Boards and Beyond:

Basic Pharmacology

A Companion Book to the Boards and Beyond Website

Jason Ryan, MD, MPH

2018 Edition

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 Table of Contents

Enzymes 1 Drug Elimination 10

Enzyme Inhibitors 4 Pharmacokinetics 14
Dose Response 6

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 Enzymatic Reactions

P
S

Enzymes E

Jason Ryan, MD, MPH

S + E ⇄ ES ⇄ E + P

Enzymatic Reactions Michaelis-Menten Kinetics

S + E ⇄ ES ⇄ E + P
V = Reaction velocity
Rate of P formation
Vmax

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

[S]

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Michaelis-Menten Kinetics Michaelis-Menten Kinetics
At Vmax, enzymes saturated (doing all they can)
Eventually, reach Vmax Only way to increase Vmax is to add enzyme

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Enzyme Kinetics Michaelis-Menten Kinetics
Vmax V = Reaction velocity
Rate of P formation
More Enzyme
Vmax Vmax

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

[S] [S]

Michaelis Constant (Km) Michaelis Constant (Km)

V = Vm * [S] V = Vm * [S] = Vm * [S] = Vm

Km + [S] [S] + [S] 2 [S] 2

Key Points:
Km has same units as [S] When V = Vm/2
At some point on graph, Km must equal [S] [S] = Km

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Michaelis Constant (Km) Michaelis Constant (Km)
Small Km Vm reached at low concentration [S]
Large Km Vm reached at high concentration [S]
Vmax

V = Vm* [S] Vmax

Km + [S]

V = Vm* [S]
Vmax/2
Km + [S]

Km
[S]
Km
[S]

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Michaelis Constant (Km) Key Points
Small Km Substrate binds easily at low [S] Km is characteristic of each substrate/enzyme
High affinity substrate for enzyme Vm depends on amount of enzyme present
Large Km Low affinity substrate for enzyme Can determine Vm/Km from
Michaelis Menten plot V vs. [S]
Vmax Lineweaver Burk plot 1/V vs. 1/[S]

V = Vm* [S]
Vmax/2
Km + [S]

Km
[S]

Lineweaver Burk Plot Lineweaver Burk Plot

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

Vm

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

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 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 S

E E E I

Competitive Non-competitive
Competes for same site as S Binds different site S
S + E ⇄ ES ⇄ E + P Lots of S will overcome this Changes S binding site
S cannot overcome this
Effect similar to no enzyme

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Competitive Inhibitor Non-competitive Inhibitor
Same Vm Lower Vm
Higher Km Same Km
max

Normal Inhibitor
With inhibitor
Vmax Vmax

Vmax/2

Km Km Km
[S]
[S]

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Competitive Inhibitor Competitive Inhibitor
Inhibitor

1 Normal 1 Normal

-1
Km
Vm Vm

-1 -1
Km Km

Non-competitive Inhibitor Inhibitors

Inhibitor

Normal
Similar to S Different from S
Bind active site Bind different site
Overcome by more S Cannot be overcome
Vm unchanged Vm decreased
Km higher Km unchanged

Vm

-1
Km

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 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 Morphine
Drug B produces same effect with 50mg
Drug A is 10x more potent than drug B
More potent not necessarily superior Analgesia
Low potency only bad if dose is so high it’s hard to
Aspirin
administer

Dose (mg)

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Dose-Response Dose-Response
For many drugs we can measure response as we Graded or quantal responses
increase the dose Graded response
Can plot dose (x-axis) versus response (y-axis) 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
↓EC50 = ↑Potency
Emax Emax

Effect E50
Effect E50

10 20 30 40 50 60 1 10 100
Dose
Log [Dose]

Graded Dose Response Curve Graded Dose Response Curve

EC50/Potency EMax/Efficacy
A >B>C Emax B>A
Emax
Emax

A B A B
C Efficacy
Effect E50
Effect
50

Potency

Log [Dose] Log [Dose]

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Competitive Antagonists Non-competitive Antagonists

Emax Emax
Receptor Receptor
Agonist Receptor Agonist + Agonist Receptor Agonist +
Competitive Antagonist Max
Effect E50
Effect E50 Effect
Non-Competitive Antagonist

E50

EC50

Log [Dose] Log [Dose]

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 Spare Receptors Spare Receptors
Agonist +
“Spare” receptors: Activate when others blocked Low Dose
Non-Competitive
Maximal response can occur even in setting of blocked Antagonist
Emax
receptors Agonist +
Experimentally, spare receptors demonstrated by High Dose
using irreversible antagonists Non-Competitive
Effect Antagonist
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 Effect similar to agonist

plus NC antagonist
Produce less than full effect
Emax
Full
Agonist Max
Effect Effect

