensin Antagonists (ACEi is the DOC for chronic heart failure), Beta1 blockers (dopamine and dobutamine), Non-selective Beta Blockers (Carvedilol, Labetalol, Metoprolol), PDEi (Inamrinone, Milrinone), Vasodilators (Nitroprusside, Nitroglycerin) Arrhythmogenesis increased by inhibits Na/K ATPase; increases intracellular Ca, increasing Narrow therapeutic index, Arrhythmias, diarrhea, hypokalemia, hypercalcemia, cardiac contractility; for heart failure, Nodal arrythmias vomiting, visual changes hypomagnesemia

Anti-Arrhythmics A. Class 1 Antiarryhtmics

ii. Class 1B: Lidocaine, Mexiletene, Tocainide, Phenytoin

Arrhythmias, lupus-like syndrome (procainamide), hypotension, cinchonism (quinidine), thrombocytopenia (quinidine), antimuscarinic effect (disopyramide), quinidine reduces digoxin Hyperkalemia exacerbates cardiac clearance toxicity Hyperkalemia, exacerbates cardiac toxicity. Lidocaine is the least highly selective use and state-dependent INa block; cardiotoxic among conventional minimal effect in normal tissue; no effect on IK; DOC for anti-arrhythmics ; only affect ventricular arrhythmia post-myocardial infarction, Digoxinischemic tissue; lidocaine is never induced arrhythmia ; Mexilitine can be used for CNS stimulation, Allergy, Arrhythmias, given P.O due to significant first neuropathic pain depression, Agranulocytosis pass effect

iii. Class 1C: Flecainide, Propafenone, Encainide, Moricizine

Selective use and state-dependent block of INa; slowed conduction velocity and pacemaker activity; for refractory Increased arrhythmias (proarrhythmic effect), arrhythmias CNS excitation

i. Class 1A: Procainamide, Disopyramide, Quinidine,

Use- and state-dependent block of INa channels; some block of Ik channels. Slowed conduction velocity and pacemaker activity; prolonged action potential duration and refractory period; for atrial and ventricular arrhythmias especially after myocardial infarction

B. Class 2 Antiarrythmics

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hyperkalemia exacerbates cardiac toxicity contraindicated for post MI arrhythmias

i. Propranolol, Esmolol

Block of beta-receptors, decrease in cAMP results to decreased Na and Ca current and suppression of cardiac pacemaker activity; for Post MI prophylaxis against sudden death, thyrotoxicosis, acute perioperative and thyrotoxic Bronchospasm, AV block, Hypotension, Cardiac arrhythmias, Supraventricular tachycardia depression

C. Class 3 Arrhythmics

In CHF, reduces progression and decreases incidence of potentially fatal arrhythmias. Sotalol is a betablocker anti arrhythmic that has class 3 properties Group with the greatest risk for TDP

i. Dofetilide, Ibutilide,

Selective Ik block ; prolonged action potential and QT interval; for treatment and prophylaxis of atrial fibrillation Torsade de pointes

ii. Sotalol

Ik block and beta-adrenoceptor block; for ventricular Dose-related torsade de pointes, excessive betaarrhythmias, Supraventricular tachycardia, Atrial fibrillation blockade (sinus bradycardia, asthma) NONE

iii. Amiodarone, Dronedarone

Strong Ik block produces marked prolongation of action potential and refractory period. Group 1 activity slows conduction velocity; groups 2 and 4 activity confer additional anti arrhythmic activity; for refractory arrhythmia, used off label in many arrhythmia

NONE

Amiodarone has Class 1, 2 3 and 4 activity therefore is the MOST Microcrystalline deposits in cornea and skin, EFFICACIOUS of all anti-arrhythmics, paresthesias, Pulmonary fibrosis, Tremor, Thyroid amiodarone has longest among all dysfunction (hyper- or hypo-) anti-arrhythmics (1-10 weeks)

D. Class 4 Antiarrythmatics i. Non-dihydropyridine calcium channel blocker: Verapamil, Diltiazem E.Miscellaneous Antiarrythmics

i. Adenosine

Block voltage-gated L-type calcium channels (cardiac >vascular), decreased AV conduction velocity ; for Angina, Constipation, Pretibial edema, Nausea, Flushing, Hypertension, Supraventricular tachycardia, migraine, Gingival hyperplasia, heart failure, AV block, Raynaud's Phenomenon, Vasospasm dizziness, sinus node depression

should be avoided in Ventricular tachycardia

Increase in diastolic Ik of AV node that causes marked hyperpolarization and conduction block; reduced ICa; For AV nodal arrhythmias, DOC for paroxysmal supraventricular tachycardia

Flushing, Transient chest pain, Dyspnea, Hypotension

DOC for paroxysmal supraventricular tachycardia, Duration of action is only 15sec

Inhibits carbonic anhydrase. In proximal tubule, In glaucoma, secretion of aqueous humor is reduced and in mountain sickness, metabolic acidosis increases respiration; for glaucoma, diuresis for edema with alkalosis.

Drowsiness, Sulfa Allergy, Renal calcium stones, Paresthesias, hyperchloremic metabolic acidosis, hepatic encephalopathy in cirrhotic patients, potassium wasting diuresis is self-limiting after 2-3 days

Diuretics A. Carbonic Anhydrase Inhibitors

i. Acetazolamide, Dorzolamide, Brinzolamide, Dichlorphenamide, Methanolamide B. Loop Diuretic

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i.Furosemide, Bumetanide, Torsemide

Inhibit Na/K/2Cl transporter in thick ascending limb of loop of Henle, Cause powerful diuresis and increased Ca excretion; for Heart failure, Hypertension, Pulmonary Edema, Hypercalcemia, Acute renal failure, Anion overdose

Hypokalemic metabolic alkasis, dehydration, Ototoxicity, Potassium wasting, Sulfa allergy, Hyperuricemia, Hypocalcemia, Hypomagnesemia, Nephritis

C. Thiazide Diuretics

Synergistic ototoxicity with aminoglycosides. Efficacy decreased by NSAIDs ; causes hypocalcemia in contrast with thiazide diuretics which cause hypercalcemia

Inhibit Na/Cl transporter in distal convolutes tubes. Causes moderate diuresis and reduced excretion of calcium; For Hypokalemic metabolic alkalosis, Potassium hypertension Hypercalciuria, Heart failure, Nephrogenic wasting, dilutional hyponatremia, Hyperglycemia, diabetes insipidius, renal calcium stones hyperuricemia, sulfa allergy, hyperlipidemia

Synergistic effect with loop diurectics. Efficacy decreased by NSAIDs ; causes hypercalcemia in contrast with loop diuretics which cause hypocalcemia

i. Spironolactone, Eplerenone (Aldosterone Antagonist)

Steroid inhibitors of cytoplasmic aldosterone receptor in cortical collecting ducts. Reduce K excretion; for Hyperaldosteronism, Heart failure, Hypokalemia, Hypertension

Hyperkalemia, impotence, Benign prostatic hyperplasia, Hyperchloremic metabolic acidosis, anti-androgenic effect (Spironolactione)

Eplerenone reduces progression of DM nephropathy and reduces mortality post MI

ii. Amiloride, Triamterene (Na channel Blocker)

Inhibitor of ENaC (Epithelial sodium channels) in cortical collecting duct, reduces Na reabsorption and K excretion; for hypokalemia

Hyperkalemia, kidney stones, metabolic acidosis, Acute renal failure (with indomethacin), should should never be given with never be given with potassium supplements potassium supplements

i. Hydrochlorothiazide, Chlorthalidone, Indapamide, Metolazone D. Potassium-Sparing Diuretics

E. Osmotic Diuretics Osmotically retains water in tubule by reducing reabsorption in proximal tubule, descending limb of Henle's loop, and collecting ducts; in the periphery, Transient volume expansion (hyponatremia, i. Mannitol, Glycerin, Isosorbide, mannitol extracts water from cells; for Rhabdomyolysis, pulmonary edema; followed by hypernatremia) Urea Hemolysis, Increased intracranial pressure, Acute glaucoma nausea, headache, dehydration, vomiting

used to maintain high urine flow

F. ADH Agonists/ Antagonists

i. Antidiuretic hormone, Desmopressin, Vasopressin G. ADH Antagonists: Conivaptan, Tolvaptan, Lixivaptan, Demeclocycline, Lithium

Agonists at V1 and V2 ADH receptors. Activate insertion of aquaporin water channels in collecting tubule. Vasoconstriction; For central diabetes insipidus, hemophilia, Nocturnal enuresis, von Willebrand's disease Hypertension, Hyponatremia Infusion site reactions, hyperkalemia, Nephrogenic diabetes insipidus, Bone and Teeth Antagonist at V1, V2 receptors; for SIADH and abnormalities(demeclocycline), Renal failure Hyponatremia (Lithium, demeclocycline)

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Increases the factor VIII activity of patients with mild hemophilia A or von Willebrand disease Central Pontine Myelinosis may occur with rapid correction of hyponatremia

3. DRUGS WITH IMPORTANT ACTION ON SMOOTH MUSCLES Histamine, Serotonin and the Ergot Alkaloids A. H1 antagonists

diminish or abolish the major actions of histamine in the Sedation, should not be given to neonates body by competitive, reversible blockade of histamine H1- because they are more susceptible to receptor sites on tissues ; used primarily for the alleviation antimuscarinic effects of conditions such as urticarial rashes and nasal allergy that are characterised by type I hypersensitivity ; are of value in preventing urticaria and are used to treat urticarial rashes and mild angioedema

i. 1st Generation: Diphenhydramine, Dimenhydrinate, Chlorpheniramine, Meclizine, Promethazine

Reversible blockade of histamine H1-receptor sites on tissues ; anti-nausea and antiparkinsonism effect, for allergic reactions, for sedation and motion sickness (Diphenhydramine Dimenhydrinate, Cyclizine, Meclizine, Promethazine), for chemotherapy-induced vomiting (Diphenhydramine)

Anticholinergic effects, orthostatic hypotension (promethazine), sedation

ii. 2nd Generation: Loratadine, Desloratadine, Cetirizine, Levocertirizine, Fexofenadine

Reversible blockade of histamine H1-receptor sites on tissues ; for allergic reactions

headache, dry mouth, hyperkinesia, malaise, may No sedation and antimuscarinic cause arrhythmia due to blockade of cardiac effects ; usual half-life: 12-24h potassium channels (acrivastine, astemizole, cetirizine, loratadine, and terfenadine) No blocking action on H1 receptor

Surmountable competitive pharmacologic block of H2 receptors, reduction of nocturnal acid secretion in gastirc and duodenal ulcer, accelerate healing and prevent recurrences ; for PUD, GERD and ZES

CYP450 inhibitor, antiandrogen effects, decreased used in the ICU setting to prevent hepatic blood flow (cimetidine), weak enzyme gastric erosion and hemorrhage ; inhibitory effect (Ranitidine) usual half-life: 1-3h

B. H2 antagonists i. Cimetidine, Ranitidine, Famotidine, Nizatidine

C. Serotonin Agonists

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Possess antimuscarinic, adrenalineantagonising, serotonin antagonising, and local anaesthetic effects. Some have calcium-channel blocking activity ; Sedating antihistamines may enhance the sedative effects of CNS depressants including alcohol, barbiturates, hypnotics, opioid analgesics, anxiolytic sedatives, and antipsychotics ; all are PO but can be given topical (nose and eyes) ; negligible on H2 receptors more likelyeffect to block autonomic

receptors, also has alpha1 blocking and local anesthetic effect ; Cyclizine (more anti-motion sickness action less sedative and and autonomic effects); Promethazine (less anti-motion sickness, more sedative and autonomic effects ; Usual half-life: 4-12h

i. 5HT1D receptor agonist: Sumatriptan, Naratriptan, Almotriptan, Eletriptan, Frovatriptan, Rizatriptan, Zolmitriptan

Agonist at the 5HT1D receptor in the blood vessels causing Injection site reaction, paresthesia, dizziness, vasocontriction ; 1st line treatment for Acute migraine and warm/hot sensation, chest pain, coronary cluster headache attacks vasospasm

all are per orem only except for Sumatriptan which can also be given intranasally, transdermal and IV ; All has 2-27hrs DOA exc for sumatriptan DOA: 2-4h

i. 5HT3 receptor antagonist: Ondansetron, Granisetron, Dolasetron, Alosetron

Selectively block 5HT3 receptors ; For antiemesis in patients post-chemotherapy or post-operation

E. Ergot Alkaloids

most are partial agonists at alpha receptors and 5HT receptors but some are potent agonist at dopamine receptors Mixed partial agonist effects at 5-HT2 and a-adrenoceptors, gangrene (secondary to ischemia) in overdose, causes vasoconstriction; For Migraine attacks (but 5HT1D unusual hyperplasia of the retroperitoneal, are preferred) retropleural or subendocardial cavity --> hydronephrosis, cardiac valvular and conduction system malfunction Mixed partial agonist effects at 5-HT2 and a-adrenoceptors, marked uterine contraction, GI upset (nausea, causes vasoconstriction; For control of post-partum vomiting, diarrhea) bleeding

Dolasetron can increase QRS and QT (proarrhythmic effect) duration so never use in patients with heart disease

D. Serotonin Antagonists

i. Vasoselective: Ergotamine

ii. Uteroselective: Ergonovine

Constipation, headache, malaise

The Eicosanoids: Prostaglandins, Thromoboxanes, Leukotrienes and related compounds

can cause epinephrine reversal due to partial agonist effect on alpha receptors (REMEMBER: All partial agonist will act as antagonist in the present of a full agonist) uterus becomes more sensitive to ergots during pregnancy, produce very powerful and long-lasting contraction leading to decreased bleeding, Never give before delivery of placenta

A. Prostaglandin E1 analog i. Misoprostol, Gemeprost

PGE1 analogue, activated EP receptor, causes increased HCO3 and mucus secretion in stomach and uterine contraction; For prevention of ulcer in patients who take high doses of NSAIDs due to arthritis, abortifacient

Abdominal pain, Uterine cramping, teratogen, miscarriage

ii. Alprostadil

PGE1 analogue, causes vascular smooth muscle relaxation Apnea, hypotension, priapism, lightheadedness, and vasolidation; For Maintenance of patent ductus arrhythmia arteriosus (PDA), Erectile dysfunction

B. Prostaglandin E2 analog

12

Misoprostol's intended use is for NSAID-induced gastritis, may also be used together with Mifepristone or Methotrexate as safe abortifacient given as injection into the cavernosa for erectile dysfunction

i. Dinoprostone, Sulprostone

Low concentrations contract, higher concentrations relax uterine and cervical smooth muscle, soften cervix at term before induction with oxytocin; For cervical ripening, induction of labor, abortifacient

Cramping, Fetal trauma

approved abortifacient in the 2nd trimester, although effective in inducing labor, it produces more SE than other oxytocics

C. Prostaglandin F2a analog i. Latanoprost, Arboprost, Bimatoprost, Travoprost, Unoprostone

PGF2a analogue, increases outflow of aqueous humor thus vomiting, diarrhea, transient bronchoconstriction Latanoprost may cause changes in reduces intraocular pressure; For glaucoma the color of the iris and may lengthen eyelashes

D. Prostaglandin I2 analog i. Epoprostenol, Beraprost, Iloprost, Treprostinil

E. Leukotriene antagonists

PGI2 analogue, activates IP receptor, causes vasolidation and reduces platelet aggregation; For severe pulmonary Hypertension and reducing platelet aggregation in dialysis machines

Hypotension, headache, flusing

used primarily for pulmonary hypertension (esp Treprostinil IV)

i. Lipoxygenase inhibitor: Zileuton see entry on Drugs used for Asthma ii. LT receptor blocker: Montelukast, Zafirlukast F. Corticosteroids

see entry on Drugs used for Asthma see entry on Drugs used for Asthma

G. Non-steroidal anti-inflammatory see entry on Analgesics drugs Drugs used in Asthma A. Beta2-selective agonist (short-acting) i. Albuterol/Salbutamol, Levalbuterol, Terbutaline, Metaproterenol, Pirbuterol, Procaterol, Fenoterol

Activates beta2-receptors in bronchial smooth muscle leading to bronchodilation ; DOC for acute asthma attacks

Tachycardia, Nervousness, tremors, restlessness, Increase toxicity when used for arrhythmias when used excessively, loss of COPD (May precipitate arrythmias) responsiveness (tolerance, tachyphylaxis) and in patients with heart disease; usual DOA: 2-4hrs, all are given inhalational, Salbutamol and terbutaline is also available PO, terbutaline can also be given IV

B. Beta2-selective agonist (long acting)

13

ii. Salmeterol, Formoterol, Cleneterol, Bambuterol

Activates beta2-receptors in bronchial smooth muscle leading to bronchodilation, potentiates corticosteroid action; For Asthma prophylaxis

Tachycardia, Nervousness, tremors, restlessness, Increase asthma mortality when arrhythmia when used excessively, loss of used alone; May precipitate responsiveness (tolerance, tachyphylaxis) arrhythmias; usual DOA: 12hrs

Blocks muscarinic receptors in bronchial smooth muscle and prevent bronchoconstriction mediated by vagal discharge; For acute BA attack and COPD

anti-muscarinic effects (dry mouth, blurred vision More effective and less toxic than etc.) beta agonists for COPD, Tiotropium has longer DOA than Ipratropium, Ipratropium given as aerosol has little systemic effects, has no effect on the chronic inflammation aspect of BA

C. Muscarinic receptor agonist i. Ipratropium, Tiotropium

C. Methylxanthine i. Theophylline, Aminophylline, Pentoxifylline

D. Mast cell Stabilizer i. Cromolyn, Nedocromil, Lodoxamide

Phosphodiesterase inhibitor, Adenosine receptor CNS stimulation (Insomnia, seizure, Anorexia), antagonist, causes bronchodilation and increased strength Cardiac stimulation (Arrhythmias), Tremors, of contraction of diaphragm; For asthma especially in increased BP, diuresis, inc GI motility nocturnal attacks, Intermittent claudication (pentoxifylline), very useful in COPD

Antidote in overdosage is BB. Higher clearance in adolescents and smokers. Narrow therapeutic window; usual DOA: 12hrs

Prevents calcium influx and stabilizes mast cells, preventing Cough, Airway irritation degranulation and release of histamine, leukotrienes and mediators; for Asthma prophylaxis and allergies (oral, nasal and ophthalmic drops)

No bronchodilator action but can prevent bronchoconstriction caused by antigens (both in the early and late BA responses), unusually insoluble chemicals so rarely used

Inhibit synthesis of arachidonic acid by inhibiting Phospholipase A2, Reduces expression of COX and LT, inc responsiveness of Beta receptors in the airway, bind to intracellular receptors and activate Glucocorticoid response elements in the nucleus leading to synthesis of substances that prevent full expression of inflammation and allergy ; DOC for Asthma prophylaxis, First line treatment for moderate to severe BA, COPD, Allergic rhinitis, also used as anti-inflammatory for other conditions such as auto-immune diseases and cancer, also for immune

For status asthmaticus: use IV prednisolone or hydrocortisone ; prednisolone is the active metabolite of prednisone

E. Corticosteroid i. Fluticasone, Beclomethasone, Budesonide, Flunisolide, Mometasone, Triamcinolone, Ciclosenide

F. Leukotriene synthesis inhibitor

Oropharyngeal candidiasis, mild growth retardation observed in children, Minimal systemic steroid steroid toxicity (eg, adrenal suppression), Mild growth retardation

14

i. Zileuton

Inhibitor of 5-lipoxygenase. Reduces synthesis of leukotrienes. Prevents airway inflammation and bronchoconstriction; For asthma prophylaxis

Flulike syndrome, headache, drowsiness, dyspepsia, hepatitis, elevation of liver enzymes (more than LT receptor blockers)

No bronchodilator action, not recommended for acute BA attack

Blocks leukotriene-1 receptor, prevents airway inflammation and bronchoconstriction; For asthma prophylaxis

Gastrointestinal upset, Insomnia, elevation of liver enzymes

No bronchodilator action, not recommended for acute BA attack

Binds IgE antibodies on sensitized mast cells and prevents activation by BA triggers and subsequent release of inflammatory mediators; For prophylaxis of severe, refractory asthma not responsive to all other drugs

Long term toxicity not yet well documented

humanized murine monoclonal antibody, very expensive and only administered IV

G. Leukotriene Antagonist i. Montelukast, Zafirlukast, Pranlukast H. Anti-IgE antibody i. Omalizumab

4. DRUGS THAT ACT ON THE CENTRAL NERVOUS SYSTEM Sedative-Hypnotics A. Short-acting benzodiazepines

i. Midazolam, brotizolam, triazolam, oxazepam, etizolam

bind GABA-A receptor subunits to increase frequency of chloride channel opening which causes membrane hyperpolarization ; For acute anxiety, panic attacks, anesthesia induction and preoperative sedation (esp Midazolam), insomnia (Triazolam)

causes anterograde amnesia, decreased psychomotor skills, unwanted daytime sedation, tolerance, dependence liability and rebound insomnia or anxiety.

additive CNS depression if used with ethanol, antihistamines, antipsychotics, opioids and TCAs, decreased REM sleep, use lower doses in the elderly when used for insomnia

causes anterograde amnesia, decreased psychomotor skills, unwanted daytime sedation, tolerance, dependence liability and unwanted daytime sedation.

additive CNS depression if used with ethanol etc, decreased REM sleep, High dose BZD and Barbs may suppress seizure but at the expenses of marked sedation EXCEPT Clonazepam and Phenobarbital, Lorazepam is preferred over Diazepam in Status Epilepticus due to its long distribution halflife, use lower doses in the elderly when used for insomnia

B. Intermediate-acting benzodiazepines

i. Lorazepam, Alprazolam, Estazolam, Clonazepam, Lormetazepam, Nitrazepam, Temazepam

bind GABA-A receptor subunits to increase frequency of chloride channel opening which causes membrane hyperpolarization; For anxiety disorders even panic disorders (Alprazolam and Clonazepam), insomnia (Estazolam), skeletal muscle relaxation, seizure disorders (Clonazepam), status epilepticus (Lorazepam), tranquilizers, Bipolar disorder (Clonazepam), infantile spasm (Clonazepam)

C. Long-acting Benzodiazepine

15

bind GABA-A receptor subunits to increase frequency of chloride channel opening which causes membrane hyperpolarization; For anxiety disorders, insomnia (Flurazepam), skeletal muscle relaxation (e.g. cerebral palsy - Diazepam), seizure disorders, tranquilizers, for status epilepticus (Diazepam), anesthesia (Diazepam), alcohol withdrawal (Diazepam and Chlordiazepoxide)

causes anterograde amnesia, decreased psychomotor skills (esp Diazepam and Flurazepam), unwanted daytime sedation, tolerance, dependence liability and rebound insomnia or anxiety.

additive CNS depression if used with ethanol etc., decreased REM sleep, Flunitrazepam is used as a date-rape drug, use lower doses in the elderly when used for insomnia

antagonist at benzodiazepine sites on GABA-A receptor ; for benzodiazepine overdose.

agitation, confusion, and precipitates benzodiazepine withdrawal syndrome for those with benzodiazepine dependence.

Seizures and arrhythmias may occur when administered in patients who took both TCAs and benzodiazepines

dependence liability is greater than benzodiazepine, acute intermittent porphyria.

additive CNS depression if used with ethanol etc., CYP450 inducer, Thiopental has highest lipid solubility

F. Short and intermediate-acting barbiturates bind to GABA-A receptor sites (distinct from benzodiazepines) to increase duration of chloride channel opening, block glutamic acid neurotransmission, at high i. Pentobarbital, secobarbital, doses can block Na channels ; For insomnia and amobarbital, butalbital, preoperative sedation (Secobarbital), for status epilepticus dependence liability is greater than butabarbital, talbutal, aprobarbital (Phenobarbital) benzodiazepine, acute intermittent porphyria.

additive CNS depression if used with ethanol etc., CYP450 inducer

i. Diazepam, chlorazepate, chlordiazepoxide, flurazepam, quazepam, flunitrazepam D. Benzodiazepine antagonist

i. Flumazenil E. Ultrashort-acting barbiturates

i. Thiopental, Methohexital, Thiamylal

bind to GABA-A receptor sites (distinct from benzodiazepines) to increase duration of chloride channel opening, block glutamic acid neurotransmission, at high doses can block NA channels ; For anesthesia induction (esp Thiopental)

G. Long-acting barbiturate bind to GABA-A receptor sites (distinct from benzodiazepines) to increase duration of chloride channel opening, block glutamic acid neurotransmission, at high doses can block Na channels ; For insomnia, seizure i. Phenobarbital, mephobarbital, disorders (Phenobarbital), status epilepticus primidone (Phenobarbital)

additive CNS depression if used with ethanol, CYP450 inducer, Phenobarbital may be excreted unchanged in the urine, High dose BZD and Barbs may suppress seizure dependence liability is greater than but at the expenses of marked benzodiazepine, acute intermittent porphyria, sedation EXCEPT Clonazepam and severe respiratory and cardiovascular depression Phenobarbital

H. Imidazopyridine sedative-hypnotics

16

i. Zolpidem, Zaleplon, Eszopiclone I. Atypical Sedative-Hypnotics

i. Partial Serotonin Agonist: Buspirone

ii. Melatonin receptor agonist: Ramelteon

lack anti-convulsant, anti-anxiety and muscle relaxant effects, effects are reversed with Flumazenil, very rapid onset of action, may dec. REM sleep, rebound inc on withdrawal bind selectively to a subgroup of GABA-A receptors, acting from chronic use, increasing use like benzodiazepines to enhance membrane day-after psychomotor depression, few amnestic due to rapid onset with minimal hyperpolarization, only interact with GABA-A receptors effects; tolerance, dependence liability and effects on the sleep pattern and with alpha-1 subunit ; For insomnia and sleep disorder esp. withdrawal symptoms is less than that of cause less daytime cognitive when sleep onset is delayed benzodiazepines impairment as compared to BZD minimal abuse liability, minimal CNS depressant effects, tolerance and withdrawal ; no anticonvulsant or non-specific chest pain, tachycardia, palpitations, muscle relaxant property ; slow partial agonist at 5-HT1A receptors and possibly D2 dizziness, nervousness, tinnitus, GI distress, onset of action (>1week), receptors, precise MOA of anxiolytic effect is unkown ; For paresthesias, dose-dependent pupillary metabolized by CYP3A4, safe for generalized anxiety disorders constriction pregnant patients

activates melatonin receptors (MT1 and MT2 receptors) in the suprachiasmatic nuclei in the CNS --> decreased latency Dizziness, fatigue, decreased testosterone, of sleep onset increased prolactin

minimal rebound insomnia or withdrawal symptoms, minimal abuse liability, metabolized by CYP450 (increased levels in the presence of CYP1A2 or CYP2D6 inhibitors

nystagmus, diplopia, sedation, gingival hyperplasia, hirsutism, anemias, peripheral block voltage-gated Na channel ; DOC for generalized tonic- neuropathy (absent DTRs), osteoporosis, fetal clonic seizures, DOC for partial seizures, status epilepticus, hydantoin syndrome, abnormalities in Vit D arrhythmias, migraine metabolism

CYP450 inducer , metabolism is non-linear (elimination shift from 1st order to zero order at moderate to high dose levels) , Fosphenytion is a water-soluble prodrug of phenytoin ; phenytoin is preferred in prolonged therapy for status epilepticus because it is less sedating.

