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Basic Pharmacology Book Color
Basic Pharmacology Book Color
2019 Edition
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Table of Contents
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Enzymatic Reactions
P
S
Enzymes E
S + E ⇄ ES ⇄ E + P
V = Vm* [S]
Km + [S]
[S]
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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]
Key Points:
Km has same units as [S] When V = Vm/2
At some point on graph, Km must equal [S] [S] = Km
V = Vm* [S]
Vmax/2
Km + [S]
Km
[S]
Km
[S]
2
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]
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
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
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
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
Dose (mg)
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]
Emax
Emax
A B A B
C Efficacy
Effect E50
Effect
50
Potency
Emax Emax
Receptor Receptor
Agonist Receptor Agonist + Agonist Receptor Agonist +
Competitive Antagonist Max
Effect E50
Effect E50 Effect
Non-Competitive Antagonist
E50
EC50
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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 Agonist
Log [Dose]
100% 100%
Agonist Agonist
Partial
Response
Agonist Total
Response
Binding Response
Partial
Agonist
Response
0% 0%
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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]
ED50 LD50/
TD50
Log [Dose]
Log [Dose]
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Elimination
Zero Order First Order
Plasma Concentration
Plasma Concentration
Drug Elimination
Jason Ryan, MD, MPH
Time Time
Plasma Concentration
5units
Ethanol
5units
Phenytoin
2units
Aspirin
1units
Time
Time
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-
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 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
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Phase II Metabolism 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
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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
1gram 1g/L
Unknown Volume
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
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
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
Half-Lives
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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