Flashcards in Pharm General USMLE Deck (81):
1st order kinetics
-most drugs follow 1st order kinetics
-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
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
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)
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
For first-order kinetics:
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.
The propensity of a drug to bind with a receptor. k1/k2 is a measure of affinity; 1/KD (k dissociation)
The ability of a drug to initiate a response after binding to the receptors; --EFFICACY; K3
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)
Something opposing or resisting the action of another
AFFINITY NO INTRINSIC ACT (K3=0)
Affinity with WEAK intrinsic activity (K3<1)- E.G., NALORPHINE;
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
Action: Modulates gene expression in nucleus
Location: cytoplasm or nucleus
Drug Example: Estrogen, corticosteroid, thyroid hormone
Receptor Type: ion channel
Action: opens to permit ion diffusion
Location: cell membrane
Drug Example: Acetycholine on nicotinic acetycholine receptor
Receptor Type:Transmembrane Tyrosine Kinase
Action: phosphorylates cytoplasmic protiens
Location: cell membrane
Drug Example: Insulin
Action: Activates a cytoplasmic protein kinase (STAT)
Location: Cell membrane & cytoplasm
Drug Example: Cytokines
Receptor Type:G-Protein Coupled
Action: Activates a membrane G protein that modulates an enzyme or channel
Location: Cell membrane
Drug Example: Norepinephrine, Acetycholine (on a muscarinic receptor)
in dose response curve
response is proportional to dose
Graded dose-response curve is:
The log dose-effect relationship in 1 PATIENT
ALLOWS YOU TO COMPARE POTENCY OF DIFFERENT DRUGS by COMPARING EC50
Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of its maximal effect; the lower the dose required to produce a given effect, the higher the potency.
Signicance of potency in graded dose-response curve
The maximal effect
Efficacy of a drug may be limited by its propensity to produce a toxic effect.
Signicance of maximal efficacy in graded dose-response curve
Slope reflects the mode of action of a drug AKA-- describes drug binding to its receptors.
AKA-- its COUPLING/SIGNAL MECHANISM
2) Slope has some relationships to margin of safety of drug. i.e., STEEP SLOPES =DRUG IS MORE DANGEROUS, E.G, PHENOBARB HAS STEEPER SLOPE THAN VALIUM
Signicance of slope in graded dose-response curve
differentiate between characteristics of a competitive antagonist (“surmountable”) and an irreversible antagonist (“insurmountable”)
Competitive Antagonism: “Surmountable”
Irreversible Antagonism: “Insurmountable”“noncompetitive”
predict the effect of a competitive antagonist on the dose-response curve of an agonist
predict the effect of an irreversible antagonist on the dose-response curve of an agonist.
when two drugs compete for the same receptor site
Physiological antagonism (FUNCTIONAL ANTAGONISM)
when two drugs act on different receptors to cause opposite effects on the same physiologic function
E.G., EPI IN ANAPHALAXIS (BRONCHIODIALATION VS BRONCHIOONSTRICTION)
when one drug antagonizes the actions of a second drug by binding to and inactivating the second drug.
E.G., EDTA VS LEAD, HG ANTACIDES VS TETRACYCLINES
Differences in the magnitude of response among individuals given the same dose of drug.
Quantal dose-effect curve:
Select an end point or a specified effect and determine the number of individuals at each dose who show the specified effect (“all-or-none”). Plot as a cumulative frequency distribution.
median effective dose (ED50)
The dose of a drug required to produce a specified intensity of effect in 50% of individuals.
Median lethal dose (LD50):
The dose of a drug required to produce death in 50% of individuals.
LD50/ED50 or TD50/ED50
(50% lethal dose over 50% median effective dose OR 50% toxic dose over 50% median effective dose)
large TI means drug is safer (AKA more desireable) small TI less safe (less desireable)
An antagonist may increase the number of receptors in a critical cell or tissue by preventing down-regulation caused by an endogenous agonist. When the antagonist is abruptly withdrawn, one can get an exaggerated response or supersensitivity to an endogenous agonist.--E.G., PROPRANOLOL
Supersensitivity may result from “up-regulation” or synthesis of additional receptors.
Exposure to an agonist ligand may result in “down-regulation”---an actual decrease in number of receptors. This process may contribute to “pharmacodynamic tolerance”. --E.G., MORPHINE
If a drug produces its usual effect at a very LOW dosage
If unusually LARGE doses of the drug are required to produce the effect.