Antiseizure Drugs

i. Phenytoin, Fosyphenytoin, Mephenytoin, Ethotoin

17

ii. Carbamazepine, Oxcarbazepine

iii. Valproic acid

iv. Phenobarbital v. Ethosuximide, Phensuximide, Methsuximide vi. Diazepam

CYP450 inducer, Oxcarbazepine has less drug interactions, metabolism diplopia, cognitive dysfunction, drowsiness, may be inhibited by other drugs block voltage-gated Na channels and decreases glutamate ataxia, blood dyscrasias, Stevens-Johnson such as Propoxyphene and valproic release ; DOC for trigeminal neuralgia, DOC for generalized syndrome, erythematous rash, teratogen (spina acid ; may be used for acute manic tonic-clonic seizures, DOC for partial seizures, for bipolar bifida and craniofacial anomalies), hyponatremia phase and as prophylaxis in the disorders (Oxcarbazepine) depressive phase CYP450 inhibitor ; also have the same effect on Ca currents like blocks high-frequency firing of neurons which modifies Ethosuximide ; Other MOA include amino acid metabolism ; DOC for bipolar disorder (acute enhancing K channel permeability ; mania), DOC for generalized tonic-clonic seizures and drowsiness, nausea, tremor, alopecia, weight BZDs are commonly required at absence seizure, partial seizures, myoclonic seizures, also gain, hepatotoxicity (esp in infants), neural tube initiation therapy of valproic acid ; used for Bipolar disorders defects DOC for acute manic illness May also act on Na channels and as antagonist at some glutamate receptors ; primary anticonvulsant in infants, children and pregnant see notes above ; For status epilepticus in children cognitive dysfunction, dependence patients inhibit low threshold (T-type) Ca currents esp in thalamic neurons ; DOC for absence seizure

GI distress, lethargy, headache and behavioural changes.

see entry on Sedative-Hypnotics

Long half-life

viii. Lamotrigine, Zonisamide

blocks Ca++ channels, increases GABA release ; For neuropathic pain such as postherpetic neuralgia, partial seizures, migraine dizziness, sedation, ataxia, nystagmus, tremor blocks Na and Ca++ channels and decreases glutamate , Zonisamide only blocks Na channels ; For generalized tonicclonic seizures, DOC for partial seizures, myoclonic dizziness, ataxia, nausea, rash, SJS / TEN seizures, absence seizures, bipolar disorder. (lamotrigine), severe skin reaction (Zonisamide)

eliminated in the kidneys in their unchanged form ; structural analogues of GABA but does not activate GABA receptor directly ; also have the same effect on Ca currents like Ethosuximide primarily undergoes glucuronidation reaction ; Lamotrigine may be used for acute manic phase and as prophylaxis in the depressive phase

ix. Levetiracetam

Bind synaptic protein selectively inhibiting hypersynchronization of epileptiform burst firing ; For generalized tonic-clonic seizures, partial seizures

It is not metabolized by CYP450 enzymes, eliminated in the kidneys in their unchanged form

vii. Gabapentin, Pregabalin

dizziness, sedation, weakness, irritability, hallucinations, psychosis

18

Antiseizure drugs with the most number of MOA, undergo both hepatic and renal metabolism, drowsiness, dizziness, ataxia, psychomotor Topiramate can also block Na slowing, memory impairment, paresthesias, channels and potentitae action of weight loss, acute myopia, glaucoma, myopia, GABA and block glutamate receptor, urolithiasis ; felbamate causes hepatic failure and Felbamate may also block hematotoxic (can cause ITP, aplastic anemia) glutamate receptors

x. Topiramate, Felbamate

multiple actions on synaptic function, probably via actions on phosphorylation (Na, Ca, GABA, AMPA-glutamate, carbonic anhydrase), Felbamate also facilitate the inhibitory actions of GABA but its exact MOA is still unknown ; For generalized tonic-clonic seizures, partial seizures, absence seizures, migraine ; Felbamate is only for severe refractory seizure states

xi. Vigabatrin

Irreversibly inactivates GABA aminotransaminase (GABA-T) which terminates the action of GABA ; For GTC seizure visual field defects

None

xii. Tiagabine

Inhibits GABA transporter (GAT-1) in neurons and glia thus inhibiting its reuptake, leading to prolongation of GABA effects ; For partial seizures asthenia or weakness, dizzines

None

General Anesthetics A. Inhalational General Anesthetics

ii. Desflurane

This group in general increase the threshold for firing of CNS neurons Lowest Potency (highest MAC) and least cardiotoxic; additive CNS Facilitates GABA-mediated inhibition, block brain NMDA depression with many agents and Ach-N receptors; used as anesthesia for minor surgery megaloblastic anemia on prolonged exposure; especially opioids and sedativeand dental procedures Euphoria (laughing gas), bronchodilation hypnotics additive CNS depression with many agents especially opioids and sedative-hypnotics ; all inhaled Facilitates GABA-mediated inhibition, block brain NMDA anesthetcis cause bronchodilation and Ach-N receptors ; For general anesthesia bronchospasm, peripheral vasodilation except Desflurane

iii. Sevoflurane

Facilitates GABA-mediated inhibition, block brain NMDA and Ach-N receptors; For general anesthesia

iv. Isoflurane

Facilitates GABA-mediated inhibition, block brain NMDA and Ach-N receptors ; For general anesthesia

v. Enflurane

Facilitates GABA-mediated inhibition, block brain NMDA and Ach-N receptors ; For general anesthesia

i. Nitrous Oxide

additive CNS depression with many peripheral vasodilation, renal insufficiency (due to agents especially opioids and Flourine release), bronchodilation sedative-hypnotics catecholamine-induced arrhythmias, peripheral vasodilation, bronchodilation spike-and-wave activity in EEG, muscle twitching, breath-holding, myocardial depression, renal insufficiency (due to Flourine release), dec cardiac output, bronchodilation

19

additive CNS depression with many agents especially opioids and sedative-hypnotics additive CNS depression with many agents especially opioids and sedative-hypnotics ; has pungent odor which limits its use

vi. Halothane

Facilitates GABA-mediated inhibition, block brain NMDA and Ach-N receptors ; For general anesthesia

vii. Methoxyflurane

Facilitates GABA-mediated inhibition, block brain NMDA and Ach-N receptors ; For general anesthesia

catecholamine-induced arrhythmias, myocardial additive CNS depression with many depression, post-operative hepatitis, dec cardiac agents especially opioids and output, bronchodilation sedative-hypnotics Highest potency and lowest MAC (very slow onset and recovery); additive CNS depression with many renal insufficiency (due to Flourine release), agents especially opioids and bronchodilation sedative-hypnotics

see notes above

are respiratory and circulatory depressants --> dec cerebral blood flow --> dec ICP

B. Intravenous General Anesthetics i. Barbiturates: Thiopental, Methohexital, Thiamylal

ii. Benzodiazepine: Midazolam, Brotizolam, Triazolam, Oxazepam, Etizolam see notes above iii. Phencyclidine derivative: Ketamine

see notes above

Blocks excitation by glutamate at NMDA receptors; For dissociative anesthesia (analgesia, amnesia and catatonia but with retained consciousness)

rapid entry into the brain (<1min) Midazolam is a usual adjunct with inhalational anesthetics and IV opioids, has a slow onset but longer DOA

CV stimulation, hypertension, increased ICP, Reduces delirium by pretreatment delirium, Dissociative anesthesia, post-op effects: with benzodiazepine, congener of disorientation, hallucination, excitation Phencyclidine / angel dust

pain at injection site, myoclonus, postoperative Minimal effects on CV and nausea and vomiting, adrenocortical suppression respiratory functions, no analgesic (on prolonged administration) properties, short DOA Antidote is Naloxone / Naltrexone ; Neuroleptanesthesia (analgesia + amnesia) happens when Fentanyl, Droperidol and Nitrous oxide are Interacts with mu, sigma, kappa receptors for endogenous given together ; faster recovery with v. Opioid analgesics: Fentanyl, opioid peptides ; For high risk patients who might not respiratory depression, chest wall rigidity (which remifentanil ; these drugs have fast morphine, alfentanil, remifentanil survive general anesthesia may cause impaired ventilation) and constipation onset of action "milk of anesthesia", additive effects with sedative-hypnotic drugs ; as rapid as thiopental and also bradycardia, vasodilation, hypotension, negative with fast recovery ; antiemetic Potentiates GABA-A receptors, blocks Na channels; For inotropism, pain at injection site, anterograde action ; Fospropofol is the waterprolonged sedation esp in ICU patients and also in OPD amnesia, dystonia, priapism, paresthesia soluble prodrug form of propofol vi. Propofol, Fospropofol surgeries (Fospropofol) but with slower onset and recovery iv. Imidazole derivative: Etomidate

Modulates GABA-A receptors containing beta3 subunits; For general anesthesia to patients with limited cardiac or respiratory reserve

Local Anesthetics

20

this group can cause antibody formation in some patients

A. Ester Local Anesthetics i. Procaine

ii. Benzocaine

iii. Cocaine

iv. Tetracaine B. Amide Local Anesthetics

Blockade of Na channels slows which prevents axon potential propagation; For local anesthesia Blockade of Na channels slows which prevents axon potential propagation; For local anesthesia, topical anesthesia

Blockade of Na channels slows which prevents axon potential propagation, with intrinsic sympathomimetic activity; For local anesthesia, topical anesthesia Blockade of Na channels slows which prevents axon potential propagation; For local anesthesia, spinal anesthesia, epidural anesthesia, topical ophthalmic anesthesia

light-headedness, sedation, restlessness, nystagmus, seizures, respiratory, CV depression

Shortest half-life among local anesthetics

light-headedness, sedation, restlessness, nystagmus, seizures, respiratory, CV depression

light-headedness, sedation, restlessness, nystagmus, seizures, respiratory, CV depression, abuse liability, severe hypertension, cerebral hemorrhage, cardiac arrhythmia, MI

Use cautiously in sunburns, Topical only with intrinsic sympathomimetic activity so it does not need an alpha agonist (like epinephrine) to limit its systemic absorption; causes mood elevation due to action on dopamine receptor ; All local anesthetics are vasodilators EXCEPT cocaine ; Topical only

light-headedness, sedation, restlessness, nystagmus, seizures, respiratory, CV depression

also available as Ophthalmic solution

i. Lidocaine

Blockade of Na channels slows which prevents axon potential propagation; For local anesthesia, antiarrhythmia (group 1B activity), used for post-MI and for digitalis light-headedness, sedation, restlessness, toxicity nystagmus, seizures, respiratory, CV depression

ii. Prilocaine

Blockade of Na channels slows which prevents axon potential propagation; For local anesthesia, dental anesthesia

light-headedness, sedation, restlessness, nystagmus, seizures, respiratory, CV depression

iii. Bupivacaine

Blockade of Na channels slows which prevents axon potential propagation; For local anesthesia, epidural anesthesia, intrathecal anesthesia

light-headedness, sedation, restlessness, nystagmus, seizures, respiratory, CV depression, severe CV toxicity, hypotension and arrhythmias

causes methemoglobinemia (antidote: methylene blue) Use with caution in pregnant women and patients with cardiac disease (may cause heartblock, arrhyhtmia and hypotension)

iv. Ropivacaine

Blockade of Na channels slows which prevents axon potential propagation; For local anesthesia, epidural anesthesia

light-headedness, sedation, restlessness, nystagmus, seizures, respiratory, CV depression, cardiotoxicity

Longest half-life among local anesthesia

Skeletal Muscle Relaxant A. Depolarizing Neuromuscular Blocker

21

Frequently administered with Epinephrine to avoid systemic absorption

muscle pain, hyperkalemia, increased intragastric pressure leading to regurgitation (aspiration), increased intraocular pressure, malignant hyperthermia

Metabolized by pseudocholinesterase ; may cause malignant hyperthermia if given together with inhaled anesthetics

B. Non-Depolarizing Neuromuscular Blocker

a common SE for this group is Histamine release

effects are easily reversed by giving AChE inhibitors such as Neostigmine

i. Mivacurium (short-acting: 1020mins DOA)

respiratory paralysis, apnea, and moderate histamine release

ii. Atracurium (intermediateacting)

respiratory paralysis, apnea, and moderate histamine release and bronchospasm

iii. Vecuronium (intermediateacting)

respiratory paralysis and apnea

iv. Rocuronium (intermediateacting)

respiratory paralysis and apnea, hypersensitivity

Undergoes elimination in bile; reverse effects with Neostigmine reverse effects with Neostigmine; Suggamadex is a novel reversal agent for rocuronium; most rapid onset time (60-120 sec)

respiratory paralysis, apnea, hypotension and recurarization

Relatively contraindicated in myocardial ischemia; reverse effects with neostigmine

respiratory paralysis, apnea, tachycardia, hypertension, recurarization

Reverse effects with Neostigmine, may cause heart block

i. Succinylcholine

v. Tubocurarine (long-acting)

vi. Pancuronium (long-acting)

Agonist at Ach-N receptors causing initial twitch then persistent depolarization ; For skeletal muscle relaxation during intubation and general anesthesia

Competitive antagonists at skeletal muscle nicotinic acetylcholine receptors; For skeletal muscle relaxation during intubation and general anesthesia Competitive antagonists at skeletal muscle nicotinic acetylcholine receptors; For skeletal muscle relaxation during intubation and general anesthesia, euthanasia, lethal injection, strychnine poisoning

Anti-Parkinsonism and other drugs for movement disorders A. Dopamine Precursor

22

Metabolized by pseudocholinesterase; reverse effects with Neostigmine Undergoes Hoffman elimination (rapid spontaneous breakdown); reverse effects with Neostigmine ; converted to Laudanosine which can cause seizures

i. Levodopa-carbidopa

Levodopa is a dopamine precursor, carbidopa inhibits peripheral metabolism via dopa decarboxylase; Drug of choice for parkinson’s disease

GI upset (emesis), dyskinesia (choreoathetosis), behavioural changes (anxiety, agitation, confusion, delusion), on-off phenomena, wearing-off phenomena, postural hypotension, tachycardia

Contraindicated in patients with history of psychosis; hypertensive crisis occurs when used with MAO inhibitors, ameliorates signs of parkinsonism and decreases mortality rate ; patient response decreases with time but is improved when given together with COMT inhibitors

Partial agonist at dopamine D2 receptors in brain; For Parkinson’s disease which is levodopa intolerance, hyperprolactinemia

anorexia, nausea, vomiting, dyskinesia, postural hypotension, behavioural changes, erythromelalgia (Bromocriptine), pulmonary infiltrate (Bromocriptine)

Ergot alkaloids

anorexia, nausea, vomiting, dyskinesia, postural hypotension, behavioural changes (more prominent compared to levodopa)

Contraindicated for patients with active peptic ulcer disease, psychotic illnesss or recent MI ; decrease dose in renal dysfunction ; Neuroprotective ; Ropirinole is metabolized by CYP1A2

severe nausea, dyskinesia, hypotension, drowsiness and sweating

Premedicate with Trimethobenzamide to prevent severe nausea

B. Dopamine Agonist

i. Bromocriptine, Pergolide

ii. Pramipexole, Ropinirole

iii. Apomorphine C. MAO type B inhibitor

i. Selegiline, Rasagiline

Partial agonist at dopamine D3 receptors in brain, Roprinole is a D2 agonist; For Parkinson’s disease Partial agonist at dopamine D3 receptors, antagonist at 5HT and alpha adrenoceptors; For off-periods of Parkinson’s disease, alcoholism, opiate addiction, erectile dysfunction, alzheimer’s disease

Selective inhibitors of MAO type B leading to decreased degradation of dopamine, increases response to levodopa/carbidopa; Only as adjunct to levodopa for parkinson’s disease but Rasigiline can be given alone (more insomnia, mood changes, dyskinesias, GI distress potent) and hypotension

serotonin syndrome occurs when used with SSRI and Meperidine ; Selegiline is hepatically metabolized into desmethyl selegiline (which is neuroprotective) and amphetamine

Block L-dopa metabolism by inhibiting catechol-Omethyltransferase in periphery and CNS, prolongs response to levodopa; used in the wearing-off phenomena of parkinson’s disease, as adjuncts to levodopa

Entacapone only acts in the periphery while Tolcapone acts both in the periphery and CNS.

D. COMT inhibitor

i. Entacapone, Tolcapone

dyskinesias, GI distress, postural hypotension, sleep disturbance, orange discoloration of urine, hepatotoxicity (tolcapone only), neuroleptic malignant syndrome, rhabdomyolysis

E. Antiviral

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i. Amantadine

enhances dopaminergic transmission by unknown mechanism, maybe by influencing the synthesis, release or reuptake of dopamine; For Parkinson’s disease and influenza

behavioural changes (restlessness, agitation, insomnia, hallucination, psychosis), livedo reticularis, GI disturbances, urinary retention, postural hypotension, peripheral edema

May improve bradykinesia, rigidity and tremor ; has antimuscarinic action

drowsiness, inattention, confusion, delusions, hallucinations, atropine-like effects

Exacerbate tardive dyskinesias that result from prolonged use of antipsychotic drugs; improve tremor and rigidity with little effect on bradykinesia

F. Anticholinergic

i. Benztropine, Biperiden, Trihexyphenidyl, Orphenadrine

Decrease the excitatory actions of cholinergic neurons on cells in the striatum by blocking muscarinic receptors; as adjunct for parkinson’s disease and extrapyramidal symptoms caused by antipsychotics

Antipsychotics and Lithium A. Typical Antipsyhotics

may also be used for pruritus and as sedatives

has no effect on negative symptoms

ii. Other Phenothiazines: Thioridazine, Fluphenazine, Perphenazine, Prochlorperazine, Trifluoperazine

extrapyramidal dysfunction, tardive dyskinesia, hyperprolactinemia, atropine-like effects, failure Blocks D2 receptors >> 5-HT2 receptors; For schizophrenia of ejaculation, postural hypotension, retinal and other psychotic disorders, antiemesis deposits (thioridazine), cardiotoxicity (prochlorperazine) (arrhythmias - thioridazine)

iii. Butyrophenol: Haloperidol, Droperidol

Blocks D2 receptors >> 5-HT2 receptors; For schizophrenia extrapyramidal dysfunction, tardive dyskinesia, and other psychotic disorders, huntington’s disease and hyperprolactinemia, neuroleptic malignant tourette’s syndrome syndrome

prototype of all typical antipsychotics Thioridazine has the Strongest autonomic effects; only antipsychotic with fatal overdose ; Fluphenazine and Trifluoperazine have very significant parkinson-like effect ; Fluphenazine has less sedation compared to other antipsychotics causes the most extrapyramidal symptoms of all typical antipsychotics ; has the weakest autonomic effects

B. Atypical Antipsychotics

may be used for mania and psychotic symptoms in Alzheimer's dementia and Parkinsons disease

extrapyramidal dysfunction, tardive dyskinesia, hyperprolactinemia, atropine-like effects, failure of ejaculation, postural hypotension, marked Blocks D2 receptors >> 5-HT2 receptors; For schizophrenia sedation, corneal and lens deposits, neuroleptic i. Phenothiazine: Chlorpromazine and other psychotic disorders malignant syndrome, contact dermatitis

i. Clozapine

Extrapyramidal dysfunction (less), hyperprolactinemia (less), postural hypotension, weight gain, hyperglycemia, hyperlipidemia, Blocks 5-HT2 receptors >> D2 receptors; For schizophrenia myocarditis, agranulocytosis, seizures, ileus, (refractory, suicidal) and other psychotic disorders hypersalivation (sialorrhea)

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cure both negative and positive symptoms Only antipsychotic that reduces the risk of suicide ; may be effective for drug-resistant types ; weight gain, agranulocytosis, seizure and hyperglycemia is prominent

iii. Quetiapine

Extrapyramidal dysfunction (less), Blocks 5-HT2 receptors >> D2 receptors; For schizophrenia, hyperprolactinemia (less), postural hypotension, weight gain and hyperglycemia is bipolar disorders, anorexia nervosa and depression weight gain, hyperglycemia, hyperlipidemia prominent, safe in pregnancy Extrapyramidal dysfunction (less), hyperprolactinemia (less), postural hypotension, weight gain, somnolence, fatigue, sleep paralysis, Blocks 5-HT2 receptors >> D2 receptors; For schizophrenia, hypnagogic hallucinations, cataracts, priapism, QT bipolar disorders (manic) prolongation (TDP) can cause TDP, safe in pregnancy

iv. Risperidone

Blocks 5-HT2 receptors >> D2 receptors; For schizophrenia, Extrapyramidal dysfunction (less), bipolar disorders, depression, intractable hiccups, tourette hyperprolactinemia (marked), insomnia, syndrome photosensitivity

Only antipsychotic approved for schizophrenia in the youth

v. Ziprasidone

Blocks 5-HT2 receptors >> D2 receptors; For schizophrenia, Extrapyramidal dysfunction (less), postural bipolar disorders (acute mania) hypotension, QT prolongation (TDP)

Increased mortality in elderly patients with dementia-related psychosis ; can cause TDP

vi. Aripiprazole

Blocks 5-HT2 receptors >> D2 receptors; For schizophrenia, Extrapyramidal dysfunction (less), GI upset, bipolar disorders, depression, autism, cocaine dependence tremor, hypersensitivity (rare)

vii. Lithium (mood stabilizer)

Uncertain MOA but the proposed MOA is by inhibiting the enzyme involved in the recycling of neuronal membrane phosphoinositides which causes depletion of phosphatidylinositol bisphosphate, thus consequently decreasing IP3 and DAG --> decrease in neurotransmission ; For bipolar disorder, recurrent depression, schizoaffective disorder

ii. Olanzapine

Tremor, sedation, ataxia, aphasia, thyroid enlargement, hypothyroidism, reversible nephrogenic diabetes insipidus, edema, acneiform skin eruption, leukocytosis, teratogen (ebstein’s anomaly), bradycardia, some drugs (NSAIDs, ACEi, diuretis etc) can increase Lithium toxicity while caffeine and theophylline can decrease its toxicity

Antidepressants A. Tricyclic Antidepressants

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Least sedating atypical antipsychotics Contraindicated in sick sinus syndrome; treat overdose with hemodialysis ; high volume of distribution ; clinical benefit is seen only after weeks of use ; antipsychotic agents or BZDs are commonly required at initiation therapy of Li and valproic acid ; Contraindicated in lactation ; Natriuresis stimulates reflex increase in the reabsorption of Li and Na in the PCT

i. Imipramine, Clomipramine, Desipramine, Amitryptyline, Nortryptiline

Block NE and 5-HT transporters leading to potentiation of NT action at postsynaptic receptors; For MDD (most effective), bipolar disorder, acute panic attacks, ADHD, chronic pain states, as sleeping aid, OCD (Clomipramine) ; this group is very useful for patients with psychomotor retardation, sleep disturbance, poor appetite and weight loss

Additive depression of the CNS with other central depressants ; Imipramine is metabolized to desipramine while amitriptyline is metabolized to nortriptyline ; longterm use may lead to downregulation of Beta receptors leading to a decrease in BP and depression excessive sedation, fatigue, confusion, of cardiac conduction ; has sympathomimetic effects, atropine-like effects, significant muscarinic receptor orthostatic hypotension, cardiomyopathies, blocking effect esp Amitriptyline ; arrhythmias, tremors, paresthesias, weight gain ; lower seizure threshold ; may 3Cs of overdose: Coma, Cardiotoxicity, interfere with antihypertensive Convulsions action of Clonidine

B. SSRI

i. Fluoxetine, Paroxetine, Citalopram, Escitalopram, Sertraline, Fluvoxamine

Inhibits neuronal reuptake of serotonin by inhibiting Serotonin Transporter (SERT); DOC for OCD, for MDD, anxiety, panic attacks, phobias, PTSD, GAD, bulimia, premenstrual dysphoric disorder, alcohol dependence

nausea, vomiting, headache, anxiety, agitation, drowsiness, insomnia, erectile dysfunction, EPS, QT prolongation (citalopram), withdrawal syndrome

Serotonin syndrome when used with MAOIs ; minimal inhibitory effect on cholinergic or adrenergic receptors ; lower seizure threshold ; this group can decrease appetite leading to weight loss ; Increased risk for suicide in children and adolescents ; Fluoxetine, Fluvoxamine and Paroxetine are CYP450 inhibitors

Inhibits neuronal reuptake of serotonin and norepinephrine by binding to transporters for both 5HT and NE; For MDD, fibromyalgia, neuropathic pain, menopausal symptoms

dizziness, insomnia, sedation, GI distress, hypertension (venlafaxine), hepatotoxicity (duloxetine), withdrawal syndrome even in just one missed dose, CNS stimulation (Venlafaxine), liver dysfunction (Duloxetine)

venlafaxine has less affinity for NE transporter than desvenlafaxine and duloxetine ; differ from TCA in lacking blockade of H1, M and alpha receptors ; Increased risk for suicide in children and adolescents

