Principles: Pharmacokinetics and Pharmacodynamics Flashcards
(28 cards)
What model of enzyme kinetics is depicted? What shape is the curve?
How does Km relate to the affinity of the enzyme for its substrate?
What is Vmax directly proportional to?
Michaelis-Menten kinetics. A hyperbolic curve.
Km is inversely related to affinity of the enzyme for its substrate.
Vmax is directly proportional to enzyme concentration.
Most reactions follow a hyperbolic curve. If sigmoid-shaped, then usually cooperative kinetics (hemoglobin).
What kind of plot is this?
As the y-intercept of the graph increases, how does Vmax change?
As the x-intercept moves rightward, how does Km change?
Lineweaver-Burk plot
As Y-intercept increases, Vmax decreases.
As x-intercept moves right, Km increases, enzyme affinity decreases.
What feature of an enzyme inhibition plot (shown below) differentiates competitive from noncompetitive inhibitors?
The competitive inhibitor line will cross the uninhibited line (competitively!).
Noncompetitive inhibitors do not.
Do reversibly competitive inhibitors, irreversibly competitive inhibitors or noncompetitive inhibitor…
- Resembles substrate?
- Inhibition overcome by increasing [S]?
- Bind active site?
- Effect Vmax? How?
- Effect Km? How?
- Effect pharmacodynamics? How?
- Competitive inhibiors (both types) resemble substrate. Noncompetitive do not.
- Only reversible inhibitors can be overcome by increasing [S]
- Competitive inhibitors (both types) bind the active site
- Vmax is reduced for irreversible competitive and noncompetitive inhibitors. Vmax is unchanged for reversible competitive inhibitors.
- Km is increased for reversible competitive inhibitors. Other types have no effect.
- Potency is decreased for reversibly competitive inhibitors. Efficacy is reduced for irreversible competitive and noncompetitive inhibitors
What are pharmacokinetics?
The effects of the body on the drug.
ADME: Absorption, Distribution, Metabolism, Excretion.
What are pharmacodynamics?
Effect of the drug on the body.
Includes concepts of receptor binding, drug efficacy, drug potency, and drug toxicity.
What is bioavailability?
Bioavailability (F) = Fraction of administered drug that reaches systemic circulation unchanged.
For an IV drug, F = 100%
Orally: F < 100% due to incomplete absorption and first-pass metabolism.
What is the equation for volume of distribution?
What are compartments of distribution, in order from least to greatest volume?
What types of drugs go into each compartment?
Vd = amount of drug in the body / plasma drug concentration
Compartments:
- Low Vd:Blood (4-8L). Large/charged molecules; plasma protein bound
- Medium Vd: ECF. Small hydrophilic molecules
- High Vd: All tissues including fat. Small lipophilic molecules, especially if bound to tissue proteins.
Vd of plasma protein-bound drugs can be altered by liver and kidney disease (reduce protein binding, increase Vd).
What is half life?
A drug with a half life is undergoing what order elimination?
How many half lives until a drug is at steady state?
Equation for half life?
Half life: Time required for the amount of drug in body to decrease by 1/2 during elimination (or constant infusion).
First order elimination.
A drug infused at a constant rate takes 4-5 half lives to reach steady state.
t(1/2) = (0.693 x Vd)/ CL
CL = clearance.
What is the definition of clearance?
What is its equation?
Clearance: Volume of plasma cleared of drug per unit time.
Clearance impaired with defects in cardiac, hepatic, or renal function.
CL = rate of elimination of drug / plasma drug concentration
OR
CL = Vd x Ke (elimination constant)
What is the formula for loading dose?
Loading dose = (Cp x Vd) / F
where
Cp = Target plasma concentration at steady state
Vd = volume of distribution
F = bioavailability
What is the formula for maintenance dose?
Maintenance dose = (Cp x CL x τ) / F
Where:
Cp = target plasma concentration at steady state
CL = clearance
τ (tau) = Dosage interval if not administered continuously.
F = bioavailability
How does renal or liver disease change maintenance dose and loading dose?
Usually decreases maintenacne dose.
Loading dose usually unchanged.
What determines time to steady state?
t(1/2).
Independent of dose and dosing frequency.
What is zero-order elimination?
What drugs are characterized by their zero-order elimination?
Zero order elimination means that rate of elimination is constant regardless of drug concentration.
Acronym: PEA - pea is round, like the 0 in zero-order.
Phenytoin, Ethanol, and Aspirin (at high/toxic concentrations)
What is first-order elimination?
Rate of elimination is proportional to the drug concentration (constant fraction of drug is excreted per unit time). Cp decreases exponentially with time.
Flow-dependent elimination.
How does drug ionization affect drug elimination?
Ionized species trapped in urine and cleared quickly.
Neutral forms can be reabsorbed.
What are some examples of weak acid drugs?
What can you give to treat an overdose situation?
Examples: Phenobarbital, methotrexate, aspirin.
Trapped in basic environments - give bicarbonate.
RCOOH (lipid soluble) -> RCOO- + H+
What are some examples of weak base drugs?
What can you give in an overdose situation?
Example: Amphetamines.
Trap in an acidic environment with ammonium chloride.
RNH3+ (trapped) <- RNH2 (lipid soluble) + H+
What are some examples of phase I reactions?
How does this relate to geriatrics?
Reduction, oxidation, hydrolysis with cytochrome P450 usually yield slightly polar water-soluble metabolites (often still active).
Geriatric patients lose phase I first.
What are some examples of phase II reactions?
How does this relate to geriatrics?
Conjugation (Glucuronidation, Acetylation, Sulfation). Usually yields very polar inactive metabolites (renally secreted)
Geriatric patients have GAS (phase II).
Slow acetylators have greater side effects from certaind rugs because of reduced rate of metabolism.
The graph below shows two drugs that act at the same receptor.
What pharmacological principle is illustrated? In other words,
Efficacy - the maximal effect a drug can produce.
High efficacy drug classes: Analgesic medications, antibiotics, antihistamines, decongestants.
Partial agonists have less efficacy than full agonists.
The graph below illustrates two drugs that share a target.
What differs between these drugs?
Potency - amount of drug needed for a given effect.
The more potent a drug, the greater its affinity for the target (receptor). Highly potent drugs include chemotherapeutic drugs, antihypertensive drugs, and lipid-lowering (cholesterol) drugs.
How does a competitive antagonist shift a dose/response curve?
Shifts curve to the right (decreases potency) with no change in efficacy.
Can be overcome by increasing concentration of agonist substrate.
Example: Diazepam + flumazenil (competitive antagonist) on GABA receptor.
See graphs on page 242.
