Pharm General USMLE Flashcards
1st order kinetics
- most drugs follow 1st order kinetics
- exponential
- a constant fraction of drug present is eliminated per unit of time
- rate of process is proportional to drug concentration
Half-time (t1/2) is independent of drug concentration
0 order kinetics
- Encountered only occasionally
- constant amount of the drug is eliminated per unit time, i.e., rate is independent of drug concentration
Half-time (t1/2) increases with dose and is dependent on drug concentration
Describe the cartesian and plot for first-order kinetics
inversely parabolic
Describe the semi-log plot for first-order kinetics.
linear sloped down
Describe the cartesian and semi-log plots for zero-order kinetics
linear sloped down and parabolic
Describe the cartesian and semi-log plots for mass-law kinetics.
This is a mixed-order system. e.g. Renal tubular secretion of drugs for which there is a maximum tubular transport capacity. If plasma level is too high (i.e., exceeds Tm), you get zero-order until level falls, and then you get first-order kinetics.
Rate of process is a function of drug concentration, the concentration of the enzymes and their affinity
The half-time, t 1/2, can be estimated as follows
t 1/2 = 0.693/Ke
• Where Ke is the elimination rate constant
Describe the time course of plasma drug levels following IV bolus
Two phases:
1) Distribution phase
2) Elimination or equilibrium phase
b. The exponential (first-order) processes of absorption or elimination are essentially complete after 4-5 half-times.
Describe the time course of plasma drug levels following oral administration
sharp increase then inversely parabolic decent (1st order) – semilog plot shows flat slope
Describe the time course of plasma drug levels following IV infusion
During IV infusion, the drug concentration continues to rise until the rate of elimination equals to the constant (zero order) rate of infusion, then a plateau level of drug concentration is maintained.
Describe the factors that affect the time course of plasma levels following IV infusion.
1) Plateau state:
• Attained after 4-5 half-times.
• Time to plateau is independant of dose.
2) Plateau concentration:
• Proportional to dose.
• Proportional to half-time.
• Inversely proportional to dosage interval (time in b/n dosing)
Define bioavailability
Defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route. For an IV dose of a drug, the bioavailability is 100%.
Measured by comparing plasma levels (AUC) of a drug after a particular route of administration (e.g., oral) with the achieved by IV injection. AUC reflects the extent of drug absorption.
What are the factors that influence drug bioavailability.
1) First-pass hepatic metabolism, e.g., propranolol
2) Solubility of drug: Drugs that are too hydrophilic or too lipophilic are poorly absorbed. For a drug to be readily absorbed, it must be largely lipophilic yet have some solubility in aqueous solution.
3) Chemical instability in gastric pH.
4) Nature of drug formulation, e.g., particle size, salt form, crystal polymorphism and the presence of inactive ingredients can influence the ease of dissolution and alter the rate of absorption.
• Distinguish between maintenance and loading dose regimen.
Comparison of maintenance versus loading dose regimen:
1) Loading dose: • Immediate therapy. • May cause initial drug toxicity. 2) Maintenance dose: • Eliminates risk of toxic effects. • Permits accurate adjustment of dosage during drug accumulation.
t 1/2 ( half life)=
For first-order kinetics:
*t 1/2 = 0.693/Ke
Ke =rate constant of elimination
Ke =
For first-order kinetics:
*Ke =0.693/t1/2
Vd (volume of distribution =
- Vd = amount of drug in body/plasma concentration
Vd is large when the drug is highly concentrated in tissues; Vd is small when the drug is extensively bound to plasma protein.
Cl (clearance) =
Clearance (Cl): Total body clearance of the drug is defined as the volume of blood or plasma effectively cleared of drug by elimination(metabolism and excretion) per unit time.
It is the sum of clearance from all organs of elimination. As elimination of most drugs is carried out largely by the kidney and the liver, then
- Cl = Cl renal + Cl hepatic
IV infusion rate=
IV Infusion: The infusion rate equals elimination rate at STEADY STATE.
- Infusion rate= CP X Cl(amt/time)(amt/vol)(vol/time)
intermittent injection dose =
*Dose = C pav X Cl X dosage interval
where C pav = average plasma concentration at the plateau
oral maintenance and loading doses during a dosage regimen.
Loading D.= Css x Vd / F; M Dose= Css x Cl x interval / F
describe the classical receptor theory (“occupancy theory”) of Clark.
“The intensity of drug effect (response) is proportional to the fraction of receptors occupied by the drug.
The law of mass action predicts that the rate of formation of Drug-Receptor complex (DR) is proportional to the concentration of Drug (D)and Receptor (R )
describe the concept of “spare receptors”
Modifications of the classical theory:
Spare receptors: Receptors are said to be “spare” for a given pharmacologic response when the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of all available receptors.
affinity efficacy
The propensity of a drug to bind with a receptor. k1/k2 is a measure of affinity; 1/KD (k dissociation)
intrinsic activity
The ability of a drug to initiate a response after binding to the receptors; –EFFICACY; K3
agonist
A drug capable of combining with receptors to initiate drug actions; it possesses affinity and intrinsic activity.
AFFINITY & INTRINSIC ACTIVITY E.G., MORPHINE; (K3=1)
antagonist
Something opposing or resisting the action of another
AFFINITY NO INTRINSIC ACT (K3=0)
e.g., NALOXONE
partial agonist
Affinity with WEAK intrinsic activity (K3<1)- E.G., NALORPHINE;
ALLOSTERIC MODULATORS:
BINDS TO A DIFFERENT SITE FROM THE AGONIST: INCREASED OR DECREASED AGONIST REPONSE
Can be allosteric activator or antagonist e.g., bdz(BENZODIAZAPINE I.E. VALUM ,increased GABA EFFECT
describe receptor-effector coupling
The binding of a drug with its receptor results in a conformational change (e.g. alteration of molecular configuration or charge distribution.) that triggers a chain of events leading to a pharmacological response.
describe different types of transmembrane signaling
1) INTRACELLULAR RECEPTORS for lipid-soluble agents (e.g. corticosteroids; sex hormones; thyroid hormone).
2) TRANSMEMBRANE RECEPTORS bound to a protein tyrosine kinase or other enzymes: (e.g. insulin, epidermal growth factors).
3) CYTOKINE RECEPTORS bound to a separate tyrosine kinase (JAK): Activation of STAT transcription molecules ( e.g. interferons, interleukins)
4) Receptors located on MEMBRANE ION CHANNELS: Ligand-gated ion channels—e.g. acetylcholine, GABA, excitatory AA.
5) Cell-surface receptors coupled to an effector enzyme by G proteins: Altered intracellular concentrations of “second messengers”. e.g. cyclic adenosine-3’, 5’-monophosphate (cAMP)Ca++/phosphoinositide
describe the structure-activity relationship (SAR) of drugs
Affinity and intrinsic activity of a drug are intimately related to its chemical structure (“receptor selectivity”).
Relatively minor modification in the molecule may result in major changes in pharmacological properties; determined by stereospecificity, specific functional groups, etc. Ex: Adrenergic agonist/antagonists