C. SNRI

i. Venlafaxine, Duloxetine, Desvenlafaxine D. Serotonin antagonist

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i. Trazodone, Nefazodone

May cause arrhythmias in px with pre-existing cardiac disease ; short t1/2 so given BID to TID, has significant muscarinic receptor blocking effect esp Nefazodone ; sedation, GI disturbance, orthostatic CYP450 inhibitors ; Trazodone also hypotension, priapism, hyperprolactinemia, liver has significant alpha1 and H1 dysfunction (nefazodone) blocking effect

Blocks 5-HT2A receptors, weak inhibitor of NE and 5HT transporters; For MDD, as sleeping aid (trazodone)

Increased risk for suicide in children and adolescents

E. Tetracyclics

i. Amoxapine

ii. Mirtazapine

iii. Bupropion

Strong norepinephrine reuptake inhibitor and weak serotonin reuptake inhibitor, blocks dopamine D2 receptors; For MDD Increases amine release from nerve endings by antagonism of presynaptic a2 adrenoceptors, also blocks serotonin 5HT2A receptors; For MDD, appetite stimulation, as sleeping aid Inhibits neuronal reuptake of dopamine and norepinephrine, increase dopamine and norepinephrine activity; For MDD and smoking cessation, alcohol dependence

autonomic effects, akathisia, parkinsonism (due to dopamine receptor blockade), seizures, cardiotoxicity

Lowers seizure threshold, has significant muscarinic receptor blocking effect

weight gain, marked sedation, dizziness, blurred vision and nightmares

has significant muscarinic receptor and alpha2 blocking effect Lowers seizure threshold, for smoking cessation ; no effect on 5HT or NE receptors or amine transporters ; CYP450 inhibitor

weight loss, agitation, anxiety, dizziness, dry mouth, aggravation of psychosis, seizures, priapism

F. MAO Inhibitors

i. Phenelzine, tranylcypromine, selegiline

Inhibits MAO type A and type B, increases CNS levels of NE and serotonin, Phenelzine and Tranylcypromine are nonselective MAO inhibitors while Selegiline is a MAO-B selective inhibitor; For MDD unresponsive to other agents ; dizziness, insomnia, orthostatic hypotension, useful in patients with significant anxiety, phobic features blurred vision, arrhythmia, diarrhea, and hypochondriasis hyperthermia, CNS stimulation, seizure

Hypertensive crisis when taken with tyramine-rich food, serotonin syndrome when taken with SSRI ; this group is structurally related to amphetamine ; CYP450 inhibitors ; longterm use may lead to downregulation of Beta receptors (leading to decrase in BP) ; lower seizure threshold ; selegiline may be given as skin patch

Opioid Analgesics and Antagonists A. Full Agonist

TRIAD: miosis, coma, respiratory depression

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Additive CNS depression with other depressants

i. Morphine

Strong agonist at u receptors; For severe pain, pain associated with acute MI, for pulmonary edema

miosis, restlessness, respiratory depression, increased ICP, postural hypotension, urinary retention, pruritus, addiction liability

ii. Fentanyl

Strong agonist at u receptors; For severe pain, adjunct in anesthesia, chronic pain and breakthrough cancer pain

restlessness, respiratory depression, increased ICP, postural hypotension, urinary retention, pruritus, addiction liability

iii. Meperidine

Strong agonist at u and k receptors, inhibits pain neurotransmission, muscarinic blocking actions; For moderate to severe pain, labor analgesia, spasmodic pain (biliary, renal), preoperative sedation

restlessness, respiratory depression, increased ICP, postural hypotension, urinary retention, pruritus, addiction liability, seizures

iv. Methadone

Strong agonist at u receptors, inhibits pain neurotransmission, binds NMDA receptors and antagonizes miosis, restlessness, respiratory depression, the effects of glutamate; For moderate to severe pain, increased ICP, postural hypotension, urinary opioid dependence, opioid withdrawal retention, pruritus, addiction liability

B. Partial Agonist / Moderate Agonist Strong agonist at u receptors, inhibits pain neurotransmission, binds NMDA receptors and antagonises miosis, restlessness, respiratory depression, the effects of glutamate; For moderate to severe pain, increased ICP, postural hypotension, urinary i. Hydrocodone, oxycodone opioid dependence, opioid withdrawal retention, pruritus, addiction liability

ii. Dextrometorphan, codeine

Decreases sensitivity of cough receptors, depressing the medullary cough center through sigma receptors stimulation; For cough suppression

Exerts hemodynamic effects on the pulmonary circulation ; significant first-pass effect ; metabolized in the body to morphine-6-glucuronide which has equal analgesic activity as morphine May be given transdermally or via lollipop; ohmefentanyl is the most potent opioid Only opioid that does not cause miosis and biliary contraction ; opioid of choice for pain relief in pancreatitis ; metabolized to normeperidine which can cause seizure therefore contraindicated in patients with seizure disorder ; if given with MAOi --> Hyperpyrexic coma, if given with SSRI --> Serotonin syndrome Used in methadone maintenance therapy (MMT) for opioid dependence; currently being investigated as a novel treatment for leukemia

there is genetic variation in the metabolism of codeine and its derivatives

hallucination, confusion, excitation, increased or decreased pupil size, nystagmus, seizures, coma, codeine is metabolized by CYP2D6 respiratory depression, addiction liability to morphine

C. Weak Agonist i. Propoxyphene, levopropoxyphene, dextropropoxyphene

Weak agonist at u receptors, inhibits pain miosis, respiratory depression, increased ICP, neurotransmission; For mild to moderate pain, restless leg postural hypotension, urinary retention, pruritus, Withdrawn because of fatal syndrome addiction liability, fatal arrythmias cardiotoxicity

D. Mixed Agonist-Antagonist

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i. Nalbuphine, buprenorphine, butorphanol, pentazocine

Strong agonist at k receptors, weak antagonist activity at u receptors; For moderate to severe pain, opioid sedation, dizziness, sweating, nausea, anxiety, dependence, alcohol dependence, balance anesthesia, for hallucinations, nightmares, respiratory depression opioid withdrawal states (buprenorphine) (less), tolerance, dependence liability

Buprenorphine reduces craving in alcohol dependence, buprenorphine and nalbuphine is resistant to Naloxone

Competitively blocks u, sigma and k receptors, rapidly reverses effects of opioid agonists; For opioid overdose, opioid and alcohol dependence (naltrexone)

Precipitates abstinence syndrome in Px with opioid dependence ; Naloxone and Nalmefene is IV (DOA: 12-24 hrs) while Naltrexone is PO (DOA: 48h)

E. Opioid Antagonist

i. Naloxone, naltrexone, nalmefene

pruritus, nausea, vomiting

F. Dual-acting

i. Tramadol

Weak agonist at u receptors, inhibits neuronal reuptake of Lower seizure threshold ; CI in Px serotonin and norepinephrine; For moderate pain, chronic taking SSRI and those with history of pain syndrome, neuropathic pain seizures, nausea, dizziness, pruritus, constipation seizure

5. DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Agents Used in Anemias and Hematopoietic Growth Factors A. Hematopoietic growth factor i. Ferrous sulfate, Ferrous gluconate, Ferrous Fumarate, Iron Required for the biosynthesis of heme and heme Black stools, shock, lethargy, dyspnea, abdominal dextran, Sodium Ferric Gluconate containing proteins, including hemoglobin and myoglobin; pain, necrotizing gastroenteritis, death, organ complex, Iron sucrose For Iron deficiency anmia, iron supplementation failure, hemochromatosis, metabolic acidosis None B. Heavy metal chelator i. Deferoxamine, Deferasirox

Chelates excess iron; For acute and chronic iron poisoning

Hypotension, Neurotoxicity, ARDS, Increased susceptibility to infections

None

No significant toxicity

Hydroxocobalamin has a longer t1/2 than cyanocobalamin ; has a storage of up to 5yrs in the liver

C. Hematopoietic growth factor

i. Cyanocobalamin, Hydroxocobalamin

Cofactor required for essential enzymatic reactions that form tetrahydrofolate, convert homocysteine to methionine and metabolize methylmalonyl-CoA; For vitamin B12 deficiency, megaloblastic anemia

D. Hematopoietic growth factor Precursor of an essential donor of methyl groups used for synthesis of amino acids, purines and deoxynucleotide; For i. Folic acid, Folacin Megaloblastic anemia, prevention of neutral tube defects (Pteroylglutamic acid), Folinic acid (spina bifida), prevention of coronary artery disease No significant toxicity

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only modest amounts are stored in the body

E. Hematopoietic growth factor

i. Epoetin Alfa, Darbepoetin alfa, Agonist of erythropoietin receptors expressed by red cell Methoxy Polyethylene Glycolprogenitors; For Anemia, associated with chronic renal Epoetin Beta failure, cancer, HIV infection and prematurity

Hypertension, Thrombosis, Pure red cell aplasia

Performance-enhancing drug in athletes ; darbepoietin is once a week administration, while Methoxy Polyethylene GlycolEpoetin Beta is 1-2x per month

F. Myeloid growth factor

Binds receptors on myeloid progenitors and stimulates cell maturation and proliferation ; Accelerates neutrophil recovery and reduces incidence of infection; For i. (G-CSF) Filgrastim, Sargamostim neutropenia associated with chemotherapy, (GM-CSF), Pegfilgrastim myelodysplasia, and aplastic anemia Edema, Fever, Arthralgia

Pegfilgrastim has longer t1/2

G. Megakaryocyte growth factor i. Oprelvekin(IL-11), Thrombopoietin

Recombinant form of an endogenous cytokine; activates IL -11 receptors ; For secondary prevention of fatigue, headache, anemia, fluid accumulation in thrombocytopenia in patients undergoing chemotheraphy the lungs, dizziness, transient atrialarrythmias given SC OD

Agents Used in Dyslipidemia

A. HMG-CoA Reductase Inhibitors: Simvastatin, Atorvastatin, Rosuvastatin, Fluvastatin, Pravastatin, Lovastatin, Pitavastatin, Cerivastatin,

Inhibits rate-limiting enzyme in cholesterol biosynthesis (HMG-CoA reductase), Increased hepatic cholesterol uptake, Increased high affinity LDL receptors which leads to decreased LDL levels ; DOC for hypercholesterolemia (high LDL), decreases risk of acute coronary syndromes, ischemic Hepatoxicity, Myopathy, Rhabdomyolysis, stroke Gastrointestinal distress, Teratogen

30

has direct anti-atherosclerotic effect, and can prevent bone loss ; Increased risk of myopathy and rhabdomyolysis when used with fibrates ; Given before bedtime because cholesterol synthesis predominantly occurs at night ; simvastatin and lovastatin are prodrugs, all the rest are in their active form already ; Rosuvastatin, Atorvastatin and Simvastatin have greater maximal effect than other statins ; if given together with resins give at least 1hr before or 4hrs after resin administration (resins decrease the absorption of statins) ; has CYP450 dependent metabolism

B. Bile Acid Binding Resin: Colesevelam, Colestipol, Cholestyramine

C. NPC1L1 transporter inhibitor: Ezetimibe

D. Sterol absorption blocker: Sitosterol

non-absorbable polymers that bind bile acids and similar steroids in the intestines preventing their reabsorption, increases cholesterol utilization for replacement, modestly lowers LDL levels by increasing hepatic LDL receptors ; For hypercholesterolemia (high LDL), pruritus in cholestasis, digitalis toxicity Selective inhibitor of the NPC1L1 transporter decreasing intestinal absorption of cholesterol and other phytosterols, decreases cholesterol hepatic pool, increases hepatic LDL receptors ; For Hypercholesterolemia (High LDL), phytosterolemia Cholesterol analog, takes the place of dietary and billiary cholesterol, decreasing intestinal absorption of cholesterol and other phytosterols ; For Hypercholesterolemia (high LDL), phytosterolemia

Decreases VLDL synthesis and LDL cholesterol concentrations, decreases hormone-sensitive lipase activity leading to decreased LDL levels, Increases HDL cholesterol by decreasing its catabolism ; DOC for increasing HDL levels, for Hypercholesterolemia (low HDL, high LDL/VLDL), E. Nicotinic Acid derivatives: Niacin hypertriglyceridemia

F. Fibrates: Gemfibrozil, Fenofibrate, Bezafibrate

Constipation, Bloating, Gritty taste, Gallstone formation, steatorrhea, malabsortion of fat soluble substances (vitamin k, folate)

Synergistic LDL-lowering effect with Hepatoxicity (increased with statin use), Myositis statins ; is a prodrug

Gastrointestinal upset, bloating, impotence (rare), coronary events

Flushing, nausea, vomiting, Pruritus, Acanthosis nigricans, Rashes, Gastrointestinal irritation, Hepatoxicity (mild), Hyperuricemia, Impaired glucose tolerance, Arrhythmias, Ambylopia

Activates PPAR-α and increases expression of lipoprotein lipase and apolipoproteins (apoA-I, apoA-II) leading to enhanced clearance of TG-rich lipoproteins, Lowers Nausea, Rashes, Leukopenia, nausea, vomiting, triglycerides, Increases HDL ; DOC for hypertriglyceridemia increased risk of cholesterol gallstones

Drugs for Coagulation A. Antiplatelet

Increases TGs and VLDL in patients with high TGs and combined hyperlipidemia ; Treat constipation with fiber supplements/psyllium ; Avoid in patients with diverticulitis

For arterial thrombosis only

31

NONE decreases fibrinogen and increases t-PA ; NSAIDs pre-treatment reduces flushing ; Avoid in patients with peptic ulcer disease ; Potentiates effects of antihypertensives (vasodilators, ganglion blockers) Increased risk of myopathy and rhabdomyolysis when used with statins ; Avoided in patients with hepatic or renal dysfunction ; may increase LDL in patients with familial combined hyperlipoproteinemia ; has little or no effect on LDL ; higher risk of gallstone formation if given together with resins

i. Aspirin

Nonselective, irreversible COX 1&2 inhibitor. Reduces platelet production of thromboxane A2, temporarily inhibit Prostacyclin synthesis ; For prevention or arterial thrombosis (MI, TIA, CVD), Inflammatory disorders (rheumatic fever, juvenile rheumatoid arthritis, kawasaki disease)

Reversbily inhibits the binding of fibrin and other ligands to ii. GPIIb-IIIa inhibitor: Abciximab, the platelet GPIIb-IIIa receptor ; For antithrombosis during Eptifibatide,Tirofiban PCI, Acute coronary syndromes (unstable angina, NSTEMI) Inhibits phosphodiesterase III and increases cAMP in platelets and blood vessels, Inhibits platelet aggregation and causes vasolidation ; For prevention of thromboembolic complications of cardiac valve replacement (as adjunct to warfarin), secondary prevention iii. PDE III inhibitor: Dipyridamole, of ischemic stroke (with aspirin), Intermittent claudication Cilostazol (Cilostazol only) Irreversibly inhibits binding of ADP to platelet receptors,thus reducing platelet aggregation ; For prevention and treatment of arterial thrombosis (stroke, iv. ADP inhibitor: TIA, unstable angina), Acute coronary syndromes, Clopidogrel,Ticlopidine, Prasugel Prevention of re-stenosis after PCI B. Anticoagulant

Gastrointestinal toxicity, nephrotoxicity, tinnitus, hyperventilation, hypersensitivity, HAGMA, Increased bleeding time, Nephrotoxicity (AKI and Interstitial Nephritis)

Uncoupler of oxidative phosphorylation, associated with Reye syndrome in children ; Do not use as NSAID for gout

Bleeding, Thrombocytopenia

Adjunct to thrombolysis

Headache, palpitations

additional MOA: inhibit uptake of adenosine by endothelial cells and RBC, thus increasing adenosine levels leading to inhibition of platelet aggregation ; Cilostazol is contraindicated in heart failure

Bleeding, nausea, hematologic (neutropenia, leukopenia), thrombotic thrombocytopenic purpura (Ticlopidine), dyspepsia

GI & Hematologic SE are more common with ticlopidine. Additive effects with aspirin

i. Heparin (indirect thrombin inhibitor)

For both venous and arterial thrombosis Activates antithrombin III which Inactivates thrombin or factor IIa, factor IXa & factor Xa by forming stable complexes with them ; For deep venous thrombosis, myocardial dysfunction, Pulmonary embolism, adjuvant to percutaneous coronary intervention (PCI) and thrombolytics, Atrial fibrillation, Pulmonary embolism, given with thrombolytics for revascularization procedures, given with GPIIb-IIIa inhibitors for angioplasty and stent Bleeding, transient Heparin-induced placement thrombocytopenia, Osteoporosis with chronic use

ii. LMWH: Enoxaparin, Dalteparin, Tinzaparin, Fondaparinux

Binds and potentiates effect of antithrombin III on factor Xa (more selective for Xa); For Deep venous thrombosis, Pulmonary embolism, unstable angina, myocardial infarction, adjuvant to percutaneous coronary intervention (PCI) and thrombolytics, Atrial fibrillation Bleeding, less risk of thrombocytopenia

32

DOC for anticoagulation during pregnancy ; administered IV or SC ; Monitor with aPTT, Antidote: Protamine Sulfate Does not require aPTT monitoring, Protamine sulfate is only partially effective in reversing effects ; advantage over regular heparin is higher bioavailability and t1/2 ; Fondaparinux is given SC OD

iii. Direct Thrombin Inhibitors: Lepirudin, Desirudin, Bivalirudin, Argatroban, Dabigatran

Binds to thrombin's ative site and inhibits its enzymatic action; For anticoagulation in patients with heparin induced thrombocytopenia (HIT), percutaneous coronary angioplasty (Bivalirudin with aspirin)

iv. Direct Oral Factor Xa inhibitor: bind to free and bound factor Xa ; For prevention of Rivaroxaban, Apixaban Venous thrombosis, in stroke patients with Afib Inhibits vitamin K epoxide reductase (responsible for ycarboxylation of the vitamin K- dependent clotting (factors II, VII, IX, X, Protein C & Protein S) ; For chronic anticoagulation (DVT, atrial fibrillation, valve replacement) v. Warfarin, Dicumarol EXCEPT in pregnancy

Bleeding, Anaphylactic reactions, Effectprolonging antibodies

Monitor with aPTT. No reversal agents exist ; Dabigatran is PO while all the rest are parenteral ; Bivalirudin also inhibits platelet activation

bleeding

No reversal agent

Monitor effects with PT-INR. Bleeding, Teratogen (bone defects, hemorrhage), Antidote is vitamin K or FFP. Narrow warfarin-induced skin necrosis (transient therapeutic window ; 99% proteinhypercoagulability) bound

C. Antidote

i. Protamine Sulfate

ii. Endogenous Vitamin: Vitamin K1, K2, K3 (Phytonadione, Menaquinone, Menadione)

D. Thrombolytic: Alteplase, Anistreplase, Reteplase, Streptokinase, Tenecteplase, Urokinase

E. Antiplasmin drug: Tranexamic acid

Chemical antagonist of heparin. Reverses excessive anticlotting activity of unfractionated heparin; For heparin hypotension, flushing, bradycardia, dyspnea, overdosage hypersensitivity Increases supply of reduced vitamin K, which is required for synthesis of functional vitamin K-dependent clotting and anticlotting factors ; For Vitamin K deficiency, Antidote to Severe infusion reaction when administered at a warfarin, prevention of hemorrhagic diatheses in newborns fast rate (dyspnea, chest and back pain)

Tissue plasminogen activator analog. Converts plasminogen to plasmin, which degrades the fibrin and fibrinogen, causing thrombolysis ; For acute myocardial infarction, pulmonary embolism, Ischemic stroke Competitively inhibits plasminogen activation thus inhibiting fibrinolysis ; For prevention and treatment of acute bleeding episodes in patients with high risk of bleeding (hemophilia, intracranial aneurysms, menstrual, obstetrics, thrombolytics, postperative)

Partially reverses effect of LMWHs

Bleeding, Reperfusion, Cerebral hemorrhage, Arrhythmias ; Loss of effectiveness (on 2nd use) and allergic reactions (streptokinase)

Vit K1 may be given PO or IV Tx should be done within 6 hrs, better if within 3hrs ; Antidote is AMINOCAPROIC ACID ; Streptokinase forms a complex with endogenous plasminogen, thus catalyzing the conversion of plasminogen to plasmin ; tPA is selective for fibrin-bound plasminogen

Thrombosis, hypotension, Myopathy, Diarrhea

Contraindicated in disseminated intravascualr coagulation (DIC) and genitourinary bleeding

33

F. ADH agonist: Desmopressin

Vasopressin V2 receptor agonist, Increases factor VIII activity of patients with mild hemophilia A or VWD; For hemophillia A, von Willebrand's disease, central diabetes insipidus

headaches, nausea, flushing, seizures, hyponatremia

may cause immunologic reactions and infections

Non-steroidal Anti-Inflammatory Drugs, Disease-Modifying Anti-rheumatic Drugs, Non-opioid Analgesics & Drugs Used in Gout A.Non-selective NSAID

i. Aspirin, Sodium Salicylate

ii. Ibuprofen, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Ketoprofen, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Piroxicam, Sulinidac, Tolemtin, Mefenamic acid, Ketorolac

iii. Indomethacin

See entry on Drugs for caogulation Disorder

See entry on Drugs for caogulation Disorder

Nonselective reversible COX-1 and COX-2 inhibitor. Inhibits prostaglandin and thromboxane synthesis ; For analgesia, fever and as anti inflammatory Nonselective reversible COX-1 and COX-2 inhibitor. Inhibits prostaglandin synthesis and inhibit crystal phagocytosis by macrophages ; For anti inflammatory (gout arthritis, ankylosing spondylitis), for closing PDA

low doses undergo first order kinetics while high doses undergo zero order reaction ; Long term use reduces the riskIndomethacin of colon cancer Ibuprofen and can be

Gastrointestinal bleeding (less than aspirin), Nephrotoxicity (AKI and Interstitial Nephritis), Hypersensitivity reaction

used to close PDA ; Ibuprofen and naproxen have moderate effectiveness ; Ibuprofen is relatively safe but with short halflife of 2hrs ; Naproxen and Piroxicam have longer half-lives ; Ketorolac has significant analgesic effect but not anti-inflammatory effect ; use Ketorolac only for 72hrs due to GI and renal damage ; NSAIDs may interfere with ASA's antithrombotic action

Gastrointestinal toxicity, pancreatitis, Nephrotoxicity, Serious hematologic reactions, BM suppression

Indomethacin has greater antiinflammatory effect compared to other NSAIDs

B. COX-2 Selective NSAID: Celecoxib, Etoricoxib, Parecoxib

Gastrointestinal bleeding, Nephrotoxicity (same Selective COX-2 inhibitor. Inhibits prostaglandin synthesis ; risk as nonselective NSAIDs), Myocardial For Analgesia, Anti inflammatory, Antipyretic infarction and stroke

Rofecoxib and Valdecoxib withdrawn due to incereased incidence of thrombosis

C. Non-opioid Analgesic (COX3 inhibitor) Paracetamol (Acetaminophen)

Selectively inhibits COX-3 in the CNS, Weak COX-1 and COX-2 inhibitor in the periphery, Inhibits prostaglandin synthesis ; For Analgesia and antipyretic

Preferred antipyretic in children (does not cause reye's syndrome) ; t1/2 is only 2-3h

Hepatoxicity (antidote: NAC), Renal papillary necrosis and Interstitial nephritis, Methemoglobinemia, Hemolytic anemia

D. Disease Modifying Anti-Rheumatic Drug

34

Inhibits AICAR transformylase and thymidylate synthase, with secondary effects on polymorphonuclear chemotaxis ; Nausea, Mucosal ulcers, hepatoxicity, For rheumatoid arthritis, SLE, JRA, psoriatic arthritis, hypersensitivty, Pseudolymphomatous reaction, i. Methotrexate Ankylosing spondylitis, Polymyositis teratogen, hematotoxicity Bacterial infections (URTIs), reactivation of latent tuberculosis, lymphoma, Demyelination, Reactivation of Hepatitis B, Auto antibody ii. TNF-alpha inhibitor: Infliximab, Binds or inhibits to TNF-a ; For Crohn's disease, rheumatoid formation (ANA, anti dsDNA), infusion reactions, Adalimumab, Etanercept arthritis, other rheumatic disease hepatoxicity, hematotoxicity, cardiotoxicity

iii. Azathioprine

iv. Chloroquine, Hydroxychloroquine

v. Cyclophosphamide

vi. Cyclosporine

vii. Mycophenolate Mofetil

Forms 6-thioguanine, suppressing inosinic acid synthesis, Bcell and T-cell function, Immunoglobulin production and interleukin-2 secretion ; For rheumatoid arthritis, psoriatic arthritis, reactive arthritis, polymyositis, SLE Suppression of T-lymphocyte leading to decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis, trapping of free radicals ; For rheumatiod arthritis, SLE, Sjogren's syndrome, Malaria Forms phospharamide mustard, which cross links DNA to prevent cell replication, Supresses T-cell and B-cell function ; For Rheumatoid arthritis, SLE vasculitis, Wegener's granulomatosis, severe rheumatic diseases Inhibits interleukin-1 and iterleukin-2 receptor production and secondarily inhibits macrophage-T-cell interaction and T-cell responsiveness ; For rheumatoid arthritis, SLE, Tissue transplantation active product inhibits inosine monophosphate dehydrogenase and inhibits T-cell lymphocyte proliferation ; For SLE nephritis, vasculitis, Wegener's granulomatosis, rheumatoid arthritis

DMARD of choice for Rheumatoid arthritis, Rescue agent: Leucovorin (Folinic acid)

Synergistic effects with methotrexate

Bone marrow supression, increased risk of infections, increased incidence of lymphoma, Fever, rash, hepatotoxicity, allergic reactions

Cannot give allopurinol with azathioprine (allopurinol reduces xanthine oxidase catabolism of purine analogs, increasing 6thioguanine nucleotides, leading to severe leukopenia)

Ocular toxicity, Dyspepsia, Nausea, vomiting, abdominal pain, rashes, nightmares, myopathy, neuropathy, ocular toxicity

safe for pregnant women

Hemorrhagic cystitis

Hemorrhagic cystitis, Rescue agent is Mesna

Nephrotoxicity, hypertension, hyperkalemia, hepatoxicity, Gingival hyperplasia, hirsutism

NONE

Gastrointestinal disturbances, headache, hypertension, reversible myelosupression

