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Enzyme kinetics
- Michaelis-Menten kinetics
 - [S] = concentration of substrate
- V = velocity
- Km is inversely related to the affinity of the enzyme for its substrate
- Vmax is directly proportional to the enzyme concentration
- Most enzymes follow a hyperbolic curve (Michaelis-Menten kinetics); some follow cooperative kinetics (i.e., hemoglobin) have a sigmoid curve
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Lineweaver-Burk plot
- ↑ y-intercept, ↓ Vmax
- The further to the right the x-intercept, the greater the Km and the lower the affinity
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Enzyme inhibition
- Competitive inhibitors cross each other competitively, whereas noncompetitive inhibitors do not
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Competitive inhibitors
- Resemble substrate
- Overcome by ↑ [S]
- Bind active site
- No effect on Vmax
- Increase Km
- Decreases potency (pharmacodynamics)
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Noncompetitive inhibitors
- Does not resemble substrate
- Not overcome by ↑ [S]
- Does not bind active site
- Decreases Vmax
- No change on Km
- Decreases efficacy (pharmacodynamics)
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Pharmacokinetics
factors that influence...
- Bioavailability (F)
- Volume of distribution (Vd)
- Half-life (t1/2)
- Clearance (CL)
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Bioavailability (F)
- Fraction of administered drug that reaches synstemic circulation unchanged
- For IV dose, F = 100%
- Orally: F typically <100% to incomplete absorption and first-pass metabolism
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Volume of distribution (Vd)
- Theoretical fluid volume required to maintain the total absorbed drug amount at the plasma concentration
- Vd of plasma protein-bound drug can be altered by liver and kidney disaese (↓ protein binding, ↑ Vd)
- Vd = (amount of drug in the body)/(plasma drug concentration)
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Vd
blood, ECF, all tissue
- Blood: Vd low (4-8L)
- -Drugs: large/charged molecules; plasma protein bound
- ECF: Vd medium
- -Drugs: small hydrophilic molecules
- All tissues: Vd high
- -Drugs: small lipophilic molecules, especially if bound to tissue protein
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Half-life (t1/2)
- The time required to change the amount of drug in the body by 1/2 during elimination (or constant infusion)
- Property of first-order elimination
- Drug infused at a constant rate takes 4-5 half-lives to reach steady state
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Clearance (CL)
- Relates the rate of elimination to the plasma concentration
- Clearance may be impaired with defects in cardiac, hepatic, or renal function
- CL = (rate of elimination of drug)/(plasma drug concentration)
- (elimination constant)
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Dosage calculation
- Loading dose = Cp × Vd/F
- Maintenance dose = Cp × CL/F
- -In renal or liver disease, maintenance dose ↓ and loading dose is unchanged
- Cp = target plasma concentration
- -Time to steady state depends primarily on t1/2 and is independent of dosing frequency or size
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Zero-order elimination
- -Rate of elimination is constant regardless of Cp
- -Capacity-limited elimination: constant amount of drug eliminated per unit time
- -Cp ↓ linearly with time
- Examples: Phenytoin, Ethanol, and Aspirin (at high or toxic concentrations)
- *PEA (a pea is round, shaped like a "0" in "zero-order"
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First-order elimination
- -Rate of elimination is directly proportional to the drug concentration
- -Flow dependent elimination: constant fraction of drug eliminated per unit time
- -Cp ↓ exponentially with time
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Urine pH and drug elimination
- Ionized species are trapped in urine and cleared quickly
- Neutral forms can be reabosrbed
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Weak acids
- Examples: phenobarbital, methotrexate, aspirin
- Trapped in basic environment
- Treat overdose with bicarbonate
- RCOOH ⇌ RCOO- + H+
- (lipid soluble) ⇌ (lipid soluble)
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Weak bases
- Examples: amphetamines
- Trapped in acidic environments
- Treat overdose with ammonium chloride
- RNH3+ ⇌ RNH2 + H+
- (trapped) ⇌ (lipid soluble)
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Drug metabolism
Phase I, phase II
- Phase I:
- -Reduction, oxidation, hydrolysis with cytochrome P-450 usually yield slightly polar, water-soluble metabolites (often still active)
- -Geriatric patients lose phase I first
- Phase II:
- -Conjugation (Glucuronidation, Acetylation, Sulfation) usually yields very polar, inactive metabolites (renally excreted)
- *Geriatric patients have GAS (phase II)
- -Patients who are slow acetylators have greater side effects from certain drugs because of ↓ rate of metabolism
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Efficacy
- Maximal effect a drug can produce
- High-efficacy drug classes: analgesics, antibiotics, antihistamines, decongestants
- Partial agonists have less efficacy than full agonists
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Potency
- Amount of drug needed for a given effect
- ↑ potency, ↑ affinity for receptor
- High potent drug classes: chemotherapeutics, antihypertensives, antilipid drugs
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Competitive antagonist
- ↓ potency (shifts curve to right)
- no change in efficacy
- Can be overcome by increasing the concentration of agonist substrate
- example: diazepam + flumazenil on GABA receptor
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Noncompetitive antagonist
- ↓ efficacy
- Cannot be overcome by increasing agonist substrate concentration
- Example: NE + phenoxybenzamine on α-receptors
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Partial agonist
- Acts at same site as full agonist, but with reduced maximal effect → ↓ efficacy
- Potency is a different variable and can be ↑ or ↓
- Examples: Morphine (full agonist) and buprenorphine (partial agonist) at opioid μ-receptor
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Therapeutic index
- Measurement of drug safety
- LD50/ED50 = median lethal dose/median effective dose
- TILE: Therapeutic Index = LD50/ED50
- Safer drugs have higher TI values
- Low TI value: digoxin, lithium, theophylline, warfarin
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Therapeutic window
- Measure of clinical drug safety
- Range of minimum effective dose to minimum toxic dose
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