Partial Agonist

Log [Dose]

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Partial Agonist Partial Agonist
Single Dose Agonist With Increasing Partial Agonist Single Dose Agonist With Increasing Partial Agonist

100% 100%
Agonist Agonist
Partial
Response
Agonist Total
Response
Binding Response

Partial
Agonist
Response
0% 0%

Log [Dose Partial Agonist] Log [Dose Partial Agonist]

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Partial Agonists Quantal Dose Response Curve
Pindolol/Acebutolol
Old anti-hypertensives
Activate beta receptors but to less degree that norepinephrine 100% Therapeutic Response
“Intrinsic sympathomimetic activity” (IMA)
Lower BP in hypertensive patients
Can cause angina through vasoconstriction
50%
Buprenorphine
Partial mu-opioid agonist
Treatment of opioid dependence
Clomiphene
Partial agonist of estrogen receptors hypothalamus ED50
Blocks (-) feedback; ↑LH/FSH
Infertility/PCOS
Log [Dose]

Quantal Dose Response Curve Therapeutic Index

Measurement of drug safety

100% Therapeutic Response Adverse Response

Therapeutic Index = LD50

50% ED50

ED50 LD50/
TD50

Log [Dose]

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Therapeutic Window Low TI Drugs
Often require measurement of levels to avoid toxicity
Warfarin
100%
Digoxin
Lithium
50%
Theophylline
Therapeutic
Window
Minimum Minimum
Effective Toxic
Dose Dose
LD50

Log [Dose]

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 Elimination
Zero Order First Order

Plasma Concentration

Plasma Concentration
Drug Elimination
Jason Ryan, MD, MPH

Time Time

Zero Order Elimination First Order Elimination

Constant rate of elimination per time Rate varies with concentration of drug
No dependence/variation with [drug] Percent (%) change with time is constant (half life)
No constant half life Rate = 5 * [Drug]0 Most drugs 1st order elimination
Rate = C * [Drug]1
5units
4units
Plasma Concentration

Plasma Concentration

5units
Ethanol
5units
Phenytoin
2units
Aspirin
1units

Time
Time

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Zero Order Elimination First Order Elimination

Time (hr) Amount (g) Change (g) % Time (hr) Amount (g) Change (g) %
0 20 100 0 10 100
1 15 5 75% 1 5 5 50
2 10 5 50% 2 2.5 2.5 25
3 5 5 25% 3 1.25 1.25 12.5

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Special Types of Elimination Flow-dependent Elimination
Flow-dependent Some drugs metabolized so quickly that blood flow to
Capacity-dependent organ (usually liver) determines elimination
These drugs are “high extraction” drugs
Example: Morphine
Patients with heart failure will have ↓ clearance

Capacity-dependent
Urine pH
Elimination
Many drugs are weak acids or weak bases
Rate of elimination = Vmax · C / (Km + C)
“Saturatable” High C leads to Vmax rate
When this happens zero order elimination occurs
Three classic drugs:
Ethanol Weak Acid: HA <-> A- + H+
Phenytoin
Aspirin
Weak Base: BOH <-> B+ + OH-

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Urine pH Urine pH
Drugs filtered by glomerulus Urine pH affects drug excretion
Ionized form gets “trapped” in urine after filtration Weak acids: Alkalinize urine to excrete more drug
Cannot diffuse back into circulation 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
Phenobarbital, aspirin Liver “biotransforms” drug
Sodium bicarbonate to alkalinize urine in overdose
Usually converts lipophilic drugs to
Weak base drugs
Amphetamines, quinidine, or phencyclidine Creates water-soluble metabolites for excretion
Ammonia chloride (NH4Cl) to acidify urine in overdose
Reactions classified as Phase I or Phase II
Historical: Efficacy not established, toxicity severe acidosis

Phase I Metabolism Cytochrome P450

Reduction, oxidation, or hydrolysis reactions
Often creates active metabolites Metabolize many drugs (Phase I)
Two key facts to know:
Phase I metabolism can slow in elderly patients
Phase I includes cytochrome P450 system

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Cytochrome P450 P450 Drugs
Some Examples

Inhibitors are more dangerous

Can cause drug levels to rise
Chronic EtOH Isoniazid
Cyclosporine, some macrolides, azole antifungals
Rifampin Erythromycin
Luckily, many P450 metabolized drugs rarely used
Theophylline, Cisapride, Terfenadine Phenobarbital Cimetidine
Some clinically relevant possibilities Carbamazepine Azoles
Griseofulvin Grapefruit juice
Warfarin Phenytoin Ritonavir (HIV)