NONE

35

viii. Sulfasalazine E. Antigout drugs

active metabolite inhibits the release of inflammatory bowel cytokines; For rheumatoid arthritis, inflammatory bowel disease, JRA, ankylosing spondylitis

Nausea, vomiting headache,rash, hemolytic anemia, methemoglobinemia, neutropenia, leukopenia, thrombocytopenia, pulmonary toxicity, autoantibody formation (anti dsDNA), Reversible infertility in men

Diarrhea, nausea, vomiting, abdominal pain, hepatic necrosis, acute renal failure, disseminated Inhibits microtubule assembly and LTB4 production leading intravascular coagulation, seizures, hair loss, bone i. Microtubule assembly inhibtor: to decreased macrophage migration and phagocytosis ; For marrow depression, peripheral neuritis, Colchicine gout myopathy

ii. Uricosuric agent: Probenecid, Sulfinpyrazone

iii. Xanthine oxidase inhibitor: Allopurinol, Febuxostat

are weak acids that compete with uric acid for reabsorption in the PCT leading to increased uric acid excretion ; For gout

Active metabolite (alloxanthine) irreversibly inhibits xanthine oxidase and lowers production of uric acid; 1st line treatment of chronic gout, tumor lysis syndrome

anti-IBD drugs

a general mitotic poison, may also be used for Familial Mediterranean Fever ; diarrhea is the adverse effect which signals toxicity from colchicine

Gastrointestinal irritation, rashes, nephrotic syndrome, aplastic anemia ; sulfa allergy

May precipitate acute gout during early phase of drug action (prevent by coadministering with colchicine or indomethacin) ; may be given together with antimicrobial agents (particularly Penicillins) to prolong therapeutic effect by inhibiting renal tubular secretion of antibiotics

Gastrointestinal upset, Rash, Peripheral neuritis, Vasculitis, bone marrow dysfunction, Aplastic anemia, liver dysfunction (Febuxostat)

Inhibits metabolism of mercaptopurine and azathioprine. Witheld for 1-2 wk after an acute episode of gouty arthritis (coadministered with colcichine or indomethacin to avoid an acute attack) ; Feboxustat is a newer nonpurine inhbitor of Xanthine Oxidase ; Febuxostat is more effective than Allopurinol

6. ENDOCRINE DRUGS Hypothalamic and Pituitary Hormones

36

i. Somatropin

Recombinant Growth hormone, Increases release of IGF-1 in the liver and carilage, stimulates skeletal muscle growth, amino acid transport, protein synthesis and cell proliferation ; For GH deficiency in children and genetic disease associated with short stature (Turner syndrome, Prader-Willi syndrome), failure to thrive due to chronic renal failure or SGA, AIDS wasting, improve GI function in patients who underwent intestinal resection that led to malabsorption syndrome

iii. Octreotide, Lanreotide

Recombinant IGF-1 ; For children unresponsive to GH therapy Somatostatin analog, suppresses the release of growth hormones, glucagon, insulin, gastrin, IGF-1, serotonin and gastrointestinal peptides ; For Acromegaly, pituitary adenoma, carcinoid, gastrinoma, glucagonoma, variceal bleeding

iv. Pegvisomant

GH receptor antagonist ; For acromegaly

ii. Mecasermin

v. Follitropin alfa, Follitropin beta, Urofollitropin

Gonadotropin analog (FSH analog); activates FSH receptors and mimics effects of endogenous FSH ; For Controlled ovarian hyperstimulation, infertility due to hypogonadism in men

Gonadotropin analog (LH analog); activates LH receptors vi. Menotropins, Human and mimics effects of endogenous LH ; For Controlled chorionic gonadotropin (HCG), ovarian hyperstimulation (ovulation induction), Choriogondaotropin alfa, Lutropin hypogonadotripic hypogonadism

Peripheral edema, Myalgia, Arthralgia, Intracranial hypertension, pseudotumor cerebri, slipped capital femoral epiphysis, progression of scoliosis, hyperglycemia

used as Performance enhancing drug since it increases muscle mass ; given SC

Hypoglycemia, increased LFT, intracranial HTN

remedy to hypoglycemia: give patient some snacks prior to dose

GI upset, gallstone, cardiac condution abnormality Diarrhea, nausea, flu-like syndrome, elevated LFTs, hypesensitivity reaction Headache, depression, edema, ovarian

regular release: given BID-QID SC, if slow release: every 4wks IM ; are long-acting synthetic analogs of somatostatin onset of action is expected within 2wks of usealfa and beta are Follitropin

hyperstimulation syndrome (ovarian enlargement, ascites, hypovolemia, shock), multiple pregnancies in women, gynecomastia in men

recombinant FSH forms while Urofollitropin is a purified preparation from urine of postmenopausal women

menotropins are mixtures of FSH and LH from postmenopausal Headache, depression, edema, ovarian women ; Choriogondaotropin alfa is hyperstimulation syndrome, multiple pregnancies a recombinant hCG while Lutropin is in women, gynecomastia in men a recombinant LH ; hCG given IM

37

GnRH analog, increased LH and FSH secretion with intermittent administration , reduced LH and FSH secretion with prolonged continuous administration (due to downregulation of GnRH receptors in the pituitary cells that normally release LH and FSH ; For Controlled ovarian Hot flushes, sweats, headaches, osteoporosis, hyperstimulation, endometriosis, myoma uteri, precocious gynecomastia, reduced libido, decreased puberty, prostate CA hematocrit

there is exacerbation of symptoms in males with prostate CA and children with precocious puberty during the first few weeks of therapy (remedy: co-administer Flutamide, an androgen receptor antagonist) ; Gonadorelin is a synthetic human GnRH ; Leuprolide has a long agonist activity

GnRH antagonist, blocks GnRH receptors, reduces endogenous production of LH and FSH ; For Controlled ovarian hyperstimulation (prevents premature LH surge), advanced prostate CA

Nausea, headache, hypersensitivity, hot flushes, gynecomastia, decreased libido, decreased hematocrit, osteoporosis

Does NOT cause tumor flare-up whe used for treatment of advanced prostate cancer, also less likely to cause ovarian hyperstimulation syndrome ; Degarelix is used for prostate CA while Ganirelix prevent LH surge in controlled ovulation

ix. Bromocriptine, Carbegoline

Dopamine agonist, partial agonist at dopamine D2 receptors in brain, inhibits prolactin release ; For Hyperprolactinemia, Pituitary adenoma, acromegaly, Parkinson's disease

Nausea, headache, lightheadedness, orthostatic hypotension, fatigue, behavioral changes, erythromelalgia, Raynaud's phenomenon, pulmonary infiltrates

Slightly inhibits GH release if given in high doses ; CI in patients with history of psychotic illness

x. Oxytocin

Activates oxytocin receptors, stimulates uterine contraction and labor, stimulates mammary glands, Fetal distress, placental abruption, uterine lactation and milk let-down ; For Labor induction, labor rupture, fluid retention, hyponatremia, heart augmentation, control of uterine hemorrhage post-delivery failure, seizures, hypotension

ATOSIBAN - an oxytocin antagonist used in preterm labor

xi. Desmopressin, Vasopressin

ADH agonist, Vasopressin V2 receptor agonist which causes insertion of water channels in the collecting duct leading to more water reabsoprtion, also regulates the release of factor VIII and VWF ; For Central DI, Hemophilia A, von Willebrand's disease, Variceal bleeding, colon diverticula, Headaches, flushing, nausea, hyponatremia, primary nocturnal seizures seizures

also contracts vascular smooth muscles via V1 receptor leading to vasoconstriction, used as treatment for esophageal varices or colon diverticula

vii. Leuprolide, Gonadorelin, Goserelin, Histrelin, Nafarelin, Triptorelin

viii. Ganirelix, Cetrorelix, Degarelix

38

xii. Conivaptan, Tolvaptan, Lixivaptan

ADH antagonist, Antagonist at V1a and V2 receptors ; For SIADH, Hyponatremia, offset fluid retention in acute heart failure and SIADH which causes hyponatremia (dilutional) Infusion site reactions, hyperkalemia

Central pontine myelinolysis may occur with rapid correction of hyponatremia, tolvaptan is more selective for V2 receptors

Thryoid & Antithyroid Drugs

i. Levothyroxine (T4), Liothyronine (T3)

ii. Propylthiouracil (PTU)

iii. Methimazole, Carbimazole

Thryoid hormone, activation of nuclear receptors results in gene expression with RNA formation and protein synthesis Dry skin, sweatng, tachycardia, nervousness, ; For Hypothyroidism, myxedema coma tremor, weight loss, weakness, heat intolerance Maculopapular pruritic rash, gastrointestinal distress, fulminant hepatitis, agranulocytosis, urticaria, vasculitis, lupus-like syndrome, Inhibits thyroid peroxidase reactions, blocks iodine lymphadenopathy, hypoprothrombinemia, organification, inhibits peripheral conversion of T4 into T3 ; Exfoliative dermatitis, polyserositis, arthralgia, For Hyperthyroidism, thyroid storm hypothyroidism Maculopapular pruritic rash, gastrointestinal distress, fulminant hepatitis, dose-dependent, agranulocytosis, urticaria, vasculitis, lupus-like syndrome, lymphadenopathy, Inhibits thyroid peroxidase reactions, blocks iodine hypoprothrombinemia, Exfoliative dermatitis, organification ; For Hyperthyroidism, thyroid storm polyserositis, arthralgia, hypothyroidism

Inhibit iodine organification and hormone release leading to reduced size and vascularity of thyroid gland ; For Hyperthyroidism, thyroid storm, preparation for surgical iv. Lugol Solution (Iodine in thyroidectomy to reduce the size and vascularity of the Potssium Iodide), Potassium Iodide thyroid gland, radiation prophylaxis

Iodism, acneiform rash, swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders, anaphylactoid reactions

39

T4 dose must be lowered in patients with cardiovascular disease or longstanding hypothyroidism (increased cardiosensitivity) ; Liothyronine has a faster onset but shorter half-life Drug of choice for pregnant hyperthyroid patients (does not eneter placenta and breastmilk); slow onset of action (3-4 weeks for full effect) Methimazole and Carbimazole are teratogens (causes Aplasia Cutis Congenita) ; given as once daily dosing

onset is more rapid (2-7 days) but effect is transient (thyroid gland escapes iodide block after several weeks of treatment) ; Should not be used alone (escape in 2-8 weeks); prevents radiation induced thryoid damage; prenatal exposure causes fetal goiter

v. Propranolol, Esmolol, Metoprolol, Atenolol

vi. Radioactive Iodine

Beta blocker control HR and other cardiac abnormalities of severe thyrotoxicosis, slows pacemaker activity; inhibits peripheral conversion of T4 into T3 ; For Hyperthyroidism, Bronchospasm, cardiac depression, AV block, thyroid storm, post MI prophylaxis, hypertension hypotension Iodide, emits beta rays causing destruction of thyroid parenchyma ; For hyperthyroidism, permanent cure of thyrotoxicosis without surgery and no effect on other tissues

Permanent hypothyroidism, sore throat

Adrenocorticosteroids & Adrenocortical Antagonists

Esmolol may be used to treat thyrotoxicosis-related arrhythmias; causes clinical improvement WITHOUT altering thyroid hormone levels Preferred treatment for most patients due to ease of administration, effectiveness, low expense and absence of pain; contraindicated in pregnant women or nursing mothers

iii. High Potency: Desoximetasone, Clobetasol

Glucocorticoid, activates glucocorticoid receptors, leading to altered gene transcription, Suppresses inflammation, Replaces cortisol when deficient ; For Acute adrenal insufficiency associated with life-threatening shock, chronic adrenal insufficiency (Addison's disease), congenital Adrenal suppression, growth inhibition, DM, adrenal hyperplasia, insect bites, contact dermatitis, status muscle wasting, osteoporosis, salt retention, asthmaticus, thyroid storm glucose intolerance, behavioral changes

Effects: stimulate gluconeogenesis, increased fat deposition, muscle protein and bone catabolism, lymphoid connective tissue fat and skin wasting inhibit cell-mediated immunologic functions, lymphotoxic, increased neutrophils, decreased lymphocytes eosinophils basophils and monocytes, inhibit leukocyte migration, inhibit PLA2, delay rejection in transplant patients, increased GI acid secretion (ulcer) ; Biochemical effects: induced synthesis of an inhibitor of PLA2, decreased mRNA for COX2, decrease in IL-2 and IL-3 and decrease in Platelet Activating Factor (PAF)

iv. Synthetic GCs: Prednisone, Prednisolone, Methylprednisolone, Meprednisone, Dexamethasone, Betamethasone, Triamcinolone, Beclomethasone, Budesonide

Glucocorticoid; For supressession of inflammation and immune response, hematopoeitic cancers, transplant rejection, collagen and rheumatic disease, lung maturation in preterm labor (betamethasone and dexamethasone), Adrenal suppression, growth inhibition, muscle bronchial asthma, chemotherapy-induced vomiting, wasting, osteoporosis, salt retention, glucose hypercalcemia, mountain sickness intolerance, behavioral changes (psychosis)

prednisolone is the active metabolite of prednisone ; this group has a long t1/2, reduced saltretaining effect and better penetration of lipid barriers

i. Low Potency: Desonide ii. Med Potency: Fluticasone, Mometasone

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v. Mineralocorticoid: Fludrocortisone, Deoxycorticosterone Corticosteroid Antagonists

vi. Aminoglutethimide

vii. Ketoconazole viii. Metyrapone

ix. Mifepristone (RU486)

x. Spironolactone, Eplerenone

Additive hypokalemia with loop diurectics and thiazides ; Deoxycorticosterone is the strong agonist of mineralocorticoid receptors and precursor of aldosterone ; moderate activation of glucorticoid receptors, Increases Na Fludrocortisone also has significant reabsorption, K and H excretion ; For Chronic adrenal glucocorticoid activity ; Aldosterone insufficiency (Addison's disease), Congenital adrenal Salt and fluid retention, Hypokalemia, Congestive is implicated in myocardial and hyperplasia, adrenal replacement therapy postheart failure, muscle wastng, osteoporosis, vascular fibrosis and baroreceptor adrenalectomy glucose intolerance, behavioral changes dysfunction

Glucorticoid synthesis inhibitor, inhibits desmolase activity, blocking conversion of cholesterol to pregnenolone ; For Breast CA, Cushing syndrome Skin rash, hepatotoxicity, hypothyroidism Glucorticoid synthesis inhibitor; azole antifungal; inhibits cholesterol side chain cleavage, cytochrome P450 enzymes and other enzymes necessary for synthesis of all steroids ; For Adrenal CA, Hirsutism, Breast CA, steroid-responsive metastatic Prostate CA, Cushing's syndrome, Fungal Hepatotoxicity, many drug interactions, infections, hirsutism androgenic effect Glucorticoid synthesis inhibitor, selective inhibitor of steroid-11 hydroxylation, interfering with cortisol and corticosterone synthesis ; As diagnostic test for adrenal function Dizziness, GI disturbances

Also inhibits synthesis of all hormonally active steroids

Potent inhibitor of CYP450 enzymes

DOC for pregnant patients with Cushing's syndrome

competitive inhibitor at the GC receptor as well as progesterone receptor ; For Cushing's syndrome

abdominal pain and cramping, uterine cramping, also used as an approved nausea, headache, vomiting, diarrhea, dizziness, abortifacient for medical abortion vaginal bleeding (usually together with misoprostol)

Aldoesterone antagonist ; For hypokalemia due to other diuretics, for post-MI, hyperaldoteronism- see entry -

Hyperkalemia, gynecomastia (spironolactone) see entry -

Gonadal Hormones and Inhbitors A. Estrogen compounds

41

also with weak antagonist effect at the androgen receptor

i. Ethinyl Estradiol, Mestranol, Estradiol cypionate, Premarin

Activates etrogen receptors, leads to changes in rates of trasncription of estrogen-regulated genes ; For Primary hypogonadism, Postmenopausal hormonal replacement therapy, Osteoporosis and prevention of bone loss, Contraception, Intractable dysmenorrhea

ii. Diethylstilbestrol

B. Progestins

Increases risk of endometrial cancer and breast cancer ; Ethinyl Estradiol has low bioavailability, PO/TD/IM/Intravaginal ; Estradiol cypionate is IM with longer t1/2 ; Premarin is a mixture of conjugated estrogen used in HRT ; Ethinyl estradiol undergoes enterohepatic recirculation ; Effects of Estrogen: growth of genital structures and secondary sexual characteristics, breakthrough bleeding, nausea, breast modifies serum protein levels and tenderness, migraine, thromboembolism (DVTs), decrease bone resorption, enhances gallbladder disease, hypertriglyceridemia, coagulability of blood, increases TG hypertension, premature closure of the epiphysis and HDL levels while decreasing LDL in young females, increased risk of breast and levels, if given as continuous endometrial cancer (remedy: add progesterone infusion will inhibt FSH and LH to the preparation) release

breakthrough bleeding, nausea, breast tenderness, migraine, thromboembolism (DVTs), Synthetic estrogen (nonsteroid); activates estrogen gallbladder disease, hypertriglyceridemia, receptors; leads to changes in rates of transcription of hypertension, premature closure of the epiphysis estrogen-regulated genes ; For Atrophic vaginitis, hormone in young females, increased risk of breast and replacement therapy, prevention of adverse pregnancy endometrial cancer (remedy: add progesterone outcomes, metastatic prostate CA to the preparation)

42

associated with Infertility, ectopic pregnancy, clear cell vaginal adenocarcinoma in daughters of women treated with DES

i. Norgestrel, Medroxyprogesterone, Norethindrone, Norgestimate, Desogestrel, Megestrol

activates progesterone receptors, changes rate of transcription of progesterone-regulated genes ; For Hormone replacement therapy (given together with Estrogen, to prevent estrogen-induced endometrial cancer), contraception, assisted reproduction (for maintenance of pregnancy), anovulation induction (given in high doses to suppress FSH and LH)

Hypertension, decreased HDL, weight gain, reversible decrease in bone mineral density, delayed resumption of ovulation after use

Prevents estrogen induced endometrial cancer when used in combination with estrogens; Megesterol is used as an appetite stimulant ; given PO or as vaginal cream ; Medroxyprogesterone has a better oral bioavilability ; LNorgestrel and Norethindrone has more androgenic effect ; Norgestrel undergoes enterohepatic recirculation ; Effects of progesterone: induces secretory changes in the endometrium, stabilize the endometrium, affect carbohydrate metabolism and stimulate deposition of fat, high doses suppress FSH and LH secretion

C. Combined Hormonal Contraceptives i. Estradiol + Norethindrone

maybe rings/IUD LifetimePO/IM/TD/vaginal risk of breast cancer is NOT changed; Norethindrone is a testosterone derivative while ii. Ethinyl Estradiol + Desogestrel Drospirenone is a spironolactone iii. Ethinyl Estradiol + Combined oral contraceptive, activates estrogen and derivative that is antiandrogenic ; Drospirenone progesterone receptors, inhibits ovulation, effects on breakthrough bleeding, nausea, breast Norgestimate and Desogestrel are cervical mucus gland, uterine tubes and endometrium lead tenderness, migraine, thromboembolism (DVTs), newer progestins ; combined OCPs to decreased fertility, inhibit ovulation when given before breast cancer (earlier onset), headache, skin may be used for androgen-induced iv. Ethinyl Estradiol + the LH surge ; For Contraception, hypogonadism, acne, pigmentation, depression, weight gain acne and hirsutism ; Mestranol (Estrogen) Noregistmate hirsutism, dysmenorrhea, endometriosis hirsutism for older OCPs may also be used in OCPs Progestin-only contraceptive, activates progresterone receptors, Prevents conception by altering cervical mucus and creating a hostile endometrium ; For Contraception, Breakthrough bleeding, hair loss, dysmenorrhea, v. Medroxyprogesterone Acetate hormone replacement therapy delayednausea, return of fertility,breast osteoporosis IM depot preparation Severe vomiting, tenderness, Postcoital contraceptive, activates estrogen and/or progesterone receptors, thickens cervical mucus, inhibits vi. Levonorgestrel ovulation ; For Emergency contraception D. Selective Estrogen Receptor Modulators (SERMs)

irregular bleeding, headache, dizziness (fewer SE compared to estrogen alone and combi Must be taken within 72 hours of contraceptives) unprotected sexual intercourse

43

i. Tamoxifen, Torimefene

ii. Raloxifene

iii. Clomiphene

iv. Anastrozole, Letrozole, Exemestane

v. Danazol

vi. Mifepristone (RU486) vii. Leuprolide and Ganirelix E. Androgens

Estrogen antagonist actions in breast tissue and CNS, Estrogen agonist effects in uterus, liver and bone ; For Hormone responsive breast CA, prophylaxis of breast CA esp. in those with high risk Estrogen antagonist actions in breast tissue, uterus, and CNS, Estrogen agonist effects in liver and bone. Increases bone mineral density ; For Osteoporosis esp on post menopausal women, breast CA prevention

Partial agonist in pituitary, reduces negative feedback by estradiol, increases FSH and LH output ; For Induction of ovulation in women who want to become pregnant

Reduces estrogen synthesis by inhibiting aromatase ; For breast CA, precocious puberty Ovarian inhibitor, weak cytochrome P450 inhibitor and partial agonist of progestin and androgen receptors ; For Endometriosis, Fibrocystic disease, Hemophilia, Angioneurotic edema

Hot flushes, thromboembolism, endometrial hyperplasia, endometrial cancer

prevent osteoporosis in postmenopausal women ; Torimefene is structurally related to Tamoxifen

Hot flushes, thromboembolism

No estrogenic effect on endometrial tissue unlike tamoxifen

may cause multiple pregnancies ; FULVESTRANT: pure estrogen receptor anatgonist in all tissues Hot flushes, afterimages, headache, constipation, used in breast CA resistant to reversible hair loss, ovarian enlargement tamoxifen Effective against brest CA that have become tamoxifen-resistant ; Hot flushes, musculoskeletal disorders, Exemestane is an IRREVERSIBLE osteoporosis, joint pains inhibitor

Acne, hirsutism, weight gain, menstrual disturbances, hepatic dysfunction

Vaginal bleeding, abdominal pain, GI upset Glucocorticoid receptor antagonist, progesterone receptor (vomiting, diarrhea), uterine cramping, nausea, antagonist ; For Medical abortion, Cushing's syndrome vomiting, headache, dizziness, diarrhea see entry

see entry

44

May also act on Glucocorticoid receptors Combined with misoprostol results in abortion of 95% of early pregnancies ; as abortifacient in early pregnancy (may be used up to 49days after menses) ; complication: failure to induce complete abortion see entry may be given IV or as TD

i. Testosterone, Fluoxymesterone, Methyltestosterone

ii. Oxandrolone, Stanozolol, Nandrolone F. Anti-androgens

i. Flutamide, Bicalutamide, Nilutamide

ii. Cyproterone

iii. Finasteride, Dutasteride

Activates androgen receptors, promotes development of male characteristics, increases body muscle bulk and RBC production ; For Male hypogonadism, delayed puberty, wasting syndromes (for weight gain), certain types of anemias Activates androgen receptors, promotes development of male characteristics, increases body muscle bulk and RBC production; increased ratio of anabolic-to-androgenic activity in animals For benign and malignant prostate disease, precocious puberty, hair loss and hirsutism

Virilization and menstrual irregularities in females, paradoxical feminization in males, cholestatic jaundice, elevated LFTs

Effects of androgen: secondary sexual characteristics, fertility and libido, male pattern baldness, increases muscle mass, increased RBC production, decreased urea nitrogen excretion, maintains normal bone density ; used illegally by atheletes as performance enhancer

Virilization in females, paradoxical feminization in males; cholestatic jaundice, elevated liver this group is called "anabolic enzymes, hepatocellular CA steroids"

Competitive antagonist at androgen receptor ; For Prostate Gynecomastia, hot flushes, impotence, CA, surgical castration hepatotoxicity

GnRH analogs must be coadministered with flutamide to prevent acute flareups of prostate CA ; Bicalutamide and Nilutamide have less heaptotoxicity

Antagonist at androgen receptor. Marked progestational effect that suppresses the feedback enhancement of LH and FSH ; for Hirsutism, component of combined oral contraceptives, decreased sexual drive in men

Hepatotoxicity, Adrenal suppression, depression, gynecomastia, galactorrhea, thromboembolism Orphan drug status Dutasteride is newer with longer Androgen synthesis inhibitor, inhibits 5a reducase enzyme t1/2 ; this group is less likely to that converts testosterone to dihydrotestosterone ; For cause impotence, infertility and BPH, Male pattern baldness. Hirsutism Impotence, gynecomastia, depression decreased libido

iv. GnRH agonist and antagonists see entry v. Spironolactone for treatment of hirsutism in women vi. Ketoconazole inhibit gonadal and adrenal steroid synthesis

see entry

see entry

see entry

see entry

P ancreatic Hormones & Antidiabetic Drugs A. Insulins

45

i. Rapid Acting Insulin: Lispro, Aspart, Glulisine ii. Short Acting Insulin: Regular iii. Intermediate Acting: NPH, Lente iv. Long Acting Insulin: Detemir, Glargine, Ultralente, Lantus

Activates insulin receptors leading to a reducting of circulating glucose: promotes glucose transport and oxidation; glycogen, lipid, protein synthesis and regulation Hypoglycemia (antidote: sugar or candy, IV of gene expression ; For Diabetes mellitus, diabetic glucose, IM glucagon), insulin allergy, immune emergencies like DKA, HHS (rapid-acting), Hyperkalemia insulin resistance, lipodystrophy at injection site

Effects of insulin: increased glycogen and protein synthesis, decreased protein catabolism, increased TG storage ; rapid acting insulins are injected a few mins prior to meals and they are the preferred insulin for continuous SC infusion devices ; short-acting insulins are injected more than an hour before a meal ; intermediate acting insulins are often combined with regular and rapid acting insulins ; long acting insulins are called "peakless" insulins

B. Sulfonylureas

i. Glipizide, Glibenclamide, Glimepiride, Gliclazide, Glyburide

ii. Tolazamide, Tolbutamide, Chlorpropamide

2nd generation sulfonylurea, acts as an insulin secretagogue, increases insulin secretion from pancreatic beta cells by closing ATP sensitive K+ channels leading to depolarization of the B cell; For Type 2 Diabetes Mellitus 1st generation sulfonylurea, acts as an insulin secretagogue; increases insulin secretion from pancreatic beta cells by losing ATP sensitive K+ channels ; for Type 2 Diabetes Mellitus