Hyporeactivity that develops as a result of continued EXPOSURE to the drug.
Hyporeactivity that develops RAPIDLY after administration of only a few doses of a drug-- “ ACUTE TOLERANCE”
refers to a reversible and decrease of responsiveness in the presence of the agonist: Multiple mechanisms include phosphorylation of the receptor, destruction of the receptor,or its relocation within the cell.
an actual decrease in number of receptors.
synthesis of additional receptors.
The relationship between the doses of a drug required to produce undesired and desired effects
The therapeutic index (TI) of a drug reflects its selectivity. A LARGE TI is desirable
risk-to benefit ratio
1)ALL drugs carry some degree of risk, esp. when given in high enough dose.
2) Some drugs carry a very HIGH degree of risk:
Some drugs have very steep dose-response curves or a low therapeutic index. (e.g., Warfarin)
3) Potential benefits must be considered when using drugs, esp. drugs with high toxicity.
explain the MECHANISM responsible for the SHORT duration of ANESTHETIC action of THIOPENTAL(PENTOTHAL) following IV injection.
Termination of Drug Action occurs through REDISTRIBUTION
REDISTRIBUTION happens when a highly LIPID SOLUBLE DRUG(e.g. thiopental (Pentothal) that acts on the BRAIN or CARDIOVASCULAR system is administered rapidly by IV injection.
Due to HIGH BLOOD FLOW to the brain, the drug reaches its maximum concentration in brain within a minute after IV injection. Then, the plasma concentrations falls as thiopental diffuses out of the brain and into other tissues, such as muscle.
• Thus, onset of anesthesia is rapid, but so is its termination.
identify the four important patterns of biotransformation.
1) active drug TO inactive metabolite
(2) active drug TO active metabolite
(3) inactive drug TO active metabolite (prodrug)
(4) active drug TO toxic metabolite (e.g., acetamenophen)
identify the two possible changes in drug characteristics that biotransformation of a drug accomplishes.
1) increases water solubility by making MORE POLAR metabolites, less lipid-soluble.
(2)INACTIVATES drug-but NOT always.
Prodrugs are pharmacologically inactive compounds that are converted to active metabolites in the body.
Define “Phase I” reactions.
Usually convert the parent drug to a MORE POLAR metabolite by introducing or unmasking a polar functional group (-OH, -SH, -NH2).
Define “ Phase II” reactions.
involves CONJUGATIONS which is Chemical combination of drug or metabolite with an endogenous substance (e.g. GLUCORONIC ACID, SULFATE, GLYCENE, ACETATE) to yield drug conjugates.
• In general, conjugates are POLAR molecules, EASILY EXCRETED ; usually pharmacologically INACTIVE.
biotransformation involving microsomal oxidation reactions are catalyzed by ________ which includes _______ and requires and _________.
mixed function oxidase systems (MFOs)/cytochrome P450/NADPH/ molecular O2
identify those biotransformation reactions that are carried out by the hepatic mixed function oxidase system (Cytochrome P450 Monooxygenase System).
aromatic and aliphatic hydroxylation, N -, O-, and S-dealkylation, N-oxidation, S-oxidation, deamination and desulfuration
Identify types of drugs that are capable of conjugation with glucuronic acid.
phenols, alcohols, carboxylic acids and amines
identify the major drug conjugation reactions that occur in humans.
define microsomal enzyme induction
numerous drugs and environmental chemicals(“xenobiotics”) have been shown to cause INCREASED microsomal enzyme activity CYTOCROME P450 with continued administration
What are the possible consequences of microsomal enzyme induction?
Can lead to an INCREASED rate of biotransformation and decreased level of the parent drug, resulting in TOLERANCE DEVELOPEMENT, INCREASED REACTIVE INTERMEDIATES, & DRUG INTERACTIONS
predict the renal handling of a drug when the physicochemical properties are known e.g. lipid solubility
In general, more lipid soluble compounds undergo biotransformation first beforeexcretion.
predict the renal handling of a drug when the physicochemical properties are known
Acids: alkalinizing the urine with sodium bicarbonate speeds excretion of weak acids e.g. salicylate
Bases: acidifying urine with ammonium chloride speeds excretion of weak bases e.g. amphetamine