Boards & Beyond:
Basic Pharmacology Slides
Color slides for USMLE Step 1 preparation
from the Boards and Beyond Website
Jason Ryan, MD, MPH
2020 Edition
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Table of Contents
Enzymes...................................................................1
Enzyme Inhibitors...............................................4
Dose Response......................................................6
Drug Elimination............................................... 10
Pharmacokinetics............................................. 14
iii
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
6
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]
8
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]
9
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-
11
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
14
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
15
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
16
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
18
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
19