Less hypoglycemia, weight gain, photosensitivity, Not effective in patients with cholestatic jaundice (glibenclamide) functional B cells tolbutamide and chlorpropamide Hypoglycemia, weight gain, disulfiram reaction, are highly protein bound drugs, hyperemic flush, dilutional hyponatremia, which may also cause allergic hematologic toxicity reactions and rash

C. Meglitinides

i. Repaglinide

ii. Nateglinide

Insulin Secretagogue, similar to sulfonylureas with some overlap in binding sites, reduces circulating glucose, increases glycogen, fat and protein formation and gene regulation ; For Type 2 Diabetes Mellitus Insulin Secretagogue, similar to sulfonylureas with some overlap in binding sites, reduces circulating glucose, increases glycogen, fat and protein formation and gene regulation ; For Type 2 Diabetes Mellitus

Least hypoglycemia, headache, URTI

Least Hypoglycemia, rapid onset and short DOA

Least hypoglycemia, headache, URTI

Has least incidence of hypoglycemia, may be used in CKD patients ; rapid onset and short DOA

D. Biguanides

46

i. Metformin

DOC for obese diabetics ; may also cause slowing of glucose absorption from GIT, decreased plasma glucagon ; causes a decrease in endogenous insulin production by increasing insulin sensitivity of Reduced hepatic and renal gluconeogenesis with decreased tissues "Insulin Sparing Effect" endogenous glucose production, activates AMP-stimulated GI disturbance, weight loss, lactic acidosis (esp in therefore does not have weight gain protein kinase leading to inhibition of gluconeogenesis ; For renally and hepatically impaired patients), Vit B12 as a SE ; do NOT cause Type 2 DM, Diabetes prevention, PCOS malabsorption hypoglycemia

E. Alpha Glucosidase Inhibitors

i. Acarbose, Miglitol F. Thiazolidinediones

i. Pioglitazone ii. Rosiglitazone G. Novel Antidiabetic Agents

i. Exenatide

ii. Sitagliptin, Linagliptin

Inhibits intestinal alpha-glucosidases , reduces conversion of starch and disacchardies to monosaccharidea, reduces post prandial hyperglycemia ; For Type 2 DM, Diabetes prevention

GI disturbance, hypoglycemia, increased liver enzymes, flatulence, diarrhea, abdominal pain

Regulates gene expression by binding to PPAR-gamma and PPAR-alpha which increases tissue sensitivity, increases glucose uptake in muscle and adipose tissue, inhibits hepatic gluconeogenesis, effects on lipid metabolism and distribution of body fat, control of fasting and postprandial Fluid retention, weight gain, congestive heart glucose, decreased risk of DM in high-risk patients ; For failure, fractures esp in women, cardiovascular Type 2 DM, Diabetes prevention events, hepatotoxicity (Troglitazone), macular Regulates gene expression by binding to PPAR-gamma edema, dyslipidemia, increased risk of MI ONLY ; for Type 2 DM, Diabetes prevention (Rosiglitazone) Analog of GLP-1, Binds to GLP-1 receptors which leads to reducetion of post-meal glucose excursions, increases glucose-mediated insulin release, lowers glucagon levels, slows gastric emptying time, produces satiety ; For Type 2 DM Dipeptidyl Peptidase-4 Inhibitors, blocks degradation of GLP-1, raises circulating GLP-1 levels, reduces post-meal glucose excursions, increases glucose mediated insulin release, lowers glucagon levels, slows gastric emptying time, decreases appetite ; For Type 2 DM

relatively minor glucose lowering effects ; impaired absoprtion of sucrose ; taken immediately before a meal

binds to PPAR-gamma and PPARalpha ; PPAR regulates transcription of genes encoding proteins involved in carbohydrate and lipid metabolism ; may increase risk for developing Bladder Cancer binds to PPAR-gamma ONLY

Hypoglycemia, acute pancreatitis, GI upset, nausea, vomiting

usually combined with SU or metformin ; long-acting injectables

Headache, nasopharyngitis, URTI

often combined with metformin

47

iii. Pramlintide

Analog of amylin, Binds to amylin receptors, reduce postmeal glucose excursions, lowers glucagon levels, slows gastric emptying, decreases appetite ; For Type 2 DM

Hypoglycemia, GI disturbances

used with insulin to control postprandial glucose

iv. Colesevelam hydrochloride

Bile acid binder, lowers glucose through unknown mechanisms ; For Type 2 DM

constipation, dyspepsia, myalgia, asthenia

None

Agents That Affect Bone Mineral Homeostasis A. Vitamin D Metabolites and Analogs INACTIVE Vitamin D; Regulates gene tanscription via the vitamin D receptor; stimulates intestinal calcium absorption, bone resorption, renal calcium and phosphate reabsorption, decreases PTH, promote innate immunity ; For Vitamin D deficiency states (intestinal osteodystrophy, CKD, chronic liver disease, hypoparathyroidism, nephrotic Hypercalcemia, hyperphosphatemia, i. Cholecalciferol, Ergocalciferol syndrome) osteoporosis, psoriasis hypercalciuria

ii. Calcitriol, Doxercalciferol, Paricalcitol, Calcipotriene

ACTIVE Vitamin D; Regulates gene tanscription via the vitamin D receptor; stimulates intestinal calcium absorption, bone resorption, rena calcium and phosphate reabsorption, decreases PTH, promote innate immunity ; For Secondary hyperparathyroidism in CKD, hypocalcemia in hypoparathyroidism, psoriasis

Hypercalcemia, hyperphosphatemia, hypercalciuria ; Doxercalciferol, Paricalcitol and Calcipotriene cause less hypercalcemia and hypercalciuria

B. Bisphosphonates

48

given topically for psoriasis ; given with calcium supplements for osteoporosis The active form Calcitriol is preferred in patients with CKD, chronic liver disease and hypoparathyroidism ; Doxercalciferol is a prodrug that is converted in the liver to 1,25dihydroxyvitaminD ; Paricalcitol, Calcipotriene are analogs of calcitriol and are used topically for psoriasis and are being investigated for malignancies and inflammatory disorders

i. Alendronate, Risedronate, Ibandronate, Pamidronate, Zoledronate, Etidronate, Tiludronate, Zoledronic acid

Pamidronate, Zoledronic acid and Etidronate are used IV for hypercalcemia in Paget's disease and cancer ; all other preparations and Etidronate can be given PO but with low bioavailability (<10%) ; Treatment regimen: oral OD (alendronate, risedronate, Suppress the activity of osteoclasts in part via inhibition of ibandronate), weekly PO farnesyl pyrophosphate synthesis, inhibit resorption and Adynamic bone, Esophagitis, Osteonecrosis of the (alendronate, risedronate), monthly formation of bone by acting on the basic hydroxyapatite Jaw, renal impairment, GI irritation (remedy: take PO (ibandronate), quarterly crystal structure ; For Paget's disease of the bone, lots of water and keep patient in an upright injection (ibandronate), annual IV Hypercalcemia esp in malignancies, Osteoporosis position for 30mins after intake of drug) (zoledronate)

C. Hormones

i. Teriparatide

Recombinant PTH, Acts via cognate G protein coupled receptors, stimulates bone formation when given in low intermittent doses

ii. Calcitonin

Acts via cognate G protein coupled receptors; suppresses bone resorption ; For Paget's disease of the bone, hypercalcemia, osteoporosis, tumor marker for thyroid CA Rhinitis, Nausea, vomiting, facial flushing

hypercalcemia, arthralgia, rhinitis, nausea, weakness, dizziness, pharyngitis, dyspepsia, rash

D. Selective Estrogen Receptor Modulators (SERMs) Interacts selectively with estrogen receptors, inhibits PTHstimulated bone resorption without stimulating breast or endometrial hyperplasia, delay bone loss in posti. Raloxifene menopausal women see entry

used IV for osteoporosis given as injection or as nasal spray ; used for osteoporosis but is less effective than bisphosphonates and teriparatide

see entry

E. Rank Ligand (RANKL) Inhibitor

i. Denosumab F. Calcium Receptor Antagonist

i. Cinacalcet

Monoclonal antibody, binds to RANKL and prevents it from stimulating osteoclast differentiation and function, blocks bone resorption ; For postmenopausal osteoporosis increased risk of infection

as potent as bisphosphonates ; given SC every 6months which avoid the GI SE

Activates the calcium sensing receptors in the parathyroid gland, inhibits PTH secretion ; For secondary hyperparathyroidism in CKD, hypercalcemia in patients hypocalcemia, adynamic bone disease (profound considered a Calcimimetic with parathyroid CA decreae in bone cell activity) (decreases PTH)

7. CHEMOTHERAPEUTIC DRUGS

49

Beta-Lactam & Other Cell Wall-Active & Membrane-Active Antibiotics A. Penicillin

i. Natural Penicillins: Penicillin G, Binds to penicillin-binding proteins, inhibits Penicillin V (narrow spectrum transpeptidation in bacterial cell walls ; DOC for syphillis, penicillin) for streptococcal, meningococcal, G+ bacilli, spirochete infection

hypersensitivity, GI disturbances

ii. Anti-Staphylococcal Penicillins: Methicillin, nafcillin, oxacillin, Binds to penicillin-binding proteins, inhibits cloxacillin (very narrow spectrum) transpeptidation in bacterial cell walls; For staphylococcal infections

hypersensitivity, GI disturbances, interstitial nephritis (methicillin), neutropenia (nafcillin)

iii. Extended Spectrum Penicillin: Ampicillin, Amoxicillin

Binds to penicillin-binding proteins, inhibits transpeptidation in bacterial cell walls ; For enterococci, Listeria, E. coli, Proteus, H. influenza, Moraxella

hypersensitivity, GI disturbances, pseudomembranous colitis (ampicillin), rash (ampicillin)

iv. Antipseudomonal Penicillin: Binds to penicillin-binding proteins, inhibits Piperacillin, ticarcillin, carbenicillin transpeptidation in bacterial cell walls ; For Pseudomonas, Enterobacter, Klebsiella hypersensitivity, GI disturbances B. Cephalosporins

i.First Generation: Cefazolin, Binds to penicillin-binding proteins, inhibits cefadroxil, cephalothin, cephapirin, transpeptidation in bacterial cell walls ; For surgical cephradine, cephalexin prophylaxis, bone infections, infections due to staph and strep, E. coli, Klebsiella, G+ cocci

Bactericidal ; excreted unchanged in the urine ; capable of entering the blood brain barrier Inactivated by beta-lactamase (penicillinase) ; given IM but Pen V can be given PO ; increased activity against enterococci when given together with aminoglycosides Resistant to inactivation by betalactamase (penicillinase) ; all penicillins are excreted unchanged in the urine EXCEPT for Nafcillin which is excreted in the bile Inactivated by beta-lactamase (penicillinase), enhanced effect when used with beta-lactamase inhibitors (clavulanic acid, sulbactam) ; ampicillin undergoes enterohepatic recirculation ; synergistic effect with aminoglycosides Inactivated by beta-lactamase (penicillinase), enhanced effect when used with beta-lactamase inhibitors (clavulanic acid, tazobactam)

Bactericidal ; mostly IV ; all have renal excretion EXCEPT Cefoperazone and Ceftriaxone Increases nephrotoxicity of aminoglycosides ; do not cross the BBB ; minimal activity against Ghypersensitivity, injection site reactions, phlebitis, cocci, enterococci, MRSA and most GI upset G- rods

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Increases nephrotoxicity of aminoglycosides ; do not cross the ii. Second Generation: BBB ; slight less activity against G+ Cefamandole, cefaclor, cefonicid, but extended G- activity ; cefuroxime, cefprozil, loracarbef, Binds to penicillin-binding proteins, inhibits Cefuroxime has improved action ceforanide, cefoxitin, cefmetazole, transpeptidation in bacterial cell walls ; For surgical against pneumococcus and H. cefotetan prophylaxis, bone infections, infections due to staph strep influenzae ; Cefotetan and Cefoxitin and E. coli, Enterobacter, Neisseria, infections against hypersensitivity, injection site reactions, phlebitis, have good activity against B. fragilis anaerobes (Bacteroides), sinus ear and respiratory GI upset, Hypoprothrombinemia and Disulfiram and thus are used for abdominal infections by Klebsiella andHemophilus rection (cefamandole, cefotetan) and pelvic infections

iii. Third Generation: Cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime proxetil, cefdinir, ceftibuten Binds to penicillin-binding proteins, inhibits transpeptidation in bacterial cell walls ; decreased gram + coverage, increased gram – activity (pseudomonas, bacteroides), against Providencia, Serratia, Neiserria, Haemophilus ; DOC for gonorrhea (Ceftriaxone and Cefixime)

iv. Fourth Generation: Cefipime, Ceftaroline

Binds to penicillin-binding proteins, inhibits transpeptidation in bacterial cell walls ; wide coverage against gram + and gram - bacteria

Synergistic effect with aminoglycosides ; all have renal excretion EXCEPT Cefoperazone and Ceftriaxone ; all can penetrate the BBB EXCEPT Cefoperazone and Cefixime ; Ceftriaxone and Cefotaxime are the most active Cephs against Penicillin resistant Streptococcus pneumoniae ; Ceftizoxime is commonly used against Bacteroides ; should be reserved against serious infection EXCEPT ceftriaxone and cefixime ; Ceftriaxone has very good CNS hypersensitivity, GI upset, Hypoprothrombinemia penetration ; Ceftazidime has very and Disulfiram rection (cefoperazone) good action on Pseudomonas

hypersensitivity, GI upset

51

More resistant to beta-lactamase produced by Enterobacter, Haemophilus, Neisseria and Pneumococcal ; Has improved stability to chromosomal lactamase ; Ceftaroline used for MRSA

C. Other Beta-Lactams

Reserved for serious ife-threatening infections; cilastatin inhibits renal metabolism of imipenem ; given IV ; low susceptibility to B-lactamases ; active against Pseudomonas and Acinetobacter EXCEPT Ertapenem ; i. Carbapenems: ImipenemImipenem given with Cilastatin cilastatin , ertapenem, meropenem which acts as Dehydropeptidase Binds to penicillin-binding proteins, inhibits enzyme inhibitor ; Partial crosstranspeptidation in bacterial cell walls, wide coverage allergenicity with Penicillins ; against gram + gram - bacteria and anaerobes ; For Ertapenem has longer t1/2 but less infections resistant to other antibiotics EXCEPT MRSA, DOC hypersensitivity, GI upset, CNS toxicity (confusion, active against Enterococci and for Enterobacter, Citrobacter and Serratia encephalopathy, seizures) Pseudomonas Resistant to beta-lactamase, no activity against gram + bacteria or ii.Monobactam: Aztreonam Binds to penicillin-binding proteins, inhibits anaerobes ; given IV ; synergistic transpeptidation in bacterial cell walls ; used against Gram GI upset, superinfection, vertigo, headache, skin with AG ; renal excretion ; No cross– like klebsiella, pseudomonas and Serratia rash and hepatotoxicity allergenicity with Pens Most active against plasmid encoded B lactamases (Gonococci, Streptococci, E coli and H. iii. Beta-Lactamase Inhibitors: Influenzae ; not good inhibitor of Clavulanic acid , sulbactam, inducible chromosomal B tazobactam Inhibits inactivation of penicillins by bacterial betalactamases lactamase (penicillinase); used against beta-lactamase (Enterobacter,Pseudomonas, producing gonococci, streptococci, E. coli and H. influenza hypersensitivity and cholestatic jaundice Serratia) D. Other Cell Wall Synthesis Inhibitors

52

Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan --> inhibit transglycosylation --> prevent elongation and cross-linking of peptidoglycan chain ; For MRSA, PRSP, as alternative for red man syndrome, nephrotoxicity, ototoxicity, pseudomembranous colitis chills, fever, phlebitis

Narrow spectrum Treat red man syndrome by slowing the rate of infusion ; VRSA and VRE are due to D-Ala-D-Lactate formation ; teicoplanin and telavancin are not absorbed in the GIT thus used for bacterial enterocolitis, they are also eliminated unchanged in the urine ; decrease dose for renally impaired patients ; Dalbavancin has very long t1/2 (6-11 days) which permits once-weekly dosing and is more active than Vancomycin

ii. Peptide Antibiotic: Bacitracin

Interferes with a late stage oin cell wall synthesis in gram + organisms ; For gram + bacteria nephrotoxicity

Reserved for topical use only due to marked nephrotoxicity

iii. Antimetabolite: Cycloserine

Blocks incorporation of D-Ala into the pentapeptide side chain of the peptidoglycan ; For drug-resistant TB

neurotoxicity (tremors, seizures and psychosis)

only used as a second-line agent in TB

iv. Antimetabolite: Fosfomycin

inhibits cytosolic enolpyruvate transferase --> prevents formation of N-acetylmuramic acid (a peptidoglycan precursor molecule)

Diarrhea

renal excretion ; resistance emerges rapidly ; synergistic with Beta lactam and quinolones

myopathy

monitoring of CPK is needed, NOT Bactericidal (only destabilizes bacterial cell membrane)

i. Glycopeptides: Vancomycin, teicoplanin, telavancin, dalbavancin

v. Cyclic lipopeptide: Daptomycin same spectrum of activity as Vancomycin ; For VRE, VRSA, for G+ acitivity, against endocarditis and sepsis Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins & Oxazolidinones

A. Chloramphenicol (broad spectrum protein synthesis inhibitor)

Inhibits transpeptidation (catalyzed by peptidyl transferase) by blocking the binding of aminoacyl moiety of the charged tRNA to the acceptor site o mRNA at 50S subunit, basteriostatic ; For meningitis (Strep pneumonia, H influenza, Neisseria meningitides), back up for Salmonella, GI disturbance, aplastic anemia, gray baby Rickettsia, Bacteroides, Wide spectrum antibiotic syndrome

53

given PO and IV ; able to cross the placenta and BBB ; Inhibits hepatic drug-metabolizing enzymes causing many drug interactions ; resistance is due to the formation of acetyltransferase that inactivates drug ; usually used as topical agent

B. Tetracyclines: Tetracycline, doxycycline, minocycline, tigecycline, demeclocycline

Binds 30s ribosomal subunit thus preveting the binding of tRNA to mRNA, bacteriostatic ; Broad/Wide Spectrum (G+ and G-), For infections caused by Mycoplasma pneumonia, Chlamydia, Rickettsia, Vibrio, Spirochetes such as Leptospira, Peptic ulcer disease, Lyme disease, Malaria prophylaxis, Amoebiasis, Acne, Doxycycline is an alternative to macrolides as initial treatment of CAP, Alternative in syphilis, treatment of respiratory infection caused by susceptible organism, prophylaxis against infection in chronic bronchitis ; Selective uses: Tetracycline (H. Pylori PUD), Doxycycline (Lyme disease and malaria prevention), Minocycline (Meningococcal carrier state), Demeclocycline (SIADH), Tigecycline (more broad spectrum - MRSA, VRE, B-lactamase producing G- bacteria, anaerobes, Chlamydiae, Mycobacteria)

GI disturbances (enetrocolitis, nausea, diarrhea, vomiting), teratogen (tooth enamel dysplasia/discoloration), hepatotoxicity, nephrotoxicity, photosensitivity n(esp. demeclocycline), vestibulotoxicity, candidiasis, bacterial superinfection with S. aureus and C. difficile, Fanconi syndrome

C. Macrolides

i. Erythromycin, azithromycin, clarithromycin, telithromycin

Binds 30s ribosomal subunit, inhibit transpeptidation, bacteriostatic ; For community-acquired pneumonia, pertussis, diphtheria, chlamydial infections ; Eryhthromycin (Campylobacter, Chlamydia, Mycoplasma, Legionella, Corynebacterium, Chlamydophila, Legionella, Ureaplasma, Bordetella, G+ cocci, some G-), Clarithromycin and Azithromycin (coverage of Erythromycin plus greater activity against Chlamydia, Mycobacterium avium, Toxoplasma, Helicobacter, Haemophilus, Moraxella, Neiserria) ; Azithromycin is used as an alternative GI disturbance, cholestatic hepatitis, QT Ceftriaxone in Gonorrhea and to Pen G in syphilis prolongation, drug interaction

54

Tigecycline has the broadest spectrum and has the longest t1/2 (30-36hrs); do not drink with milk (decreased absorption with divalent cations like calcium) ; high Vd, cross the placenta, enterohepatic recycling ; all are excreted renally EXCEPT Doxycycline (bile) ; Resistance is due to development of efflux pumps for active extrusion of tetracyclines and the formation of ribosomal protection proteins that interfere with tetracycline binding (but not present with Tigecycline EXCEPT in Proteus and Pseudomonas) ; Tigecycline is given IV only and is unaffected by common tetracyclie resistace mechanisms good oral bioavilability but azithromycin absoprtion is impeded by food ; All macrolides inhibit CYP450 except azithromycin; azithromycin has highest Vd and slowest elimination; telithromycin is used for macrolide-resistance ; Halflives: Erythromycin (2hrs), Clarithromycin (6hrs), Azithromycin (24-48hrs) ; Resistance is due to development of efflux pumps and production of methylase enzyme ; Cross-resistance among macrolides: complete or partial resistance with drugs acting on the 50S

ii. Fidaxomicin

a narrow spectrum macrolide, for G+ and anaerobe, low oral bioavailability

iii. Telithromycin

Ketolide, structurally related to macrolide, same MOA and spectrum as erythromycin but macrolide-resistant QT prolongation, enzyme inhibitor, hepatic organisms are susceptible to telithromycin ; For CAP dysfunction

D. Lincosamides: Clindamycin, lincomycin

E. Streptogramin: QuinupristinDalfopristin

F. Oxazolidinone: Linezolid

GI upset, rashes, eosinophilia, acute cholestatic hepatitis, enzyme inhibitor

Binds 30s ribosomal subunit, inhibit transpeptidation, bacteriostatic ; For anaerobic infections (Bacteroides), alternative against gram + cocci (MRSA), endocarditis prophylaxis esp in those allergic to Pens, PCP pneumonia, toxoplasmosis (+ Pyrimethamine), skin and soft tissue infection Binds 50s ribosomal subunit, constricting the channel where polypeptides are extruded thus tRNA synthetase is also inhibited --> decreased free tRNA ; For infections caused by drug-resistant gram + cocci (MRSA, VRSA, PRSP, resistant E. faecium) Binds 23S rRNA of 50s ribosomal subunit, inhibit initiation by blockin formation of the tRNA-ribosome-mRNA ternary complex, bacteriostatic ; Reserved for infections caused by drug-resistant gram + cocci (MRSA, VRE, PRSP), Listeria, Corynebacteria

GI disturbance, skin rash, neutropenia, hepatic dysfunction, possible superinfection (Pseudomembranous colitis - C. difficile overgrowth)

Injection site reaction, anthralgia-myalgia syndrome

Thrombocytopenia, neutropenia, serotonin syndrome, neuropathy, optic neuritis

Aminoglycosides & Spectinomycin

55

as effective as Vancomycin as treatment for C. difficile possibly with lower relapse rate For CAP including multi-drug resistant organisms, A ketolide not a macrolide in chemical structure Cross-resistance between clindamycin and macrolides is common ; Resistance is due to methylation of binding sites and enzymatic inactivation ; G- aerobes are resistant because of poor penetration through th eouter membrane

Inhibits CYP450 enzymes causing multiple drug interactions ; BACTERICIDAL Inhibits CYP450 enzymes causing multiple drug interactions ; Resistance is due to decreasedaffinity of drug to binding site

A. Gentamycin, tobramycin

B. Amikacin

C. Streptomycin

D. Neomycin, kanamycin, paromomycin

AG are given IM or IV only, have concentration dependent killing, is not capabale of penetrating the blood brain barrier, low tissue penetration, SYNERGISTIC effect with cell wall synthesis inhibitors due to enhancement of transport to the inside of the bacterial cell ; mechanism of resistance of AG: plasmid-mediated formation of General MOA of all aminoglycosides (AG) is by inhibiting inactivating enzymes "group protein synthesis by binding to 30s subunit: (1) block nephrotoxicity (reversible - Acute Tubular transferase" --> catalyze the formation of the initiation complex (2) cause misreading of Necrosis esp in elderly, if given with Amphotericin acetylation of amine functions and the code on the mRNA template (3) inhibit translocation, B, Cephalosporin and Vancomycin)), ototoxicity the transfer of phosphoryl or bactericidal ; For serious infections caused by aerobic gram (irreversible), neuromuscular blockade (Curare- adenylyl groups to the oxygen – bacteria (E.coli, Enterobacter, Klebsiella, Proteus, like block --> respiratory paralysis. Remedy: atoms of the hydroxyl groups of AG, Providencia, Pseudomonas, Serratia, Haemophilus, Calcium, Neostigmine and Mechanical Ventilator) For Streptomycin, resistance is due Moraxella, Shigella), endocarditis, ocular infections ; If ; S. pneumoniae is resistant to Gentamicin, to changes in the ribosomal binding given together with Pens, may be used for Listeria, Enterococci is resistant to amikacin, gentamicin, site ; Gentamicin and tobramycin Enterococcus and G+ cocci tobramycin but NOT streptomycin are the most vestibulotoxic and Inhibits protein synthesis by binding to 30s subunit, bactericidal ; For serious infections caused by aerobic gram – bacteria (E.coli, Enterobacter, Klebsiella, Proteus, Providencia, Pseudomonas, Serratia, Haemophilus, Moraxella, Shigella), endocarditis, ocular infections, Least resistance and narrowest multidrug resistant TB (2nd line) ; If given together with nephrotoxicity (reversible), ototoxicity therapeutic window ; used for Pens, may be used for Listeria, Enterococcus and G+ cocci (irreversible), neuromuscular blockade streptomycin-resistant TB hypersensitivity, nephrotoxicity (reversible), Administered intramuscularly ; if Inhibits protein synthesis by binding to 30s subunit, ototoxicity (irreversible), neuromuscular given together with Pens can be bactericidal ; For TB, tularaemia, bubonic plague, blockade, teratogen (congenital deafness), used for enterococcal endocarditis, brucellosis injection site reactions TB plague and tularemia Limited to topical and oral use due Inhibits protein synthesis by binding to 30s subunit, to nephrotoxicity, kanamycin is bactericidal ; For skin infections, bowel preparations for most ototoxic ; Neomycin has the elective surgeries, hepatic encephalopathy, visceral hypersensitivity, nephrotoxicity (reversible), most skin reactions (allergic leishmaniasis (paromomycin) ototoxicity (irreversible), neuromuscular blockade reactions, contact dermatitis)

