Basicpharmacologyslidebook2020-online-1.pdf

Boards & Beyond: Basic Pharmacology Slides

Color slides for USMLE Step 1 preparation from the Boards and Beyond Website Jason Ryan, MD, MPH 2020 Edition

Boards & Beyond provides a virtual medical school curriculm used by students around the globe to supplement their education and prepare for board exams such as USMLE Step 1.

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Table of Contents

Enzymes...................................................................1 Enzyme Inhibitors...............................................4 Dose Response......................................................6

Drug Elimination............................................... 10 Pharmacokinetics............................................. 14

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iv

Enzymes

Enzymatic Reactions P

S

Enzymes

E

Jason Ryan, MD, MPH

S + E ⇄ ES ⇄ E + P

Michaelis-Menten Kinetics

Enzymatic Reactions

S + E ⇄ ES ⇄ E + P

V = Reaction velocity Rate of P formation

Vmax

V = Vm* [S] Km + [S]

V [S]

Image courtesy of Wikipedia/U+003F

Michaelis-Menten Kinetics

Michaelis-Menten Kinetics

• Adding S → More P formation → Faster V • Eventually, reach Vmax

• At Vmax, enzymes saturated (doing all they can) • Only way to increase Vmax is to add enzyme

1

Enzyme Kinetics Vmax

Vmax

Michaelis-Menten Kinetics

More Enzyme

V = Reaction velocity Rate of P formation

Vmax

V = Vm* [S] Km + [S]

V [S]

[S]

Michaelis Constant (Km)

Michaelis Constant (Km)

V = Vm * [S] Km + [S]

V = Vm * [S] = Vm * [S] = Vm [S] + [S] 2 [S] 2

Key Points: 1. Km has same units as [S] 2. At some point on graph, Km must equal [S]

When V = Vm/2 [S] = Km

Michaelis Constant (Km) Vmax

Michaelis Constant (Km)

• Small Km → Vm reached at low concentration [S] • Large Km → Vm reached at high concentration [S]

V = Vm* [S] Km + [S]

Vmax/2 Km

Vmax

V = Vm* [S] Km + [S]

Vmax/2

[S]

Km

2

[S]

Key Points

Michaelis Constant (Km)

• Small Km → Substrate binds easily at low [S]

• Km is characteristic of each substrate/enzyme • Vm depends on amount of enzyme present • Can determine Vm/Km from

• High affinity substrate for enzyme

• Large Km → Low affinity substrate for enzyme Vmax

• Michaelis Menten plot V vs. [S] • Lineweaver Burk plot 1/V vs. 1/[S]

V = Vm* [S] Km + [S]

Vmax/2

Km

[S]

Lineweaver Burk Plot

Lineweaver Burk Plot

V = Vm* [S] Km + [S]

1 V

1 = Km + [S] = Km + [S] V Vm [S] Vm [S] Vm[S]

Km Vm 1 Vm

1= C *1 + 1 V [S] Vm

-1 Km

3

1 S

Enzyme Inhibitors

Enzyme Inhibitors

• Many drugs work through enzyme inhibition • Two types of inhibitors: • Competitive • Non-competitive

Enzyme Inhibitors Jason Ryan, MD, MPH

Enzymatic Reactions

Enzyme Inhibitors

P

S

S I

E

E

Competitive Competes for same site as S Lots of S will overcome this

S + E ⇄ ES ⇄ E + P

Competitive Inhibitor Normal

Vmax

I

Non-competitive Binds different site S Changes S binding site S cannot overcome this Effect similar to no enzyme

Lower Vm Same Km

Vmax

Inhibitor

With inhibitor

Vmax

Vmax/2

Vmax/2 Km

E

Non-competitive Inhibitor

Same Vm Higher Km

Vmax/2 Km

P

S

Km

[S]

4

[S]

Competitive Inhibitor 1 V

1 Vm

Competitive Inhibitor 1 V

Normal

-1 Km

1 S

-1 Km

1 V

-1 Km

1 Vm

1 Vm

1 Vm

Inhibitors

Competitive

Normal

• • • • •

1 S

5

Similar to S Bind active site Overcome by more S Vm unchanged Km higher

Normal

1 S

-1 Km

Non-competitive Inhibitor Inhibitor

Inhibitor

Non-competitive • • • • •

Different from S Bind different site Cannot be overcome Vm decreased Km unchanged

Dose Response Efficacy

• Maximal effect a drug can produce

• Morphine is more efficacious than aspirin for pain control

Dose-Response Jason Ryan, MD, MPH

Potency

Pain Control

• Amount of drug needed for given effect • Drug A produces effect with 5mg • Drug B produces same effect with 50mg • Drug A is 10x more potent than drug B

