Phase A Flashcards
Michaelis-Menten kinetics
Km= [S] at (1/2)Vmax
Km is inversely related to the affinity of the enzyme for its substrate. Decreased Km means an increased enzyme affinity Vmax is directly proportional to the enzyme concentration, it is when all enzyme is saturated. Most enzymatic reactions follow a hyperbolic curve, but those that follow cooperative kinetics (hemoglobin) have a sigmoidal curve
Competitive Inhibition
Competitive inhibitors increase Km (lowering affinity), but do not affect Vmax, meaning they can be overcome by increased substrate.
Competitive inhibitors often resemble substrates, and bind to the active site.
Decreases potency
Noncompetitive Inhibition
Does not resemble substrate, does not bind active site, and cannot be overcome by increased substrate.
They decrease effective Vmax, while leaving Km unchanged.
They decrease pharmacological efficacy
Michaelis-Menten Equation
V= (Vmax [S])
(Km + [S])
Lineweaver-Burke Equation
(1/V) = Km / (Vmax [S]) + (1 / Vmax)
Bioavailabilty (F)
Fraction of administered drug that reaches systemic ciculation unchanged. For an IV dose, F = 100%.
Orally: F typically <100% due to incomplete absorption and first-pass metabolism
Volume of Distribution
Theoretical fluid volume required to maintain the total absorbed drug amount at the plasma concentration.
Vd of plasma protein -bound drugs can be altered by liver and kidney disease (decreased protein binding, increased Vd)
Vd = Dose / concentration
Examples of Volume of Distribution
Low Vd means mostly in blood, includes large/charged molecules; plasma protein bound
Medium Vd is in ECF, includes small hydrophilic molecules.
High Vd is in all tissues; small lipophilic molecules, especially if bound to tissue protein
Half Life
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.
A drug infused at a constant rate takes 4-5 half lives to reach steady state.
t(1/2) = (0.7 x Vd) / CL
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 concentration of drug) = Vd x Ke (elimination constant)
Loading Dose
Cp = target plasma concentration; = Cp x Vd / (F)
In renal or liver disease, maintenance dose decreases and loading dose is unchanged
Maintenance dose
Cp = target plasma concentration = Cp x CL / (F)
Time to steady state depends primarily on t(1/2) and is independent of dosing frequency or size
Zero-order Elimination
Rate of elimination is constant regardless of Cp (constant amount of drug eliminated per unit time).
Cp decreases linearly with time.
Examples of drugs: PEA: Penytoin, ethanol, aspirin (at high dose)
First Order Elimination
Rate of elimination is directly proportional to the drug concentration (constant fraction of the drug eliminated per unit time).
Cp decreases exponentially with time.
First Order vs. Zero Order
Zero order: 5 units per hour
First order: half of the dose per hour
Urine pH and drug elimination
Ionized species are trapped in urine and cleared quickly.
Neutral forms can be reabsorbed
Weak Base Elimination
Trapped in acidic environments.
Treat overdose with ammonium chloride.
Example: amphetamines RNH3+ (trapped) <==> RNH2 + H+ (lipid soluble)
Weak Acid Elimination
Trapped in basic environments.
Treat overdose with bicarbonate
Examples: methotrexate, aspirin, phenobarbitol
RCOOH (lipid solube) <==> RCOO- (trapped) + H+
Drug Metabolism: 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
Drug Metabolism: Phase II
Conjugation (GAS: Glucuronidation, Acetylation, Sulfation) usually yields very polar, inactive metabolites that are renally excreted.
Geriatric patients have GAS, patients who are slow acetylators have greater side effects from certain drugs because of decreased rate of metabolism
Efficacy
Maximal effect a drug can produce.
High-efficacy drug classes are analgesic medications, antibiotics, antihistamines, and decongestants.
Partial agonists have less efficacy than full agonists
Potency
Amount of drug needed for a given effect.
Increases potency means increases affinity for a receptor.
Highly potent drug classes include chemotherapeutics, antihypertensives, and antilipid drugs
Receptor Binding: Agonist plus competitive antagonist
Increases the amount of dose needed for same maximum effect.
Does not interfere with the potential maximal effect.
Decreases potency, no change in efficacy
Receptor Binding. Agonist plus noncompetitive antagonist
Decreases the maximal effect of the agonist.
Does not shift the maximal dosage of the agonist needed for maximum effect, just lowers the maximum effect.
Decreased efficacy.
Cannot be overcome with increased substrate.
Therapeutic Index
Measurement of drug safety.
LD(50) / ED(50) = median lethal dose divided by median effective dose.
TILE: Therapeutic Index = L / E
The safer the drug, the higher the TI
Therapeutic Window
Measure of clinical drug safety.
Range of minimum effective dose to minimum toxic dose
Formulas to Know
Dosing Rate (steady state) = rate of elimination
Dosing Rate = clearance x target concentration
Dosing Rate (maintenance dosing rate) = CL x TC
Half Life Formulas
Conc at time t C(t) = C(i) e(-kt), where t is the time elapsed since initial dosage K= 0.7 / t(1/2)