56

E. Spectinomycin

Inhibits protein synthesis by binding to 30s subunit, bactericidal ; For drug-resistant gonorrhoea, gonorrhoea in nephrotoxicity (reversible), ototoxicity penicillin allergic patients (irreversible), neuromuscular blockade

F. Netilmicin

Inhibits protein synthesis by binding to 30s subunit, For Treatment of serious infections bactericidal ; For serious infections caused by aerobic gram hypersensitivity, nephrotoxicity (reversible), caused by organisms resistant to – bacteria ototoxicity (irreversible), neuromuscular blockade other aminoglycosides

Sulfonamides, Trimethoprim & Quinolones

Ototoxcity of AG's can be increased by loop diuretics

B. Combination: Co-trimoxazole (Sulfamethoxazole + Trimethoprim)

low solubility in acidic urine causing formation of stones ; Resistance is GI upset, mild hepatic dysfunction, acute due to plasmin-mediated hemolysis in G6PD deficiency, nephrotoxicity (decreased intracellular (precipitate in the urine at acidic pH --> accumulation of the drug, increased crystalluria, hematuria), hypersensitivity (cross- production of PABA by bacteria, Inhibits dihydropteroate synthase, bacteriostatic ; For burn allergenicity with other related drugs such OHAs decreased sensitivity of infections, for G=, G-, Chlamydia and Nocardia, Simple oral and diurectics), exfoliative dermatitis, dihydropteroate synthetase to sulfas (UTI), Sulfacetamide (ocular infection, topical), polyarteritis nodosa, SJS, hematotoxicity sulfas and production of Mafenide and Silver sulfadiazine (burn infection, topical), (granulocytopenia, thrombocytopenia, aplactis dihydrofolate reductase that has Sulfasalazine (Ulcerative colitis and RA, oral), Sulfadizaine + anemia), kernicterus ; Drug Interactions: warfarin, decreased affnity for the drug ; Pyrimethamine + Folinic acid (Toxoplasmosis, oral) methotrexate, bilirubin sulfonamides are formulated in a Sequential blockade of dihydropteroate synthase (sulfamethoxazole) and dihydrofolate reductase (trimethoprim), bactericidal ; For UTI, respiratory, ear and GI upset, acute hemolysis in G6PD deficiency, sinus infections (Hemophilus, Moraxella, Aeromonas), DOC nephrotoxicity, hypersensitivity, hematotoxicity, Sulfonamides are weakly acidic for P. jiroveci pneumonia and Nocardiosis, toxoplasmosis, kernicterus ; trimethoprim toxicity: antifolate while Trimethroprim is a weak base Back-up for cholera typhoid fever shigellosis, G- sepsis, effects (megaloblastic anemia, leukopenia, ; remedy for antifolate effects: MRSA, Listeria granulocytopenia) Folinic acid supplement

C. Fluoroquinolones

Avoid in pregnancy due to absence of safety data

A. Sulfonamides: Silver sulfadiazine, mafenide acetate i. Short acting: Sulfisoxazole ii. Intermediate acting: Sulfamethoxazole

iii. Long acting: Sulfadoxine

57

i. First Generation Fluoroquinolones: Norfloxacin, Nalidixic acid

General SE: GI distress, skin rashes, HA, dizziness, insomnia, increased LFT, phototoxicity, CNS Inhibits DNA replication by binding to DNA gyrase and effects (dizziness, headache), tendinitis and topoisomerase IV (G+) and Topoisomerase II (G-), tendon rupture, opportunistic infection by bactericidal, inhibition of Topoisomerase II results in Candida and Streptococci ; CI in pregnancy and in blockade of relaxation of supercoiled DNA that is catalyzed children (damage growing cartilage --> by DNA gyrase while inhibition of Topoisomerase IV arthropathy), enhance toxicity of interferes with the separation of replicated chromosomal methylxanthines (theophylline) ; Mechanism of DNA during cell division ; General use of FQs: For infections resistance for Quinolones: decreased intracellular of the urogenital and GI tract by G- (gonococci, E. coli, accumulation via efflux pumps, change in porin Klebsiela, Campylobacter, Enterobacter, Pseudomonas, structure, chnages in sensitivity of target enzyme Salmonella, Shigella), respiratory tract, skin and soft tissue svia point mutations in the antibiotic binding infection ; may be used against meningococcal carrier region, mutations in the quinolone resistance state, for treatment of TB and prophylaxis in neutropenic determining region of the gyrA gene that encodes patients for DNA gyrase

ii. Second Generation Fluoroquinolones: Ciprofloxacin, ofloxacin, Enoxacin Norfloxacin

Inhibits DNA replication by binding to DNA gyrase and topoisomerase IV (G+) and Topoisomerase II (G-), bactericidal, bactericidal ; For UTI and GIT infections (gram – rods, gonococci, gram + cocci), atypical pneumonia (Mycoplasma, Chlamydophila), Mycobacteria ; increased activity against G-

GI distress, skin rashes, HA, dizziness, insomnia, increased LFT, phototoxicity, CNS effects (dizziness, headache), tendinitis and tendon rupture, opportunistic infection by Candida and Streptococci ; CI in pregnancy and in children (damage growing cartilage --> arthropathy)

58

General properties of quinolones: good oral bioavailability, high Vd, t1/2 3-8hrs, absorption is impeded by antacids, elimination is via kidneys by tubular secretion (may compete with probenecid for excretion) EXCEPT for MOXIFLOXACIN ; Norfloxacin does not achieve adequte plasma levels for use in systemic infections high resistance esp for C. jejuni, gonococci, G+ cocci like MRSA, Pseudomonas and Serratia ; are used as alternative to Ceftriaxone and Cefixime in gonorrhea ; Ofloxacin can be used against C. trachomatis

iii. Third Generation Fluoroquinolones: Levofloxacin, Gemifloxacin, Moxifloxacin, Sparfloxacin

Inhibits DNA replication by binding to DNA gyrase and topoisomerase IV (G+) and Topoisomerase II (G-), bactericidal, bactericidal ; For lung infections caused by gram + cocci, atypical pneumonia (Chlamydia, mycoplasma) ; less G- activity compared to 2nd gen but increased activity against G+ cocci, enterococci, MRSA

iv. Fourth Generation Fluoroquinolones: Trovafloxacin, Alatrofloxacin

Inhibits DNA replication by binding to DNA gyrase and topoisomerase IV (G+) and Topoisomerase II (G-), bactericidal, bactericidal ; has broad spectrum activity (gram – and gram +), enhanced activity against anaerobes

GI distress, skin rashes, HA, dizziness, insomnia, increased LFT, phototoxicity, CNS effects (dizziness, headache), tendinitis and tendon rupture, opportunistic infection by Candida and Streptococci ; CI in pregnancy and in children (damage growing cartilage --> arthropathy) GI distress, skin rashes, HA, dizziness, insomnia, increased LFT, phototoxicity, CNS effects (dizziness, headache), tendinitis and tendon rupture, opportunistic infection by Candida and Streptococci ; CI in pregnancy and in children (damage growing cartilage --> arthropathy) QT prolongation

59

"Respiratory Quinolones" ; Moxifloxacin and Gemifloxacin are the newest members of this family and are condisered to have the broadest spectrum of activity with increased activity aginst anaerobes ang atypical agents ; FQ elimination is via kidneys by tubular secretion (may compete with probenecid for excretion) EXCEPT Moxifloxacin ; NEVER use moxifloxacin in UTI ; Levofloxacin is used in CAP caused by Chlamydia, Mycoplasma and Legionella ; Gemifloxacin, Levofloxacin and Moxifloxacin can prolong QT ; Levofloxacin has superior activity against G(+) bacteria including S. pneumoniae ; All have relatively long t1/2 permitting once daily dosing ; Oral absorption is impaired by cations ; Gatifloxacin can cause hyperglycemia in DM Px and hypoglycemia in patients also receiving OHA and was withdrawn from the market in 2006 (USA)

additional SE: diabetes (gatifloxacin), hepatotoxicity (trovafloxacin)

D. Miscellaneous agents

i. Metronidazole, tinidazole

ii. Nitrofurantoin Antimycobacterial Drugs

A. Isoniazid (nicotinic acid derivative)

B. Rifamycin derivatives: Rifampicin, rifabutin, rifapentine, rifamixin

Reactive reduction by ferredoxin forming free radicals that disrupt electron transport chain, bactericidal ; For anaerobic or mixed intra-abdominal infections, vaginitis GI irritation, metallic taste, headache, dark urine, (trichomonas, gardnerella), pseudomembranous colitis, leukopenia, dizziness, ataxia, neuropathy, DOC for amoebiasis, giardiasis and brain abscess, protozoal infections seizures and disulfiram reaction Pseudomembranous colitis single OD dose can prevent Forms multiple reactive intermediates when acted upon by GI irritation, skin rashes, pulmonary infiltrates, recurrent UTI ; acidification of urine bacterial nitrofuran reductase, bactericidal ; For UTI phototoxicity, neuropathies, hemolysis in patients enhances activity ; adjust dose in (except Proteus and Pseudomonas) with G6PD deficiency renal patients Most impt drug in TB, prevent neurotoxicity by giving pyridoxine (vit B6) ; structural congener of pyridoxine ; high level resistance due to deletion of KatG gene whichh codes for catalaseperoxidase enzyme involved in bioactivation of INH, low level hepatotoxicity, neurotoxicity (seizures, peripheral resistance due to deletion og inhA Inhibits mycolic acid synthesis, bactericidal ; For TB, for neuritis, insomnia, restlessness, muscle gene which encodes the target latent infection, given as a sole drug for prophylaxis of twitching), acute hemolysis in G6PD deficiency, enzyme which is an acyl protein close contacts and skin test converters drug-induced lupus reductase ; Potent CYP450 inhibitor Potent CYP450 inducer ; rapid development of resistance if used alone ; resistance is due to changes of drug sensitivity of the polymerase enzyme; undergoes enterohepatic recirculation ; orange-colored metabolites ; delay emergence of Inhibits DNA-dependent RNA polymerase, bactericidal ; For resistance to dapsone ; Rifabutin is TB, leprosy, prophylaxis for meningococcal and equally effective as antistaphylococcal carrier states, drug-resistant infections mycobacterial agent with less drug (MRSA, PRSP) when given together with Vancomycin, can red-orange urine, light chain proteinuria, skin interaction and it is the preferred be used as sole drug in the treatment of latent TB in INH- rash, thrombocytopenia, nephritis, anti-TB for AIDS patients ; Rifamixin intolerant patient or in close contact of patients with INH- hepatotoxicity, flulike syndrome, anemia, impair is not absorbed in the GIT and is resistant strains of the organism antibody response used for traveler's diarrhea

60

dose-dependent visual disturbances (decreased visual acuity, red green color blindness, Inhibits arabinosyl transferases involved in the synthesis of retrobulbar neuritis, retinal damage, optic arabinogalactan in mycobacterial cell wall, bacteriostatic ; neuritis), headache, confusion, hyperuricemia, C. Ethambutol (butanol derivative) For TB peripheral neuritis

Resistance is due to mutation in emb gene ; dose adjustment id needed in renal patients ; always used in combination with other drugs for TB

D. Pyrazinamide (pyrazine derivative)

Unknow MOA, bacteriostatic but can be bactericidal on actively dividing mycobacteria, is metabolozed to pyrazinoic acid, t 1/2 is increased in liver and kidney disease ; For TB

hepatotoxicity, nongouty polyarhtralgia, asymptomatic hyperuricemia, myalgia, GIT irritation, maculopapular rash, porphyria, photosensitivity ; CI in pregnancy

Most hepatotoxic anti-TB drug, also known as sterilizing agent ; require metabolic conversion via pyrazinamidases in MTb ; resistance is via mutation in pncA gene which codes for pyrazinamidases and increased efflux systems ; decrease dose in hepatic and renal patients

E. Streptomycin (aminoglycoside)

for MDRTB (TB meningitis, miliary TB, severe organ TB)

see entry

see entry

GI irritation, fever, skin rashes, methemoglobinemia, acute hemolysis in G6PD deficiency patients

Most active drug against M. leprae ; used in combination with rifampicin and clofazimine ; Acedapsone is a repository form of dapsone which has drug action that can last for several months

GI irritation, skin discoloration

a phenazine dye

infusion reactions (chills, fever, muscle spasms, vomiting, hypotension), dose limiting nephrotoxicity (decreased GFR, ATN with magnesium and potassium wasting, decreased erythropoietin), neurotoxicity (seizure, neuronal damage)

Control infusion reactions by slowing the rate of infusion and premedication with antihistamines, additive nephrotoxicity with other nephrotoxic drugs (aminoglycosides) ; highly lipid soluble, poorly absorbed in the GIT ; high Vd except in the CNS with a t1/2 of 2weeks ; resistance is due to decreased level of ergosterol or change in membrane structure ; has the WIDEST antifungal spectrum

Drugs for Leprosy

Inhibition of folic acid synthesis, bacteriostatic ; For A. Sulfones: Dapsone, acedapsone leprosy, alternative for PCP pneumonia B. Clofazimine

Binds to guanine bases in bacterial DNA, bactericidal ; For leprosy

Antifungal Agents

A. Polyene antifungal: Amphotericin B

Binds to ergosterol in fungal cell membranes, forming artificial pores, fungicidal, WIDEST antifungal spectrum ; For systemic fungal infections (aspergillus, blastomyces, candida, Cryptococcus, histoplasma, mucor), for initial induction before followup treatment with azoles, can be used topically in mycotic corneal ulcers and keratitis

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B. Flucytosine

Accumulated in fungal cells by the action of permease and converted by cytosine deaminase to 5-FU, which inhibits thimidylate synthase, pyrimidine antimetabolite, fungistatic ; given together with ampho B and Triazoles For cryptococcal infection, systemic candidal infections, reversible myelosuppresion, alopecia, chromoblastomycosis hepatotoxicity

C. Azole Antifungals

i. Ketoconazole (Imidazole)

ii. Fluconazole (Triazole)

iii. Itraconazole (Triazole)

iv. Voriconazole (Triazole)

Inhibit 14α-demethylase --> decreased ergosterol production --> increased permeability of cell membrane, Inhibits fungal P450-dependent enzymes blocking ergosterol synthesis, fungistatic ; For chronic mucocutaneous candidiasis, dermatophytosis Inhibit 14α-demethylase --> decreased ergosterol production --> increased permeability of cell membrane, Inhibits fungal P450-dependent enzymes blocking ergosterol synthesis, fungistatic ; DOC for candidiasis (esophageal, oropharyngeal, vulvovaginitis), coccidioidomycosis, cryptococcal meningitis (treatment and prophylaxis) Inhibit 14α-demethylase --> decreased ergosterol production --> increased permeability of cell membrane, Inhibits fungal P450-dependent enzymes blocking ergosterol synthesis, fungistatic ; DOC for blastomycosis, sporotrichosis, dermatophytosis esp onchomycosis, chromoblastomycosis ; alternative for infections due to Aspergillus, Coccidioides, Cryptococcus and Histoplasma , for esophageal candidiasis resistant to fluconazole Inhibit 14α-demethylase --> decreased ergosterol production --> increased permeability of cell membrane, Inhibits fungal P450-dependent enzymes blocking ergosterol synthesis, fungistatic ; co-DOC for invasive aspergillosis, alternative in candidemia, for fluconazoleresistant organisms, for candidal esophagitis and stomatitis in AIDS patients

decrease dose in renal patients ; resistance is due to decreased activity of fungal permease and deaminase ; has synergistic effect when given with ampho B and Triazoles.

GI disturbances (vomiting, diarrhea), rash, hepatotoxicity, drug interaction, gynecomastia, menstrual irregularities and infertility

Limited to topical use because of systemic toxicity ; narrow antifungal spectrum ; resistance is due to chnages in the sensitivity of target enzyme ; Potent CYP450 inhibitor ; Ketoconazole is rarely used due to drug interactions and narrow spectrum

GI disturbances (vomiting, diarrhea), rash, hepatotoxicity

alternative to Ampho B in the treatment of C. neoformans, as effective as Ampho B in candidemia

GI disturbances (vomiting, diarrhea), rash, hepatotoxicity

may also be used for subcutaneous chromoblastomycosis

GI disturbances (vomiting, diarrhea), rash, hepatotoxicity, blurring of vision in 30% of patients, CI in pregnancy

wider specturm azole

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v. Posaconazole (Triazole)

vi. Clotrimazole, miconazole, ketoconazole

D: Echinocandins: Caspofungin, anidulafungin, micafungin

E. Griseofulvin

F. Terbinafine

G. Nystatin (polyene)

Inhibit 14α-demethylase --> decreased ergosterol production --> increased permeability of cell membrane, Inhibits fungal P450-dependent enzymes blocking ergosterol synthesis, fungistatic ; For Candida and Aspergillus, as prophylaxis of fungal infection during cancer chemotherapy, salvage therapy in invasive aspergillosis Inhibit 14α-demethylase --> decreased ergosterol production --> increased permeability of cell membrane, Inhibits fungal P450-dependent enzymes blocking ergosterol synthesis, fungistatic ; For mucocutaneous candidiasis, dermatophytosis, seborrheic dermatitis, pityriasis versicolor Inhibit beta-glucan synthase which produces β(1-->2) glycan which is a cellwall component, thus decreasing fungal cell wall synthesis, fungostatic ; For disseminated and mucocutaneous candidiasis who fail to respond to amphoB, for mucormycosis, salvage therapy for invasive aspergillosis

GI disturbances (vomiting, diarrhea), rash, hepatotoxicity

BROADEST spectrum triazole ; the only azole with activity against Rhizopus sp. (mucormycosis) ; Potent CYP450 inhibitor

None when administered topically

Limited to topical use because of systemic toxicity

headache, GI distress, rash, fever, flushing (histamine release), elevated liver enzymes headache, mental confusion, GI irritation, photosensitivity, hepatotoxicity, disulfiram reaction, drug interactions (decreases bioavialability of warfarin) ; contraindicated in porphyria

Interferes with microtubule function in dermatophytes, inhibits synthesis and polymerization of nucleic acids, fungistatic ; For dermatophytosis Inhibits withg ergosterol synthesis by inhibiting fungal squalene oxidase leading to increased squalene which interferes with ergosterol synthesis, fungicidal ; For dermatophytosis, onchomycosis GI upset, rash, headache, taste disturbances Binds to ergosterol in fungal cell membranes, forming artificial pores, fungicidal ; For candidiasis ((oropharyngeal, esophageal and vaginal), for GI fungal infections in patients with impaired defense mechanisms nephrotoxicity (severe)

Antiviral Agents A. Anti-Herpes

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all are given IV ; micafungin can increase levels of cyclosporine and tacrolimus given PO ; Accumulates in keratin ; potent CYP450 inducer ; absorption is increased by intake of fatty meal ; resistance is due to decreased transport of drug into the fungal cell wall given PO and topical, also accumulates in keratin, more effective than griseofulvin in onchomycosis Minimal mucocutaneous absorption, available as swish and swallow preparation

Activated by viral thymidine kinase (TK) to forms that inhibit viral DNA polymerase, guanosine analog, competitive substrate for DNA polymerase, causes chain termination after its incorporation into the viral DNA ; For infections due to HSV1, HSV2, VZV (mucocutaneous and genital herpes, prophylaxis in AIDS and in other i. Acyclovir, valacyclovir, Immunocompromised states such as organ transplant penciclovir, famciclovir, docosanol patients, herpes encephalitis, neonatal HSV infection etc. ii. Docosanol

nausea, diarrhea, headache, delirium, tremor, seizures, hypotension, nephrotoxicity

Inhibits fusion between the HSV envelope and plasma nausea, diarrhea, headache, delirium, tremor, membrane, prevents viral entry and subsequent replication seizures, hypotension, nephrotoxicity

Inhibits viral DNA polymerase causing chain termination, guanosine derivative ; For infections due to CMV, HSV1, HSV2, VZV ; For prohylaxis and treatment of CMV retinitis and other CMV infections in the immunocompromised patients

leukopenia, thrombocytopenia, mucositis, hepatotoxicity, seizures, neutropenia

iv. Cifodovir (anti-CMV)

Inhibits viral DNA polymerase causing chain termination ; For CMV retinitis, mucocutaneous HSV infections, acyclovir-resistance, ganciclovir-resistance, genital warts and molluscum contangiosum

nephrotoxicity

v. Foscarnet (anti-CMV)

Inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase, binds to pyrophosphate binding site ; as alternative for prophylaxis and treatment of CMV nephrotoxicity, electrolyte abnormalities retinitis, gancyclovir-resistant strains of CMV, HSV infection (hypocalcemia), GU ulcerations, CNS effects in patients with AIDS, also used in organ transplantation (headache, hallucination, seizures)

iii. Ganciclovir, valganciclovir (anti-CMV)

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given PO, topical and IV ; dose adjustment in renal patients ; No activity against strains of HSV with absent thymidine kinase activity ; resistance is due to changes in viral DNA polymerase ; Valacyclovir is a prodrug that is converted to Acyclovir and reached plams levels 3-5x (longer t1/2) more than acyclovir ; Penciclovir does not cause chain termination ; Famciclovir is a prodrug which is converted to Penciclovir in vivo topical preparation shortens healing time given as IV or intraocular implant (for CMV retinitis) ; No activity against strains of HSV with absent thymidine kinase activity ; CMV resistance is due to mutation in viral DNA polymerase and in the genes that code for the activating viral phosphotransferase ; Valganciclovir is a prodrug of ganciclovir with increased oral bioavialability Active against strains of HSV with absent thymidine kinase activity ; resistance is due to mutation in DNA polymerase ; dose adjustment in renal patients Active against strains of HSV with absent thymidine kinase activity ; does not require phosphorylation for antiviral activity ; resistance is due to mutations in DNA polymerase gene ; dose adjusment in renal patients

vi. Vidarabine

adenine analog ; For HSV, VZV, CMV

GI irritation, paresthesia, tremor, convulsion, hepatic dysfunction, CI in pregnancy

vii. Idoxuridine, trifluridine

pyrimidine analogs ; For herpes keratitis (HSV-1)

irritation, blurred vision, photophobia

viii. Fomivirsen

antisense oligonucleotide that binds to mRNA of CMV causing inhibition of early protein synthesis ; For CMV retinitis

iritis, vitritis, increased IOP, changes in vision

B. Drugs for HIV

i. NRTI: a. Abacavir

used topically only because it is rapidly metabolized into the inactive form and because it has a toxic potential topical only because it is too toxic fo systemic use injected intravitreally ; concurrent systemic use of anti-CMV in threapy is recommended to protect against extraocular and contralateral retinal CMV disease

Inhibit HIV reverse transcriptase after phosphorylation by cellular enzymes, acts as chain terminators via insertion into the growing DNA chain ; For HIV infection, prevention of maternal-fetal HIV transmission see specific drugs below

these are prodrugs converted by host cell kinases tp triphosphates causing competitive binding of natural nulecotides to the dNTPbinding site of Reverse Transcriptase ; resistance is due to mutation in pol gene

guanosine analog

good oral bioavailability, T1/2 is 1224hrs, resistance is slow

b. Didanosine (ddI)

NRTI

c. Emtricitabine

NRTI

hypersensitivity reaction acute pancreatitis, peripheral neuropathy, diarrhea, hepatic dysfunction, hyperuricemia, CNS effects aesthenia, GI upset, headache, hyperpigmentation of palms of soles, CI in pregnancy, children, renal and hepatic and patients

oral bioavailability is decreased by food and chelating agents ; dose adjustment in renal patients

per orem once a day treatment, dose adjustment in renal patients 80% oral bioavailability ;may also be used for Hepa B infection ; HAART, dose adjustment in renal patients

d. Lamivudine (3TC)

NRTI

GI upset, headache, fatigue, insomnia

e. Stavudine (d4T)

NRTI

peripheral neuropathy esp if given together with good oral bioavailability, dose Zalcitabine, lactic acidosis with hepatic steatosis adjustment in renal patients

f. Tenofovir

a nucleotide but acts as NRTI, competitively inhibits RT, cause chain termination after incorporation into DNA

oral bioavailabilty is 25-40% ; GI upset, asthenia, headache, Fanconi syndrome, halflife is 60hours ; also used against AKI HBV

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NRTI

peripheral neuropathy, pancreatitis, esophageal ulceration, stomatitis, arthralgias

increased oral bioavailability, dose adjustment in renal patients

Azidothymidine or AZT

BM suppression (anemia, neutropenia, thrombocytopenia), acute cholestatic hepatitis, agitation, insomnia, myalgia, headache, GI upset

dose adjustment in uremic patients and cirrhosis ; affected by enzymes inducers and inhibitors

Delavirdine and Nevirapine (rash, increased AST/ALT, Efavirenz (teratogenicity), Etravirine (increased cholesterol and triglycerides)

binds to a different binding site ; resistance is due to mutations in pol gene

NNRTI

rashes, teratogenic

metabolized by CYP3A4 and CYP2D6, affected by enzyme inducer and inhibitor

b. Efavirenz

NNRTI

CNS dysfunction, skin rash, increased plasma cholesterol, teratogenic

enhanced absorption by fatty meals, drug interactions are common

c. Etravirine

NNRTI, for drug-resistant HIV

nausea, vomiting, diarrhea, increased cholesterol, triglycerides and LFTs NEWEST NNRTI

g. Zalcitabine (ddC)

h. Zidovudine (ZDV)