• More potent not necessarily superior • Low potency only bad if dose is so high it’s hard to administer

Morphine

Analgesia

Aspirin

Dose (mg)

Dose-Response

Dose-Response

• For many drugs we can measure response as we increase the dose • Can plot dose (x-axis) versus response (y-axis)

• Graded or quantal responses • Graded response

• Example: Blood pressure • Can measure “graded” effect with different dosages

• Quantal response

• Drug produces therapeutic effect: Yes/No • Example: Number of patients achieving SBP<140mmHg • Can measure “quantal” effect by % patients responding to dose

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Graded Dose Response Curve

Graded Dose Response Curve

Emax

Effect

Effect

E50

10

20

30

40

Dose

50

1

Effect

E50

B

10

EMax/Efficacy B>A

Emax

C

A

Effect E 50

Log [Dose]

Effect

E50

B

Efficacy

Log [Dose]

Competitive Antagonists Receptor Agonist

Log [Dose]

Emax

Potency

Emax

100

Graded Dose Response Curve

EC50/Potency A >B>C

A

E50

60

Graded Dose Response Curve Emax

↓EC50 = ↑Potency

Emax

Non-competitive Antagonists Emax

Receptor Agonist + Competitive Antagonist

Effect

E50

Receptor Agonist

E50

EC50

Log [Dose]

7

Max Effect

Receptor Agonist + Non-Competitive Antagonist

Log [Dose]

Spare Receptors

Spare Receptors

• “Spare” receptors: Activate when others blocked • Maximal response can occur even in setting of blocked receptors • Experimentally, spare receptors demonstrated by using irreversible antagonists

Agonist + Low Dose Non-Competitive Antagonist

Emax

Agonist + High Dose Non-Competitive Antagonist

Effect

• Prevents binding of agonist to portion of receptors • High concentrations of agonist still produce max response

Log [Dose]

Partial Agonists

Partial Agonists

Agonist or Partial Agonist Given Alone

• Similar structure to agonists • Produce less than full effect

Emax

Effect

Full Agonist

Source: Basic and Clinical Pharmacology, Katzung

Effect similar to agonist plus NC antagonist

Max Effect Partial Agonist

Log [Dose]

Partial Agonist

Partial Agonist

Single Dose Agonist With Increasing Partial Agonist 100%

% Binding

0%

Agonist

Single Dose Agonist With Increasing Partial Agonist 100%

Partial Agonist

Response 0%

Log [Dose Partial Agonist]

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Agonist Response

Partial Agonist Response

Total Response

Log [Dose Partial Agonist]

Partial Agonists

Quantal Dose Response Curve

• Pindolol/Acebutolol • • • • •

Old anti-hypertensives Activate beta receptors but to less degree that norepinephrine “Intrinsic sympathomimetic activity” (IMA) Lower BP in hypertensive patients Can cause angina through vasoconstriction

100%

% Patients

50%

• Buprenorphine

• Partial mu-opioid agonist • Treatment of opioid dependence

• Clomiphene

• Partial agonist of estrogen receptors hypothalamus • Blocks (-) feedback; ↑LH/FSH • Infertility/PCOS

ED50

Quantal Dose Response Curve 100%

% Patients

Therapeutic Response

• Measurement of drug safety

Adverse Response

Therapeutic Index = LD50 ED50

LD50/ TD50

Log [Dose]

Therapeutic Window

Low TI Drugs • • • • •

100%

% Patients 50%

Minimum Effective Dose

Log [Dose]

Therapeutic Index

50%

ED50

Therapeutic Response

Therapeutic Window LD50

Minimum Toxic Dose

Log [Dose]

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Often require measurement of levels to avoid toxicity Warfarin Digoxin Lithium Theophylline

Drug Elimination

Elimination

First Order

Drug Elimination Jason Ryan, MD, MPH

Time

Zero Order Elimination

5units

2units

Time

Amount (g)

0

20

1 2 3

15 10 5

1units

Time

Zero Order Elimination Time (hr)

Rate = C * [Drug]1

4units

Plasma Concentration

Plasma Concentration

• Rate varies with concentration of drug • Percent (%) change with time is constant (half life) • Most drugs 1st order elimination

5units

5units

Time

First Order Elimination

• Constant rate of elimination per time • No dependence/variation with [drug] • No constant half life Rate = 5 * [Drug]0

