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48 Cards in this Set

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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
Receptor Type:Steroid

give
Action:
Location:
Drug Example
Action: Modulates gene expression in nucleus

Location: cytoplasm or nucleus

Drug Example: Estrogen, corticosteroid, thyroid hormone
Receptor Type: ion channel

give
Action:
Location:
Drug Example
Action: opens to permit ion diffusion

Location: cell membrane

Drug Example: Acetycholine on nicotinic acetycholine receptor
Receptor Type:Transmembrane Tyrosine Kinase

give
Action:
Location:
Drug Example
Action: phosphorylates cytoplasmic protiens

Location: cell membrane

Drug Example: Insulin
Receptor Type:JAK-STAT

give
Action:
Location:
Drug Example
Action: Activates a cytoplasmic protein kinase (STAT)

Location: Cell membrane & cytoplasm

Drug Example: Cytokines
Receptor Type:G-Protein Coupled

give
Action:
Location:
Drug Example
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”)
0
Competitive Antagonism: “Surmountable”
RIGHT SHIFT

DECREASE POTENCY

SAME MAX
Irreversible Antagonism: “Insurmountable”“noncompetitive”
LOW MAX

IRREVERSABLE

SAME ED50
predict the effect of a competitive antagonist on the dose-response curve of an agonist
RIGHT SHIFT

DECREASE POTENCY

SAME MAX
predict the effect of an irreversible antagonist on the dose-response curve of an agonist.
LOW MAX

IRREVERSABLE

SAME ED50
distinguish between pharmacological antagonism, physiological antagonism and chemical antagonism.
--
pharmacological antagonism
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)
Chemical antagonism
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
define variance, quantal dose-response curve, median effective dose (ED50),median lethal dose (LD50), and therapeutic index (TI).
---
Variance:
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.
Therapeutic index
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)
define supersensitivity, tolerance, tachyphylaxis, desensitization, “downregulation” and “up regulation”.
--
supersensitivity
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.
tolerance
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
Hyperreactive
If a drug produces its usual effect at a very LOW dosage
Hyporeactive:
If unusually LARGE doses of the drug are required to produce the effect.
Tolerance:
Hyporeactivity that develops as a result of continued EXPOSURE to the drug.
Tachyphylaxis
Hyporeactivity that develops RAPIDLY after administration of only a few doses of a drug-- “ ACUTE TOLERANCE”
desensitization
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.
“downregulation”
an actual decrease in number of receptors.
“up-regulation”
synthesis of additional receptors.
selectivity
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.