Inhibits HIV reverse transcriptase, no phosphorylation ii. NNRTI: Delavirdine, efavirenz, required, do not compete with nucleoside triphosphate ; etravirine, nevirapine For HIV infection

a. Delavirdine

d. Nevirapine iii. Protease Inhibitor: Atrazanavir, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Lopinavir-Ritonavir, Saquinavir, Tipranavir

used as a singledose to prevent HIV vertical transmission at the onset of labor and also given to the neonate rash, SJS, TEN General SE: hyperglycemia, insulin resistance, hyperlipidemia, altered body fat distribution (buffalo hump, gynecomastia, truncal obesity, facial and peripheral lipodystrophy) due to the cleaves precursor polyprotein to form the final structural inhibition of lipid-regulating proteins which have protein of the mature virion core, inhibits viral protein active sites with structural homology to that of processing ; For HIV infection HIV protease

good oral bioavailability,t1/2 is >24hours

a. Atazanavir

Protease Inhibitor

peripheral neuropathy, skin rash, hyperbilirubinemia, QT prolongation

Resistance is due to mutation in pol gene ; are potent CYP3A4 inhibitor esp Ritonavir per orem absorption requires acidic environment ; can penetrate CSF and seminal fluid ; is not associated with dyslipidemia, fat deposition or metabolic syndrome ; CYP3A4 and 2C9 inhibitor

b. Darunavir

Protease Inhibitor

rash, hepatotoxicity, hypersensitivity ; CI in patients with sulfa allergy

Given together with Ritonavir in patients resistant to other PIs

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Protease Inhibitor

GI upset, paresthesia, rash, CI in pregnant patients and children if drug uses propylene glycol as solvent ; does not have risk for hyperlipidemia, fat maldistribution, hyperglycaemia and insulin resistance

d. Indinavir

Protease Inhibitor

nausea, vomiting, diarrhea, thrombocytopenia, hyperbilirubinemia, nephrolithiasis, insulin resistance

e. Lopinavir-Ritonavir

used as a combination drug: uses subtherapeutic dose of ritonavir which inhibits CYP3A4 mediated metabolism of lopinavir

GI upset (well-tolerated side effects)

f. Nelfinavir

Protease Inhibitor

Diarrhea

g. Ritonavir

Protease Inhibitor ; subtherapeutic doses inhibit CYP3A4mediated metabolism of other Pis (Indnavir, Lopinavir, Saquinavir) which permits lower dose of the other PI

good oral bioavailability esp when taken with meals ; affected by GI upset, bitter taste, paresthesia, increased LFT's enzyme inducer and inhibitors

h. Saquinavir

Protease Inhibitor ; given together with low dose Ritonavir to improve compliance and decrease GI upset nausea, vomiting, diarrhea, dyspepsia, rhinitis

i. Tipranavir

Protease Inhibitor ; given with Ritonavir for PI-resistant HIV GI upset, rash, hepatotoxicity

affected by enzyme inducers and inhibitors newer drug ; induces P-glycoprotein transporters which leads to alteration of GI absorption of other drugs

a. Fusion Inhibitor: Enfuvirtide, Docosanol

Binds to gp41 subunit of viral envelope glycoprotein, preventing fusion of viral and cellular membranes ; For previously drug-treated patients with persistent HIV replication despite ongoing therapy

subcutaneous and usually given together with other HIV agents

b. CCR5 receptor antagonist: Maraviroc

Blocks viral attachment by blocking CCR5, a transmembrane protein involved in the attachment of HIV cough, diarrhea, muscle and joint pains, increased good tissue penetration ; affected to host cell ; For HIV infection LFTs by enzyme inhibitors and inducers

c. Fosamprenavir

a prodrug that is converted to the active drug Amprenavir ; absorption is impaired by fatty food ; used with lowdose Ritonavir decreased bioavailability in the presence of food ; affected by enzyme inhibitors and inducers there is increased compliance with this drug ; Ritonavir has “boosting effect” on other PI due to enzyme inhibitory effect absorption is increased by food, short half-life ; has the most favorable safety profile for pregnancy

iv. Entry inhibitors:

injection site reaction, hypersensitivity reaction, increased incidence of bacterial pneumonia

C. Drugs for Influenza

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i. Uncoating inhibitors: Amantadine, rimantadine

ii. Neuraminidase inhibitors: Oseltamivir, Zanamivir, Peramivir D. Drug for HBV and HCV

Inhibit early step replication and prevent uncoating by binding to M2 proton channels ; For influenza A and rubella Inhibits neuraminidase which cleaves sialic acid residues from viral proteins and surface proteins of infected cells , decrease release of progeny virus ; For influenza A and B, shortens duration of symptoms

GI irritation, dizziness, cerebellar dysfunction (ataxia, dysarthria), livedo reticularis GI effects (Oseltamivir), bronchospasm in asthmatics and cough with throat discomfort (Zanamivir )

cytokine, increased activity of JAKS leading to phosphorylation of signal transducers and activation of transcription (STATS) which causes increased formation of antiviral proteins , also increases NK cells that destroy infected liver cells, Degrades viral RNA via activation of host cell RNAse (ribonuclease) ; For chronic HBV, HCV infection, Kaposi sarcoma, genital warts, prevents dissemination of HZV in cancer patients and decreased CMV shedding after renal transplantation

alopecia, myalgia, severe depression, flu-like syndrome, thyroid dysfunction, reversible hearing loss, neutropenia ; Contraindications include autoimmune disease, history of cardiac arrhythmia and pregnancy

Inhibits HBV DNA polymerase causing chain termination after incorporation into the viral DNA ; For lamivudineresistant Hepatitis B infection, suppresses HBV replication and improves liver histology and fibrosis

Lactic acidosis, renal toxicity, severe hepatomegaly with steatosis

iii. Entecavir

guanosine nucleoside, inhibits DNA polymerase

headache, dizziness, fatigue, nausea

iii. Lamivudine (3TC)

see entry, also active for HBV, rapidly suppresses HBV replication

see entry

i. Interferon-α

ii. Adefovir, Dipivoxil, Telbivudine, Tenofovir

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Amantadine is also used in treating parkinsonism ; should be given within 48hrs of exposure ; Rimantadine has longer halflife and doe snot need dose-adjustment for renally-impaired Px ; there is increased resistance observed with amantadine DOC for influenza (including H1N1) ; Oseltamivir is PO while Zanamivir is intranasal ; Peramivir has been given temporary emergency use authorization by US FDA for H1N1 in

slow absorption, given IM or SC once a day 3x week but the PEGform is only given once a week, given topically for genital warts Dipiroxil is a prodrug of Adefovir ; Telbivudine is a newer drug (nucleoside analog) but develpoment of resistance is rapid, it is as effective as lamivudine ; Tenofovir is an anti-RT drug that is also effective in chronic HBV, it is active against lamivudine and entecavir-resistant strains is as effective as lamivudine, longer t1/2 of 12hrs Coinfection between HBV and HIV may increase the risk of pancreatitis with lamivudine use ; longer t1/2 in HBV infected cells than in HIV (lower dose required in HBV than in HIV)

Inhibits guanosine triphosphate formation, prevents capping of viral mRNA, blocks RNA-dependent RNA polymerase, inhibit replication of many DNA and RNA viruses like Influenza A and B, parainfluenza, paramyxo

iii. Ribavirin

viruses, HCV and HIV ; For HCV infection (with IFN-α) and RSV infection, decreases mortality in viral hemorrhagic fevers

haemolytic anemia, conjunctival and bronchial irritation, teratogen

given PO, IV or aerosol, avoid concomitant administration of anatcids ; Early IV administration of ribavirin decreases mortality in viral hemorrhagic fevers ; monotherapy is NOT effective

Antiprotozoal Drugs A. Antimalarial drugs

i. Chloroquine, hydroxychloroquine

ii. Quinine, Quinidine gluconate

iii. Mefloquine

iv. Primaquine

accumulates in the food vacuole of plasmodia —> Prevents polymerization of heme into hemozoin —> inc heme concentration which is toxic to the parasite, Blood schizonticide ; For malaria (non-falciparum, chloroquinesensitive), DOC for acute attacks of non-Falciparum and sensitive Falciparum malaria, used as chemoprophylaxis except in regions where P. falciparum is resistant, for autoimmune diseases such as rheumatoid arthritis, amoebic liver abscess Complexes with double stranded DNA to prevent strand separation —> blocks DNA replication and transcription to RNA, blood schizonticide ; For malaria (chloroquineresistant) and severe falciparum malaria (quinidine), given together with Doxycycline and or Clindamycin to shorten duration of disease Unknown MOA, blood schizonticide ; For chemoprophylaxis (chloroquine-resistant areas) ; 1st line drug (weekly administration) for prophylaxis in all areas with Chloroquine resistance), alternative to quinine in acute attacks and uncomplicated infections from falciparum malaria 8-aminoquinoline, Forms quinoline-quinone metabolites which are electron-transferring redox compounds that act as cellular oxidants, tissue schizonticides, gametocides ; For malaria, eradicates liver stages of P. vivax and P. ovale (radical cure of P. vivax and P. ovale), alternative as primary prevention, terminal prophylaxis (vivax, ovale), PCP pneumonia

May precipitate porphyria ; Chloroquine is 4-aminoquinoline derivative, can be given PO and has high Vd, absorption is decrease by antacids ; resistance is due to dec. GI irritation, skin rash, headache, severe skin intracellular accumulation via inc lesions, peripheral neuropathies, myocardial activation of membrane pumps, dec depression, retinal damage, auditory impairment, intravacuolar accumulation via psychosis transporter encoded by pfcrt gene cinchonism (headache, tinnitus, vertigo), hemolysis in G6PD deficiency, blackwater fever, blurring of vision, GI upset, disturbance n cardiac conduction ; CI in pregnancy

Quinine is commonly used with doxycycline or clindamycin to limit toxicities, PO and IV (in severe infection) ; NEVER use as prophylaxis

GI distress, skin rash, headache, dizziness, cardiac conduction defects, psychiatric disorders (psychosis), neurologic symptoms, seziures is a 4-quinoline derivatives, PO Eradicates hypnozoites in the liver, preventing malarial relapse, PO , GI distress, pruritus, headaches, should be used with a blood methemoglobinemia, hemolysis in G6PD deficient schizonticide, 14-day course of Tx patients ; CI in pregnancy after Tx with choloroquine

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v. Atovaquone-proguanil

vi. Sulfadoxine-pyrimethamine (Fansidar)

vii. Doxycycline

viii. Halofantrine , lumefantrine

ix. Artemsinin, artesunate, artemether, dihydroartemsinin x. Amiodaquine

Atovaquone disrupts mitochondrial electron transport, blood and tissue schizonticide, proguanil inhibits folate synthesis, sporonticide ; For treatment and chemoprophylaxis of chloroquine-resistant falciparum, protective vs. Mefloquine-resistant falciparum Sequential blockade of folic acid synthesis (sulfadoxine blocks Dihyrodpteroate synthetase, Pyrimethamine blocks Dihydrofolate reductase, blood schizonticide and sporonticide ; For malaria (for Chloroquine-resistant)

abdominal pain, nausea, vomiting, diarrhea, headache, rash, increased liver enzymes

also effective against Mefloquineresistant Falciparum infection ; Proguanil has a t1/2 12-16h ; Atovaquone is an alternative for P. jiroveci infection

GI disturbances, teratogen (enamel dysplasia and t1/2 is usually >100h, PO, highly discoloration), hepatotoxicity, nephrotoxicity, protein bound ; pyrimethamine is a photosensitivity, vestibulotoxicity, hemolysis sporonticide

Impairs progeny of malarial apicoplast genes, resulting in abnormal cell division, blood schizonticide ; For chemoprophylaxis in multi-drug resistant strains

GI disturbances, teratogen (enamel dysplasia and discoloration), hepatotoxicity, nephrotoxicity, Do not drink with milk (decreased photosensitivity, vestibulotoxicity absorption), PO Lumefantrine used in combination with artemether (Co-arthem) for uncomplicated falciparum infection ; Halofantrine is never used for Unknown MOA, active vs the erythrocytic stage of all 4 prophylaxis because of strains including Chloroquine-resistant, blood schizonticide abdominal pain, diarrhea, vomiting, cough, rash, cardiotoxicity and embryogenecity, ; For chloroquine-resistant malaria and severe falciparum headache, pruritus, elevated liver enzymes, Lumefantrine has minimal malaria cardiotoxicity, teratogen cardiotoxicity Co-artem is the DOC for

is metabolized in the food vacuole of protozoa —> Forms toxic free radicals in malarial food vacuole, blood schizonticide ; For malaria (falciparum and MDR strains)

nausea, vomiting, diarrhea ; SAFE in pregnancy

uncomplicated falciparum malaria in the Philippines ; Combination therapy of artemesinins with one or two long-acting antimalarial drugs (amodiaquine, mefloquine, sulfadoxine/pyrimethamine or lumefantrine) is favored to retard the development and progression of drug resistance in P. falciparum ; not given as Prophylaxis due to short t1/2 (1-3h) ; the only reliably effective meds vs Quinine-resistant strains

MOA same as chloroquine (inhibits the digestion of hemoglobin) ; For chloroquine-resistant falciparum

agranulocytosis, aplastic anemia

low-cost, given as combination with Artesunate

B. Anti-amoebiasis

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i. Diloxanide Furoate

Unknown MOA, converted to Diloxanide freebase (active amobecide), luminal amebicide ; DOC for asymptomatic cyst carrier of E. histolytica

ii. Emetine, dehydroemetine

Inhibits protein synthesis by blocking ribosomal movement along messenger RNA, tissue amebicide ; back up drug for GI distress, muscle weakness, CV dysfunction severe intestinal, hepatic and extraintestinal amebiasis (arrhythmias and CHF)

ii. Iodoquinol

halogenated hydroxyquinoline, Unknown MOA, luminal amebicide ; Alternative to Diloxanide for mild to severe intestinal amebiasis

iii. Metronidazole, Tinidazole, Secnidazole

iv. Paromomycin

v. Nitazoxanide

flatulence, nausea, abdominal cramps

GI distress, thyroid enlargement, skin reactions due to iodine toxicity, neurotoxicity (peripheral neuropathy, visual dysfunction)

Reactive reduction by ferredoxin forming free radicals that disrupt electron transport chain, tissue amebicide ; DOC for severe intestinal wall disease and in hepatic abscess and other extra intestinal amebic disease, DOC for trichomoniasis, also used for giardiasis, bacterial vaginosis (Gardnerella vaginalis), anaerobic infections, H. pylori PUD

Usually used in combination with metronidazole, PO given PO, IV or topical, Metronidazole t1/2 is 6-8h, Tinidazole t1/2 is 12-14h; dose adjustment in renal patients, well distributed even in CSF ; active against protozoan and bacteria GI irritation, metallic taste, headache, dark urine, (Bacteroides and Clostridium, DOC leukopenia, dizziness, ataxia, neuropathy, for Pseudomembranous colitis) ; seizures, disulfiram reaction, opportunistic causes potentiation of warfarin infections, parestheisa, CI in pregnancy action ; bets taken with meals may be given together with tetracycline in mild intestinal disease ; superior to Diloxanide in asymptomatic carries but SE limits headaches, dizziness, rashes, arthralgia its use

An aminoglycoside, Inhibits protein synthesis, binds to 16S ribosomal subunit, luminal amebicide ; For intestinal amebiasis, cryptosporidiosis Reactive reductions by ferredoxin forming free radicals that disrupt electron transport chain, tissue amebicide ; For metronidazole-resistant amebiasis, giardiasis, cryptosporidiosis (DOC) GI distress

C.Drugs for Pneumocystis and Toxoplasmosis Sequential blockade of dihydropteroate synthase (sulfamethoxazole) and dihydrofolate reductase (trimethoprim), bactericidal ; DOC for prophylaxis and treatment of Pneumocystosis, prophylaxis (T. gondii, I. i. Co-trimoxazole belli)

converted in vivo into Diloxanide freebase which is the amoebicide Reserved only for situations where metronidazole can’t be used , given SC or IM , usually given together with luminal amebicides

GI upset, acute hemolysis in G6PD deficiency, nephrotoxicity, hypersensitivity, hematotoxicity, kernicterus

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may also be used in helminthic infections

Recommended at CD4 count < 200, given daily, PO or IV

ii. Pentamidine

Unknown MOA but may involve inhibition of glycolysis or interference with NA metabolism of Protozoans and Fungi ; For prophylaxis and treatment of pneumocystosis and trypanosomiasis

iii. Pyrimethamine-sulfadiazine

gastric irritation, glossitis, neurologic symptoms (headache, insomnia, tremors, seizures), Sequential blockade of dihydropteroate synthase hematotoxicity (megaloblastic anemia, (sulfadiazine) and dihydrofolate reductase (pyrimethamine) thrombocytopenia), pseudomembranous colitis ; DOC for prophylaxis and treatment of toxoplasmosis (clindamycin)

Administered by nasal spray/aerosol, given once a month if used for prophylaxis, IV or IM for 21 days if for Tx of active disease an alternative drug for Toxoplasmosis is Clindamycin ,give daily for 3-4 weeks if for Tx of active toxoplasmosis , if for Toxoplasma encephalitis, give for at least 6 weeks

iv. Atovaquone

Atovaquone disrupts mitochondrial electron transport ; For mild to moderate PCP, as chemoprophylaxis for abdominal pain, nausea, vomiting, diarrhea, Chloroquine resistant malaria (with Proguanil) fever, increased liver enzymes

has increased absorption in the presence of food, PO

i. Pentamidine

Unknown MOA but may involve inhibition of glycolysis or interference with NA metabolism of Protozoans and Fungi ; For hemolymphatic stage of T. gambiense and T. rhodiense, For prophylaxis and treatment of pneumocystosis

do not use for latter stages because it does not cross the BBB, also used for Kala-azar and PCP

ii. Suramin

Polyanionic compound, Unknown MOA ; DOC for early hemolymphatic stages of African sleeping sickness, Alternative to Ivermectin in onchocerciasis

respiratory stimulation followed by depression, hypotension, hypoglycaemia, anemia, neutropenia, hepatitis, pancreatitis, inhalant route has minimal SE fatigue, nausea, vomiting, seizures, shock fever, rash, headache, paresthesia, neuropathies, renal abnormalities (proteinuria), chronic diarrhea, haemolytic anemia and agranulocytosis

iii. Eflornithine

Suicide inhibitor of ornithine decarboxylase ; DOC for advanced west African sleeping sickness

diarrhea, vomiting, anemia, thrombocytopenia, leukopenia, seizures

D. Drugs for Trypanosomiasis

iv. Melarsoprol

v. Nifurtimox

respiratory stimulation followed by depression, hypotension, hypoglycaemia, anemia, neutropenia, hepatitis, pancreatitis, inhalant route has minimal SE

Organic arsenical, inhibits enzyme sulfhydryl (-SH) groups in trypanosomes ; DOC for African sleeping sickness GI irritation, reactive encephalopathy Nitrofurazone derivative, Inhibits trypanothione reductase which is unique to the parasite ; DOC for Chagas disease / American Sleeping sickness (Trypanosoma cruzi), alternative for African sleeping sickness, also for nausea, vomiting, fever, rash, restlessness, mucocutaneous leishmaniasis insomnia, neuropathies, seizures

Drugs for Leishmaniasis

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Do not cross blood brain barrier , Used in combination with melarsoprol Crosses blood brain barrier, PO, IV Crosses BBB, administered parenterally because it causes GI upset

Does not cross BBB

GI symptoms, fever, rash, arthralgia, healdache, myalgia, sterile abscesses, cardiotoxicity

IV ; alternative for leishmaniasis are as follows: Pentamidine or Miltefosine (for visceral leishmaniasis), Fluconazole or Metronidazole (for cutaneous leishmaniasis) and Amphotericin B (for mucocutaneous leishmaniasis)

A. Mebendazole

Selectively inhibits microtubule synthesis and glucose uptake in nematodes, ovicidal ; Whipworm infections (drug of choice), Also a primary drug (together with albendazole) for ascariasis, pinworm, Trichinosis, Visceral larval migrans GI irritation, agranulocytosis, alopecia, Elevated (backup) liver enzymes

Greatly affected by enzyme inducers and inhibitors ; Contraindicated in pregnancy, Use cautiously in patients with Cirrhosis and children <2y.o.

B. Albendazole

primary drug for ascariasis, ancylostomiasis, trichuriasis ; safety in pregnant and children is not yet Inhibits microtubule assembly, larvicidal and ovicidal ; DOC established ; Improved penetration for Ascariasis, Hookworm, Pinworm, Hydatid disease ; Also (> Praziquantel) of the subarachnoid used for Whipworm infections, Cutaneous & Visceral Larva space in Neurocysticersosis migrans, Cysticercosis (larval stages of T. solium), reversible leukopenia, alopecia, elevation of liver Should not be given to patients with Angiostrongylus cantonensis, Capillaria philippinensis function tests, bone marrow suppression Cirrhosis

C. Diethylcarbamazine

Immobilizes microfilariae by an unknown mechanism —> inc susceptibility to host defense mechanism ; DOC for filariasis and eye worm disease (Loa-Loa)

headache, malaise, weakness, anorexia, filarial fever (fever, rashes, ocular damage, joint and muscle pain, lymphangitis)

D. Ivermectin

Intensifies GABA-mediated neurotransmission in nematodes —> immobilizes parasites —> removal by reticuloendothelial system ; Used for Strongyloidiasis (drug of choice), Onchocerciasis, Cutaneous larva migrans, Filariasis (back up)

Antidote for Mazzoti reaction: antihistamine and NSAIDs ; CI in Mazzotti reaction (fever, headache, dizziness, pregnancy, children 5 y.o. and Avoid rashes, pruritus, tachycardia, hypotension, pain in concomitant use with other drugs muscles and joints and lymph glands), corneal that enhance GABA activity opacities (Barbituraates, BZDs etc)

E. Pyrantel pamoate

Stimulates nicotinic receptors at NMJ of nematodes —> depolarization-induced paralysis, Causes release of ACh and inhibition of Cholinesterase, Kills adult worms not eggs ; DOC for pinworm, may be used also for Hookworm, GI distress headache, weakness, dizziness, Trichostrongylus and Ascaris infections insomia, rash, fever,

vi. Sodium Stibogluconate Anthelmintics

Pentavalent antimony, Inhibits glycolysis or effects on NA metabolism ; DOC for Leishmaniasis

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May cause mazzotti reaction when used for onchocerciasis

Contraindicated in patients with hepatic dysfunction (may cause an increase in LFT) ; No study on pregnant and children <2y.o.

F. Thiabendazole

Structural congener of Mebendazole, same MOA as Mebendazole, Selectively inhibits microtubule synthesis and glucose uptake in nematodes, Inhibits fumarate reductase. Ovicidal, has anti-inflammatory and immunosuppressive action in the host ; Used for Trichinosis (drug of choice), Strongyloidiasis (backup)

G. Praziquantel

Increases membrane permeability to calcium —> contraction of trematode and cestode muscle —> muscle paralysis, vacualization and death ; DOC for trematodes (schistosoma, paragonimus, clonorchis, opistorchis, Fasciolopsis, Heterophyes) and cestodes (taenia, diphyllobothrium, Hymenopelsis) together with Niclosamide ; for infection by small and large intestinal flukes ; alternative to Albendazole in Cysticerci

H. Niclosamide

Uncouples oxidative phosphorylation or by activating ATPases, scoleces and segments are killed but NOT Ova ; alternative drug to Praziquantel for cestode infection (Taenia, Diphyllobotrium), not effective in cystecercosis (use Albendazole or Praziquantel instead) or Hydatid disease (use Albendazole), effective in the Tx of infections from small and large intestinal flukes

I. Piperazine

GABA agonist —> paralyze ascaris —> expelled by normal peristalsis , block ACh at the myoneural junction --> expulsion via normal peristalsis ; As alternative for ascariasis

GI upset

Contraindicated in pregnancy, impaired renal or hepatic function or with a history of epilepsy or chronic neurologic disease

J. Bithionol

Unknown MOA ; co-DOC (with Triclabendazole) for Tx of Fascioliasis (sheep liver fluke), as alternative for paragonimiasis

Nausea,vomiting, diarrhea, abdominal cramps, phototoxicity, rash

do not use in Px <8y.o.