• Ethanol • Phenytoin • Aspirin

Plasma Concentration

Plasma Concentration

Zero Order

Change (g) 5 5 5

First Order Elimination

% 100

75%

Time (hr)

Amount (g)

0

10

1

50%

2

25%

3

10

5

2.5

1.25

Change (g) 5

2.5

1.25

% 100 50 25

12.5

Special Types of Elimination

Flow-dependent Elimination

Capacity-dependent Elimination

Urine pH

• Flow-dependent • Capacity-dependent

• • • • •

• Some drugs metabolized so quickly that blood flow to organ (usually liver) determines elimination • These drugs are “high extraction” drugs • Example: Morphine • Patients with heart failure will have ↓ clearance

• Many drugs are weak acids or weak bases

Follows Michaelis-Menten kinetics Rate of elimination = Vmax · C / (Km + C) “Saturatable” → High C leads to Vmax rate When this happens zero order elimination occurs Three classic drugs:

Weak Acid: HA <-> A- + H+

• Ethanol • Phenytoin • Aspirin

Weak Base: BOH <-> B+ + OH-

Urine pH

Urine pH

• Drugs filtered by glomerulus • Ionized form gets “trapped” in urine after filtration • Cannot diffuse back into circulation

• Urine pH affects drug excretion • Weak acids: Alkalinize urine to excrete more drug • Weak bases: Acidify urine to excrete more drug

Weak Acid: HA <-> A- + H+

Weak Acid: HA <-> A- + H+

Weak Base: BOH <-> B+ + OH-

Weak Base: BOH <-> B+ + OH-

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Examples

Drug Metabolism

• Weak acid drugs

• Many, many liver reactions that metabolize drugs • Liver “biotransforms” drug • Usually converts lipophilic drugs to hydrophilic products

• Phenobarbital, aspirin • Sodium bicarbonate to alkalinize urine in overdose

• Weak base drugs

• Amphetamines, quinidine, or phencyclidine • Ammonia chloride (NH4Cl) to acidify urine in overdose • Historical: Efficacy not established, toxicity severe acidosis

• Creates water-soluble metabolites for excretion

• Reactions classified as Phase I or Phase II

Phase I Metabolism

Cytochrome P450

• Reduction, oxidation, or hydrolysis reactions • Often creates active metabolites • Two key facts to know:

• • • •

• Phase I metabolism can slow in elderly patients • Phase I includes cytochrome P450 system

Intracellular enzymes Metabolize many drugs (Phase I) If inhibited → drug levels rise If induced → drug levels fall

P450 Drugs

Cytochrome P450

Some Examples

• Inhibitors are more dangerous

Inducers

• Can cause drug levels to rise • Cyclosporine, some macrolides, azole antifungals

• • • • • •

• Luckily, many P450 metabolized drugs rarely used • Theophylline, Cisapride, Terfenadine

• Some clinically relevant possibilities • Some statins + Inhibitor → Rhabdo • Warfarin

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Chronic EtOH Rifampin Phenobarbital Carbamazepine Griseofulvin Phenytoin

• • • • • •

Inhibitors Isoniazid Erythromycin Cimetidine Azoles Grapefruit juice Ritonavir (HIV)

Phase II Metabolism

Slow Acetylators

• Conjugation reactions

• Genetically-mediated ↓ hepatic N-acetyltransferase • 50% Caucasians and African-Americans • Acetylation is main route isoniazid (INH) metabolism

• Glucuronidation, acetylation, sulfation

• Makes very polar inactive metabolites

• No documented effect on adverse events

• Also important sulfasalazine (anti-inflammatory) • Procainamide and hydralazine • Can cause drug-induced lupus • Both drugs metabolized by acetylation • More likely among slow acetylators

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Pharmacokinetics

Pharmacokinetics • • • • •

Pharmacokinetics

Absorption Distribution Metabolism Excretion All impact drug’s ability to achieve desired result

Jason Ryan, MD, MPH

Drug Administration

Bioavailability (F)

• Enteral

• Fraction (%) of drug that reaches systemic circulation unchanged • Suppose 100mg drug given orally • 50mg absorbed unchanged • Bioavailability = 50%

• Uses the GI tract • Oral, sublingual, rectal

• Parenteral

• Does not use GI tract • IV, IM, SQ

• Other

• Inhalation, intranasal, intrathecal • Topical

Bioavailability (F)

First Pass Metabolism • • • •

• Intravenous dosing

• F = 100% • Entire dose available to body

• Oral dosing

• F < 100% • Incomplete absorption • First pass metabolism

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Oral drugs absorbed → liver Some drugs rapidly metabolized on 1st pass Decreases amount that reaches circulation Can be reduced in liver disease patients