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Phase II Metabolism Slow Acetylators

Glucuronidation, acetylation, sulfation 50% Caucasians and African-Americans

Makes very polar inactive metabolites Acetylation is main route isoniazid (INH) metabolism
No documented effect on adverse events
Also important sulfasalazine (anti-inflammatory)

Can cause drug-induced lupus

Both drugs metabolized by acetylation
More likely among slow acetylators

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 Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
All impact drug’s ability to achieve desired result
Pharmacokinetics
Jason Ryan, MD, MPH

Drug Administration Bioavailability (F)

Enteral Fraction (%) of drug that reaches systemic circulation
Uses the GI tract unchanged
Oral, sublingual, rectal Suppose 100mg drug given orally
Parenteral 50mg absorbed unchanged
Does not use GI tract
Bioavailability = 50%
IV, IM, SQ
Other
Inhalation, intranasal, intrathecal
Topical

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Bioavailability (F) First Pass Metabolism

• F = 100% Some drugs rapidly metabolized on 1st pass

Entire dose available to body
Decreases amount that reaches circulation
Oral dosing Can be reduced in liver disease patients
• F < 100%
Incomplete absorption
First pass metabolism

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 Bioavailability (F) Volume of Distribution (Vd)
Bioavailability = AUC oral x 100 Theoretical volume a drug occupies
IV
AUC IV Determined by injecting known dose and measuring
concentration
Plasma
Concentration

Oral

Time

Determining Fluid Volume Volume of Distribution (Vd)

Vd = Total Amount In Body

1gram 1g/L
1Liter Fluid
Vd = 10g = 20L
0.5g/L

1gram 1g/L
Unknown Volume

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Volume of Distribution (Vd) Volume of Distribution (Vd)
Useful for determining dosages
Vd = Amount Injected Example:
C C0 Effective [drug]=10mg/L
Vd for drug = 10L
Plasma • Dose = 10mg/L * 10L = 100mg
Concentration

Extrapolate
C0

Time

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Fluid Compartments Volume of Distribution (Vd)
Drugs restricted to vascular compartment: ↓Vd
3L Large, charged molecules
Plasma
Often protein bound
12L
Warfarin: Vd = 9.8L
Total Body Extracellular
Water 9L Drugs that accumulate in tissues: ↑↑Vd
36L 24L Interstitial
Small, lipophilic molecules
Intracellular
Often uneven distribution in body
Chloroquine: Vd = 13000L

Vd ↑ when drug distributes to

more fluid compartments
(blood, ECF, tissues)

Protein Binding Hypoalbuminemia

Many drugs bind to plasma proteins (usually albumin) Liver disease
This may hold them in the vascular space Nephrotic syndrome
Lowers Vd Less plasma protein binding
More unbound drug moves to peripheral
compartments
↑Vd
Required dose of drug may change

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Clearance Clearance
Volume of blood “cleared” of drug Mostly occurs via liver or kidneys
Volume of blood that contained amount of drug
Number in liters/min (volume flow) Biotransformation of drug to metabolites
Excretion of drug into bile
Renal clearance
Excretion of drug into urine
Cx = Excretion Rate

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Clearance Clearance
In liver or kidney disease clearance may fall Can also calculate from Vd
Drug concentration may rise Need elimination constant (Ke)
Toxicity may occur Implications:
Dose may need to be decreased Higher Vd, higher clearance
Supposed 10g/hour removed from body

Cx = Vd * Ke

Clearance Clearance
Cl (l/min) = Dose (g)
AUC (g*min/l)
Cx = Vd * Ke

Plasma Concentration
Area Under Curve (AUC)
Ke = Cx
Vd

Time

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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)

= 0.7 * Vd
CL

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Steady State Calculating Doses
Dose administered = amount drug eliminated Maintenance dose
Takes 4-5 half lives to reach steady state 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
In kidney/liver disease, maintenance dose may fall
Dose

Less eliminated per unit time

Less needs to be replaced with each dose
Loading dose will be unchanged

Half-Lives

Maintenance Dose Maintenance Dose

Dose Rate = Elimination Rate * If Bioavailability is <100%, need to increase dose to
account for this
= [Drug] * Clearance

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

= 25 g/min

Target Dose = 25g/min

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

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Loading Dose Steady State
Target concentration * Vd Dose administered = amount drug eliminated
Suppose want 5g/l Takes 4-5 half lives to reach steady state
Vd = 10L
Need 5 * 10 = 50grams loading dose
Divide by F if bioavailability <100%
Dose

Loading Dose = [Drug] * Vd

Half-Lives

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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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