K. Metrifonate

an organophosphate prodrug —> Dichlorvos (AchE inhibitor) -> muscle contraction —> paralysis ; Active vs Schistosoma haemoatobium

Excess cholinergic stimulation (DUMBBELSS)

CI in pregnancy

Gastrointestinal irritation, Headache, Dizziness, Drowsiness, Leukopenia, Hematuria, Hypersensitivity reactions (SJS), Hepatotoxicity (intrahepatic cholestasis, liver failure), Reactions caused by dying parasites

CI in renal and liver disease and in pregnancy

headache, dizziness, nausea, malaise, Inc ICP, seizure (neurocystecercosis) ; CI in pregnancy

Used with steroid when treating neurocysticercosis to dec swelling , contraindicated in ocular cysticercosis (may cause irreparable eye damage) ; May be used as an adjunct to Albendazole in Hydatid disease

GI distress, headache, rash, fever

Avoid ethanol consumption for 48 hours upon drug consumption ; Safety in children <2y.o. and pregnanct not yet established

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L. Oxamniquine

GI upset, pruritus, eosinophilia, urticaria, pulmonary infiltrates, fever, orange-red discoloration of urine ; CI in pregnancy and seizure disorder, proteinuria, microscopic hematuria,

effective solely in Schistosoma mansion (intestinal bilharziasis) - on male immature forms and adult schistosomal forms ; MOA is unknown

Px is not allowed to drive within 24hrs after intake of Oxamniquine

Cancer Chemotherapy

all are Cell-cycle non-specific ; Universal MOA: form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 of guanine leading to cross-linking of bases, abnormal base pairing and DNA A. Alkylating agents strand breakage Forms DNA cross-links, resulting in inhibition of DNA synthesis and function, Cell-cycle nonspecific, i. Nitrogen Mustards: Mechlorethamine has additional MOA: converts to a Cyclophosphamide, Chlorambucil, reactive cytotoxic product ; For non-hodgkin’s lymphoma, Mechlorethamine breast cancer, ovarian cancer, neuroblastoma, CLL Forms DNA cross-links, resulting in inhibition of DNA synthesis and function, Cell-cycle nonspecific ; component of regimen For testicular cancer, ovarian cancer, bladder ii. Platinum Analogs: Cisplatin, cancer and lung cancer ; Oxaliplatin is used also for Carboplatin, oxaliplatin advanced colon CA iii. Alkyl sulfonate: Busulfan

Forms DNA cross-links, resulting in inhibition of DNA synthesis and function, Cell-cycle nonspecific ; For CML

pulmonary fibrosis, adrenal insufficiency, skin pigmentation

v. Others: Procarbazine, Dacarbazine

Forms DNA cross-links, resulting in inhibition of DNA synthesis and function, Cell-cycle nonspecific ; For brain tumors, melanoma, skin cancer a reactive agent which forms hydrogen peroxide, which generates free radicals that cause DNA strand scission, cell cycle non-specific ; component of reigned For Hodgkin’s lymphoma, non-hodgkin’s lymphoma, brain tumors

B. Antimetabolites

all are cell-cycle specific , they also have immunosuppressant action

iv. Nirtosoureas: Carmustine, lomustine

Resistance is due to increased DNA repair, decreased drug permeability and production of trapping agents such as thiols bone marrow suppression, hemorrhagic cystitis, Rescue therapy is MESNA and hepatotoxicity, alopecia, SIADH, pulmonary hydration; metabolite is acrolein toxicity, cardiac dysfunction ; Mechorethamine SE which is important for include marked vesicant action, sterility, Cyclophosphamide’s anti-cancer myelosuppresion, alopecia effect and also its toxicity IV, Rescue therapy is Amifostine, decreased nephrotoxicity by giving nausea, vomiting, nephrotoxicity, neurotoxicity mannitol with forced hydration ; (peripheral neuritis), ototoxicity (acoustic nerve Carboplatin is less nephrotoxic but damage), hematotoxicity has more myelosuppression Spares the bone marrow

CNS toxicity (dizziness, ataxia), nausea and Highly lipophilic allowing ease of vomiting, bone marrow suppression, skin flushing passage through BBB into the CNS bone marrow suppression, pulmonary toxicity, hemolysis, disulfiram reaction,skin reactions, peripheral neuropathy, CNS dysfunction

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PO, can pemetrate the CSF, LEUKEMOGENIC, CPY450 inhibitor, Dacarbazine is phototoxic

i. Folate antagonist: Methotrexate

Inhibits dihydrofolate reductase, decreases synthesis of thymidylate, amino acids, purine nucleotides —> interfere with NA and CHON metabolism ; cell cycle specific ; For choriocarcinoma, acute leukemia, non-hodgkin, primary CNS lymphoma, breast cancer, head and neck cancer, bladder cancer ; also for psoriasis, rheumatoid arthritis, bone marrow suppression, pulmonary infiltrates ectopic pregnancy and fibrosis, mucositis, crystalluria, hepatotoxic

ii. Purine antagonist: 6Mercaptopurine, 6-thioguanine, fludarabine, cladribine

are activated by hypoxanthie-guanine phosphoribosyltransferase (HGPRT) to toxic nucleotides which inhibit enzymes in purine metabolism —> Inhibits de novo purine nucleotide synthesis , cell cycle specific ; For bone marrow suppression, hepatic dysfunction acute leukemia (AML, ALL), CML (necrosis, jaundice, cholestasis)

iii. Pyrimidine antagonist: 5Fluorouracil

iv. Pyrimidine antagonist: Cytarabine (ARA-C)

converted to 5-fluoro-2’-deoxyuridine-5’-monophosphate (5-FdUMP) which Inhibits thymidylate synthase, incorporation inhibits DNA synthesis and function, cell cycle specific ; For bladder cancer, breast cancer, colorectal cancer, anal cancer, head and neck cancer, liver cancer and ovarian cancer, topically for keratoses and superficial basal cell skin cancer bone marrow suppression, GI irritation, alopecia a cytosine arabinoside, activated by kinases to Ara-Cytidine Triphosphate (AraCTP) which Inhibits DNA polymerase —> inhibition of DNA synthesis and repair, inhibits ribonucleotide reductase with reduced formation of dNTPs, GI irritation, bone marrow suppression, cell cycle specific ; For AML, ALL, CML neurotoxicity

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PO, IV, Rescue therapy is Leucovorin (Folinic acid) ; cytotoxic due to formation of polyglutamate derivatives ; resistance is due to decreased drug accumulation, changes in drug sensitivity or activity of DHF reductase and decreased formation of polyglutamates ; clearance is dependent on renal function therefore adequate hydration is important to prevent crystallization into stones 6-MP metabolism inhibited by allopurinol and febuxostat , Resistance is due to decreased activity of HGPRT, increased alkaline phosphatase activity (which inactivates the toxic nucleotide) , undergo significant FPE (by xanthine oxidase) IV, can distribute to CSF, causes “thymineless” death of cells, Resistance is due to decreased activation of 5-FU, increase thymidylate synthase activity and decreased sensitivity of this enzyme ; another metabolite is 5florouridine-5’triphosphate (FUTP) which incorporates into RNA —> interfere with RNA processing and function Most specific for the S-phase of the cell cycle, Resistance is due to decreased uptake and decreased conversion to AraCTP, a cytosine arabinoside

v. Pyrimidine antagonist: Gemcitabine

a deoxycytidine analog, converted to Gemcitabine diphosphate which inhibits ribonucleotide reductase with reduced formation of deoxyribonucleotide triphosphate required for DNA synthesis, Gemcitabine triphosphate is incorporated into DNA causing chain termination, cell cycle specific ; For pancreatic cancer, bladder cancer, non-small bone marrow suppression, neutropenia, cell lung cancer, non-Hodgkins lymphoma pulmonary toxicity

C. Natural Anticancer Drugs

all are cell-cycle specific

Prevents assembly of tubulin dimers into microtubule assembly blocking the formation of mitotic spindles, causes cell arrest at metaphase, cell cycle specific ; For acute leukemias, lymphomas, wilms tumor and neuroblastoma ; Vinblastine For lymphomas, neuroblastomas, testicular i. Vinca alkaloid: Vincristine, carcinoma and Kaposi sarcoma ; Vinorelbine For non-small Vinblastine, Vinorelbine cell lung cancer and breast cancer Induces DNA breakage by inhibiting DNA topoisomerase II, inhibits mitochondrial electron transport, cell cycle specific ; Combination regimen For lung cancer, prostate cancer, ii. Podophyllotoxin: Etoposide, testicular cancer, non-hodgkin’s lymphoma, germ cell and Teniposide gastric cancer Inhibits DNA topoisomerase I which cute and relegates single DNA strands during normal DNA repair, cell cycle iii. Camptothecins: Topotecan, specific; For advanced ovarian cancer (2nd line), small cell Irinotecan lung cancer, Irinotecan For metastatic colorectal cancer Interferes with mitotic spindle synthesis by preventing microtubule disassembly into tubulin monomers, cell cycle specific ; For solid tumors - advanced breast and ovarian cancer, lung cancer, gastroesophageal cancer, prostate iv. Taxanes: Paclitaxel, Docetaxel cancer, bladder cancer, head and neck cancer

a deoxycytidine analog

Neurotixicity (areflexia, peripheral neuritis, paralytic ileus)

IV, highly distributed except in CSF, Acts primarily in M phase of cancer cell cycle, Resistance is due to increased efflux of drugs via membrane drug transporter

bone marrow suppression, alopecia, GI distress

PO, high Vd ; dose adjustment in renal patients ; Act on the Late S and early G2 phase

bone marrow suppression, diarrhea

Irinotecan can be used for metastatic colorectal cancer

Paclitaxel (neutropenia, thrombocytopenia, peripheral neuropathy, hypersensitivity), Docetaxel (neurotoxicity, bone marrow suppression)

Act on M phase

D. Antitumor antibiotics

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ii. Bleomycin

Intercalates between base pairs, inhibits topoisomerase II, generates free radicals, blocks synthesis of RNA and DNA causing DNA strand scission, causes membrane disruption, cell cycle non-specific ; Doxorubicin For Hodgkins and NonHodgkins lumphoma, myelomas, sarcomas, breast cancer, endometrial cancer, lung cancer, ovarian cancer and thyroid cancer ; Daunorubicin For acute leukemias Idarubicin For AML, Epirubicin For breast cancer and gastroesophageal ; Mitoxantrine For acute myeloid leukemias, Non-Hodgkins lymphoma, breast and gastroesophageal cancer Generated free radicals which bind to DNA and causes DNA strand breaks leading to inhibition of DNA synthesis, intercalates with DNA, cell cycle specific ; Component of regimens in Hodgkins lymphoma and testicular cancer, lymphomas and squamous cell cancer, head and neck cancer, skin cancer

iii. Actinomycin D

Binds to double stranded DNA, inhibits DNA-dependent RNA synthesis, cell cycle non-specific ; For melanoma, wilm’s tumor, choriocarcinoma, Kaposi sarcoma

iv. Mitomycin C

Metabolized into an alkylating agent that cross-links DNA ; In combination regimens for adenocarcinoma of the cervix, severe myelosuppression, toxic the heart, liver, stomach, pancreas and lungs lungs and kidneys

IV, used for hypoxic tumor cells

Tyrosine kinase inhibitor of the protein product of bcr-abl oncogene in CML ; For CML, GIST

diarrhea, myalgia, fluid retention, CHF

Resistance is due to mutation is bcrabl gene

nausea, vomiting, chills, fever, headache, cardiotoxicity (CHF)

None

i. Anthracycline: Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Mitoxantrone

alopecia, nausea, vomiting, Cardiotoxicity (dilated Rescue therapy is Dexrazoxane and cardiomyopathy, CHF) liposomal formulation of the drug

pneumonitis, pulmonary fibrosis, alopecia, mucocutaneous reactions, hypersensitivity reactions

IV, inactivated by tissue aminopeptidases, Most specific for the G2 phase of cell cycle, a glycopeptide

bone marrow suppression, skin reactions, GI irritation

None

E. Miscellaneous Anticancer Drugs i. TK inhibitor: Imatinib, Dasatinib, Nilotinib

ii. Growth Factor Receptor Inhibitor a. Her-2-neu inhibitor: Trastuzumab

recognizes a surface protein in breast CA cells that overexpress Her-2-neu receptors for epidermal growth factor

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EGFR (Epidermal Growth Factor Receptor) regulate signaling involved in cellular proliferation, invasion and metastasis and angiogenesis, it also inhibits cytotoxic activity of some anti-cancer and radiation treatment, Gefitinib and Erlotinib are capable of inhibiting EGFR’s Tyrosine Kinase domain ; Cetuximab (+ Irinotecan and Oxalipatin) For metastatic colon cancer and Head and Neck cancer ; Panitumumab For refractory colorectal cancer ; b. EGFR inhibitor: Cetuximab, Gefitinib and Erlotinib as second-line agents for non-small Panitumumab, Gefitinib, Erlotinib cell lung cancer VEGF (Vascular Endothelial Growth Factor) has a role in angiogenesis required for metastasis, Inhibits binding of VEGF to VEGFR leading to inhibition of VEGF signalling, inhibits tumor vascular permeability but enhances tumor blood flow and drug delivery ; Sorefenib Sunitinib and Pazopanib inhibits multiple receptor Tyrosine Kinase c. VEGF Inhibitor: Bevacizumab, including those associated to VEGF ; For metastatic Sorafenib, Sunitinib, Pazopanib colorectal cancer, breast cancer, diabetic retinopathy Binds to a surface protein in NHL cells, induces complement-mediated lysis, direct cytotoxicity and induction of apoptosis ; For Non-Hodgkin’s lymphoma and iv. Rituximab other lymphomas

folliculitis, diffuse hair loss, dry skin, paronychia

Erlotinib can also be used for advanced pancreatic cancer

hypertension, arterial thrombosis, impaired wound healing, proteinuria, GI perforation

may also be used in non-small cell lung CA and renal CA

hypersensitivity reaction, bone marrow suppression

None

alopecia, myalgia, depression, thyroid dysfunction, hearing loss, bone marrow suppression

None

v. Interferon alpha

Endogenous glycoproteins with antineoplastic, immunosuppressive and antiviral actions ; For hairy cell leukemia, early CML, T-cell lymphoma

vi. Asparaginase

Depletes serum asparagine ; For ALL, T-cell auxotrophic CA (leukemia and lymphomas) that require asparagine for acute pancreatitis, bleeding, severe growth hypersensitivity reaction

None

vii. All-Trans retinoic acid

Allows DNA transcription and differentiation of immature leukemic promyelocytes into mature granulocytes ; For acute promyelocytic leukemia

Only vitamin that can cure cancer, treat retinoic acid syndrome with dexamethasone

viii. Protease Inhibitor: Bortezomib

retinoic acid syndrome (dyspnea, fever, weight gain, peripheral edema)

a reversible inhibitor of 26s proteasome in mammalian cell ; For multiple myeloma peripheral neuropathy, thrombocytoppenia

F. Hormonal Anticancer Agents

i. Prednisone

Suppresses inflammation and immune response, may trigger apoptosis and work on nondividing cancer cells ; For adrenal suppression, growth inhibition, muscle CLL, Hodgkin’s lymphoma, leukemia, lymphoma wasting, osteoporosis, salt retention

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see entry

Estrogen antagonist actions in breasts tissue and CNS, estrogen agonist effects in uterus, liver and bone ; For hormone-responsive breast cancer, Toremifene For ii. SERM: Tamoxifen, Toremifene advanced breast cancer

hot flushes, thromboembolism, endometrial hyperplasia, endometrial cancer

Prevents osteoporosis and decrease risk of atherosclerosis

gynecomastia, hot flushes, impotence

GnRH analogs (leuprolide) must be co-administered to prevent acute flare-up of prostate cancer

iii. Androgen antagonist: Flutamide

Androgen antagonist ; For prostate cancer

iv. GnRH analog: Leuprolide, Goserelin Nafarelin

Increased LH, FSH secretion with intermittent hot flushes, sweats, headache, osteoporosis, administration, reduced LH and FSH secretion with gynecomastia, gynecomastia, testicular atrophy, prolonged continuous administration ; For prostate cancer impotence, bone pain

see entry

v. Aromatase inhibitor: Anastrazole, Letrozole

Reduces estrogen synthesis by inhibiting aromatase; For advanced breast cancer

Effective againsts breast cancer that have become resistant to tamoxifen

nausea, diarrhea, hot flushes, bone and back pain, dyspnea, peripheral edema

Drugs Used in the Treatment of Gastrointestinal Diseases [Divided into 2 classes: agents that reduce intragastric acidity and agents that promote mucosal defense

A. Antacids: Magnesium-Aluminum Hydroxide, Calcium carbonate, Neutralize stomach acid by reacting with protons in the Sodium bicarbonate lumen ; For peptic ulcer disease, Gastroesophagal reflux

Impairs absorption of tetracyclines, flouroquinolones,itraconazole and iron --> should not be given within 2 hours with these drugs ; When used regularly in large doses needed to significantly raise the stomach pH, antacids, decrease recurrence rate Sodium bicarbonate: Belching, metabolic of peptic ulcers ; Aluminum and alkalosis. Calcium carbonate: hypercalcemia, Magnesium are always given renal insufficiency, metabolic alkalosis (milk-alkali together to cancel out each other's syndrome) exc for Aluminum Magnesium adverse effects ; Avoid in renally Hydroxide impaired patients ; DOA: 1-2 hours

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B. H2 receptor antagonist: Competitive pharmacologic block of H2 receptors ; For Cimetidine, Ranitidine, Famotidine, peptic ulcer disease, Zollinger-Ellison syndrome, Nizatidine Gastroesophagal reflux, dyspepsia

C. Proton Pump Inhibitor: Omeprazole, Lansopraole, Rabeprazole, Pantoprazole, Esomeprazole D. Mucosal Protective Agent:

i. Sucralfate

ii. Bismuth Salicylate

Irreversible blockade of H/K ATPase in active gastric parietal cells, Long lasting reduction of meal stimulated and nocturnal acid secretion ; For Peptic ulcer disease(DOC), Zollinger-Ellison syndrome, Gastroesophageal reflux, dyspepsia polymerizes in acidic environmet —> polymers bind to injured tissue and forms a protective covering over ulcer bed, Accelerates healing of peptic ulcers and reduces recurrence rate ; For Peptic ulcer disease forms a protective coating on ulcerated tissue, stimulates mucosal protective mechanisms, direct antimicrobial effects and sequestration of enterotoxins ; For Peptic ulcer disease, Dyspepsia, Infectious diarrhea

Gynecomastia (cimetidine only), Diarrhea, headache, fatigue, Myalgias, constipation, Nosocomial pneumonia, Mental status changes, Bradycardia, Hypotension, Blood dyscrasias

Cimetidine is a potent inhibitor of CYP450. Highly effective in suppressing nocturnal acid secretion but only modest effect on mealstimulated secretion ; avoid in renally and hepatically (severe) impaired patients ; are highly selective and does not affect H1 and H3 receptors, may also reduce seceretion of pepsin ; DOA: 6-10hrs ; Reduces acid secretion by 60-70%

Diarrhea, headache, abdominal pain, Malabsorption syndrome (Vit B12, Ca, Fe, Zn, Digoxin, Ketoconazole), Infections (respiratory, enteric), Hypergastrinemia, Atrophic gastritis

usually enetric coated, t1/2 is 1-2hrs but DOA of is around 24hrs, needs 3-4 days treatment to achieve full effectiveness ; decreases bioavailability drugs that require acidity for GI absorption ; when used for PUD together with 2 antibiotics, achieve 90% cure ; Reduces acid secretion by 90-98% ; should be taken on an empty stomach since food decreases its bioavailability by 50%

constipation, dizziness, flatulence, dry mouth

Highly insoluble, requiring frequent dosing (QID) ; chemically: Aluminum Sucrose Sulfate

Black stools, darkening of tongue, Encephalopathy (Atraxia, headaches, confusion, seizures)

Reduces stool frequency and liquidity in infectious diarrhea

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PGE1 analog, Activates EP receptors, causes increased HCO3 and mucus secretion and inhibits acid secretion in the stomach, causes uterine contraction ; For Peptic ulcer disease, Prevention of NSAID-induced gastric mucosal Abdominal pain, Diarrhea, Uterine cramping, injury, Abortifacient Miscarriage

see entry, decreases ulcer in NSAIDs induced ulceration

Metoclopramide and domperidone block D2 receptors, Erythromycin stimulates motilin receptor, Increases gastric emptying and intestinal motility ; As Antiemetic for post operative/chemotherapy vomiting, Diabetic gastroparesis (drug of choice), Neostigmine for acute large bowel Parkinsonism, Extrapyramidal effects, distention Hyperprolactinemia

Domperidone does not cross the BBB (less toxic) ; Increases LES pressure (helpful in GERD)

i. Bulk-forming: Psyllium, Methylcellulose, Polycarbophil

Indigestible, hydrophilic colloids that absorb water, forming a bulky emollient gel that distends the colon and promotes peristasis ; For constipation

None

ii. Stool-softener: Docusate, Glycerine, Mineral oil iii. Osmotic: Lactulose, Magnesium oxide, Magnesium hydroxide, Sorbitol, Magnesium citrate, Sodium phosphate, Polyethylene Glycol

Soften stool material, Permitting water and lipids to penetrate the stool ; For constipation Soluble but nonabsorbable compound that result in increased stool liquidity due to an obligate increase in fecal fluid ; For Constipation, Hepatic encephalopathy (lactulose), Preparation for endoscopy (polyethylene glycol)

iv. Stimulant: Bisacodyl, Aloe, Senna, Cascara, Castor oil

Unknown. Directly stimulate enteric nervous system and colonic electrolyte and fluid secretion Lubiprostone is a Chloride channel activator which stimulates Cl secretion into the intestines leading to increased fecal fluid content, Methylnaltrexone and Alvimopan are Opioid receptor antagonist that block intestinal mu receptors, but not the CNS

iii. Misoprostol E. Prokinetics

i. Metoclopramide, Domperidone, Erythromycin, Neostigmine F. Laxatives

v. Miscellaneous: Lubiprostone, Methylnaltrexone, Alvimopan

G. Anti-diarrheals: Diphenoxylate, Loperamide, Kaolin+Pectin, Colloidal Bismuth

Diarrhea

Diarrhea, Aspiration,(Lipid pneumonitis), Malaabsorption of fat-soluble vitamins (A, D, E, K) None Diarrhea, Flatus, Abominal cramps, Electrolyte abnormalities (hyperphosphatemia, hypocalcemia, hypernatremia, hypokalemia, hypermagnesemia)

None

Diarrhea

can cause melanosis coli

mild nausea, stomach pain, mild diarrhoea, bloating, headache

NONE Do not use in children less than 4 years of age (increased chance of Activates opioid receptors in enteric nervous system. Slows causing paralytic ileus), Reverse motility with negligible CNS effects, Kaolin (+pectin) ileus by administering Betanechol. absorbs bacterial toxin and fluid leading to decreased stool Drowsiness, Nausea, Paralytic ileus, interfere with Direct m-agonist, Kaolin is hydrated liquidity ; for Diarrhea (nonspecific, noninfectious) absorption of other drugs Magnesium Aluminum Silicate

82

H. Drugs for IBS i. laxatives, antidiarrheals and low-dose TCA

see entry

see entry

see entry

ii. Anticholinergics: Dicylomine, Hyoscyamine

see entry ; antispasmodic for abdominal pain, for IBS with prominent diarrhoea

see entry

see entry

iii. 5HT3 antagonist: Alosteron

see entry ; For IBS with severe diarrhoea

severe constipation, ischemic colitis

see entry

iv. Lubiprostone

see entry ; activate type2 chloride channels in small intestines ; For IBS with predominant constipation

see entry

see entry

Blocks chemoreceptor trigger zone and enteric nervous system 5-HT3 receptors ; For Vomiting (Post chemothereaphy, postoperative)

Headache, Dizziness, Constipation, QRS and QT prolongation (Dolasetron only)

see entry

ii. Aprepitant

antagonist of the Neurokinin-1 receptor in the areas postrema that is activated by substance P and other tackykinins ; For post-chemotherapy nausea and vomiting

fatigue, dizziness, diarrhea

an enzyme inhibitor

iii. Scopoloamine

see entry ; For motion sickness emesis

see entry

see entry

Unknown. Probably inhibits production of eicosanoid inflammatory mediators (PG and LT) and interfering with cytokines ; For Inflammatory bowel disease (mild to moderate)

Gastrointestinal upset,Headaches, Arthralgias, Myalgias, Bone marrow suppression, Malaise, Hypersensitivity reactions ( severe)

Not useful for treating active flare ups of disease

see entry ; Natalizumab is a Mab that blocks intergrins in circulating leukocytes, restricted to severe refractory Crohn’s disease

multifocal leukoencephalopathy

see entry

I. Anti-emetics i. Ondansetron, Granisetron, Dolasetron, Palonosetron

J. Drugs for IBD i. Aminosalicylates: Mesalamine, Balsalazine, Olsalazine, Sulfasalazine ii. Other agents: Antibiotics, Immunosuppressibe antimetabolites (Azathioprine, 6MP, Methotrexate), anti-TNF (Infliximab), Natalizumab K. Miscellaneous Agents

For pancreatic enzyme replacement, improve digestion of fats proteins and carbohydrates ; For pancreatic i. Pancreatic lipase: Pancreatin or insufficiency due to Cystic Fibrosis, pancreatitis and Pancrealipase pancreatectomy hyperuricemia a bile acid derivative that decreases cholesterol content of bile by decreasing hepatic cholesterol secretion and other ii. Drugs that inhibit formation of effects on hepatocyte canalicular membrane ; For gallstone headache, dizziness, mild stomach pain, Gallstones: Ursodiol in patients refusing or not eligible for surgery rhinorrhea, sore throat, rash hair loss

83

Taken with every meal

None

Drugs Used For Cough

A. Mucolytics : N-acetylcysteine, Carbocysteine, Ambroxol

decrease sputum activity ; Usually derivatives of cysteine; reduce disulfide bridges that bind glycoproteins to other proteins such as albumin ; Also act as antioxidants & may reduce airway inflammation ; Orally available drugs are well-tolerated; but of little benefit in acute respiratory condition

B. Expectorants: Guiafenesin

Drowsiness, Incomplete or Infrequent Bowel may act as an irritant to gastric vagal receptors, and recruit Movements, Inducing of a Relaxed Easy State, efferent parasympathetic reflexes that cause glandular Stomach Cramps, dizziness or headache, a rash, exocytosis of a less viscous mucus mixture. or. nausea, vomiting, or stomach upset

Are often emetics (ipecac, guaifenesin)

C. Antitussives

Used for dry painful cough of neoplasia or pleural disease ; Irritative cough in inflammation of the respiratory tract (epiglottitis); in hemoptysis

DO NOT suppress in bacterial lung infections, asthma, bronchiectasis (suppurating bronchial inflammation) or chronic bronchitis where antitussives can cause harmful sputum thickening & retention

i. Centrally-acting: Opioid antitussives (codeine, dextromethorphan)

Morphine may be effective but indicated only in intractable cough from bronchial carcinoma ; Dextromethorphan has no addictive Decreases secretions in the bronchioles, thickens potential, no analgesic effect, decreased sensitivity of the medullary/ CNS cough centers sputum & inhibits ciliary activity, reducing produces less constipation and to peripheral stimuli and decreased mucosal secretion clearance of thickened sputum, Constipation inhibition of mucociliary clearance

ii. Centrally-acting: Non-opioid (butamirate citrate)

act through receptors in the brainstem to inhibit cough

Chest tightness, Disagreeable odor, Drowsiness, Fever, Hemoptysis, Increased volume of bronchial secretions, Irritation of tracheal or bronchial available as IV, PO, IM and tract, Nausea, Rhinorrhea, Stomatitis, Vomiting inhalational forms

Somnolence, nausea, vomiting, diarrhea, dizziness and hypotension

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Centrally acting antitussive but is neither chemically or pharmacologically related to opioids

iii. Peripherally-acting: Levodropropizine

Non-opoid drug with a peripheral action by inhibiting the afferent pathways that generate the cough reflex (modulates C-fibre activity)

Nausea, vomiting, heartburn, diarrhea, fatigue, weakness, drowsiness, dizziness, headache, palpitations

85

does not cause side effects such as constipation or respiratory depression which can be produced by opioid antitussives

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137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

s (ipecac, guaifenesin)

169

170