Bioavailability (F)

Volume of Distribution (Vd)

• Theoretical volume a drug occupies • Determined by injecting known dose and measuring concentration

Bioavailability = AUC oral x 100

IV

AUC IV

Plasma Concentration

Oral Time

Determining Fluid Volume 1gram

1Liter Fluid

1gram

Unknown Volume

Volume of Distribution (Vd) Vd = Total Amount In Body Plasma Concentration

1g/L

Vd = 10g = 20L 0.5g/L

1g/L

Volume of Distribution (Vd)

• Useful for determining dosages • Example:

Vd = Amount Injected C0

C0

Plasma Concentration

Volume of Distribution (Vd) • Effective [drug]=10mg/L • Vd for drug = 10L • Dose = 10mg/L * 10L = 100mg

Extrapolate C0 Time

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Fluid Compartments 12L Extracellular

Total Body Water 36L

24L Intracellular

Volume of Distribution (Vd) • Drugs restricted to vascular compartment: ↓Vd

3L Plasma

• Large, charged molecules • Often protein bound • Warfarin: Vd = 9.8L

• Drugs that accumulate in tissues: ↑↑Vd

9L Interstitial

• Small, lipophilic molecules • Often uneven distribution in body • Chloroquine: Vd = 13000L

Vd ↑ when drug distributes to more fluid compartments (blood, ECF, tissues)

Protein Binding

Hypoalbuminemia

Clearance

Clearance

• Many drugs bind to plasma proteins (usually albumin) • This may hold them in the vascular space • Lowers Vd

• • • •

Liver disease Nephrotic syndrome Less plasma protein binding More unbound drug → moves to peripheral compartments • ↑Vd • Required dose of drug may change

• Volume of blood “cleared” of drug • Volume of blood that contained amount of drug • Number in liters/min (volume flow)

• Mostly occurs via liver or kidneys • Liver clearance

• Biotransformation of drug to metabolites • Excretion of drug into bile

• Renal clearance

• Excretion of drug into urine

Cx = Excretion Rate Px

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Clearance • • • •

Clearance

• Can also calculate from Vd • Need elimination constant (Ke) • Implications:

In liver or kidney disease clearance may fall Drug concentration may rise Toxicity may occur Dose may need to be decreased

• Higher Vd, higher clearance • Supposed 10g/hour removed from body • Higher Vd → Higher volume holding 10g → Higher clearance

Cx = Vd * Ke

Clearance

Cx = Vd * Ke

Plasma Concentration

Clearance

Ke = Cx Vd

Cl (l/min) = Dose (g)

AUC (g*min/l)

Area Under Curve (AUC)

Time

Half-Life

Half-life

• Time required to change amount of drug in the body by one-half • Usually time for [drug] to fall 50% • Depends on Vd and Clearance (CL)

t1/2 = 0.7 * Vd CL

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Steady State

Calculating Doses

• Dose administered = amount drug eliminated • Takes 4-5 half lives to reach steady state

• Maintenance dose

• Just enough drug to replace what was eliminated

• Loading dose

• Given when time to steady state is very high • Get to steady state more quickly • When t1/2 is very high

25

Dose

20 15

• In kidney/liver disease, maintenance dose may fall

10

• Less eliminated per unit time • Less needs to be replaced with each dose

5 0

0

1

2

3

4

5

6

• Loading dose will be unchanged

7

Half-Lives

Maintenance Dose

Maintenance Dose

• * If Bioavailability is <100%, need to increase dose to account for this

Dose Rate = Elimination Rate = [Drug] * Clearance

Dose Rateoral = Target Dose F

Dose Rate = [5g/l] * 5L/min = 25 g/min

Target Dose = 25g/min Bioavailability = 50% Dose Rate = 25/0.5 = 50g/min

Loading Dose

• Dose administered = amount drug eliminated • Takes 4-5 half lives to reach steady state

Target concentration * Vd Suppose want 5g/l Vd = 10L Need 5 * 10 = 50grams loading dose Divide by F if bioavailability <100%

1.2

1

Dose

• • • • •

Steady State 0.8 0.6 0.4

Loading Dose = [Drug] * Vd F

0.2

0

0

0.2

0.4

0.6

Half-Lives

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0.8

1

1.2

Key Points • • • • •

Volume Distribution = Amt injected / [Drug] Clearance = 0.7 * Vd / t12 4-5 half lives to get to steady state Maintenance dose = [Steady State] * CL / F Loading dose = [Steady State] * Vd / F

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