Pharm-Pharmacodynamics

Front 1

describe the classical receptor theory (“occupancy theory”) of Clark.

Back 1

“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 )

Front 2

describe the concept of “spare receptors”

Back 2

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.

Front 3

affinity efficacy

Back 3

The propensity of a drug to bind with a receptor. k1/k2 is a measure of affinity; 1/KD (k dissociation)

Front 4

intrinsic activity

Back 4

The ability of a drug to initiate a response after binding to the receptors; --EFFICACY; K3

Front 5

agonist

Back 5

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)

Front 6

antagonist

Back 6

Something opposing or resisting the action of another
AFFINITY NO INTRINSIC ACT (K3=0)
e.g., NALOXONE

Front 7

partial agonist

Back 7

Affinity with WEAK intrinsic activity (K3<1)- E.G., NALORPHINE;

Front 8

ALLOSTERIC MODULATORS:

Back 8

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

Front 9

describe receptor-effector coupling

Back 9

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.

Front 10

describe different types of transmembrane signaling

Back 10

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

Front 11

describe the structure-activity relationship (SAR) of drugs

Back 11

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

Front 12

Receptor Type:Steroid

give
Action:
Location:
Drug Example

Back 12

Action: Modulates gene expression in nucleus

Location: cytoplasm or nucleus

Drug Example: Estrogen, corticosteroid, thyroid hormone

Front 13

Receptor Type: ion channel

give
Action:
Location:
Drug Example

Back 13

Action: opens to permit ion diffusion

Location: cell membrane

Drug Example: Acetycholine on nicotinic acetycholine receptor

Front 14

Receptor Type:Transmembrane Tyrosine Kinase

give
Action:
Location:
Drug Example

Back 14

Action: phosphorylates cytoplasmic protiens

Location: cell membrane

Drug Example: Insulin

Front 15

Receptor Type:JAK-STAT

give
Action:
Location:
Drug Example

Back 15

Action: Activates a cytoplasmic protein kinase (STAT)

Location: Cell membrane & cytoplasm

Drug Example: Cytokines

Front 16

Receptor Type:G-Protein Coupled

give
Action:
Location:
Drug Example

Back 16

Action: Activates a membrane G protein that modulates an enzyme or channel

Location: Cell membrane

Drug Example: Norepinephrine, Acetycholine (on a muscarinic receptor)

Front 17

in dose response curve

Back 17

response is proportional to dose

Front 18

Graded dose-response curve is:

Back 18

The log dose-effect relationship in 1 PATIENT
ALLOWS YOU TO COMPARE POTENCY OF DIFFERENT DRUGS by COMPARING EC50

Front 19

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.

Back 19

Signicance of potency in graded dose-response curve

Front 20

The maximal effect
Efficacy of a drug may be limited by its propensity to produce a toxic effect.

Back 20

Signicance of maximal efficacy in graded dose-response curve

Front 21

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

Back 21

Signicance of slope in graded dose-response curve

Front 22

differentiate between characteristics of a competitive antagonist (“surmountable”) and an irreversible antagonist (“insurmountable”)

Back 22

0

Front 23

Competitive Antagonism: “Surmountable”

Back 23

RIGHT SHIFT

DECREASE POTENCY

SAME MAX

Front 24

Irreversible Antagonism: “Insurmountable”“noncompetitive”

Back 24

LOW MAX

IRREVERSABLE

SAME ED50

Front 25

predict the effect of a competitive antagonist on the dose-response curve of an agonist

Back 25

RIGHT SHIFT

DECREASE POTENCY

SAME MAX

Front 26

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

Back 26

LOW MAX

IRREVERSABLE

SAME ED50

Front 27

distinguish between pharmacological antagonism, physiological antagonism and chemical antagonism.

Back 27

--

Front 28

pharmacological antagonism

Back 28

when two drugs compete for the same receptor site

Front 29

Physiological antagonism (FUNCTIONAL ANTAGONISM)

Back 29

when two drugs act on different receptors to cause opposite effects on the same physiologic function
E.G., EPI IN ANAPHALAXIS (BRONCHIODIALATION VS BRONCHIOONSTRICTION)

Front 30

Chemical antagonism

Back 30

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

Front 31

define variance, quantal dose-response curve, median effective dose (ED50),median lethal dose (LD50), and therapeutic index (TI).

Back 31

---

Front 32

Variance:

Back 32

Differences in the magnitude of response among individuals given the same dose of drug.

Front 33

Quantal dose-effect curve:

Back 33

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.

Front 34

median effective dose (ED50)

Back 34

The dose of a drug required to produce a specified intensity of effect in 50% of individuals.

Front 35

Median lethal dose (LD50):

Back 35

The dose of a drug required to produce death in 50% of individuals.

Front 36

Therapeutic index

Back 36

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)

Front 37

define supersensitivity, tolerance, tachyphylaxis, desensitization, “downregulation” and “up regulation”.

Back 37

--

Front 38

supersensitivity

Back 38

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.

Front 39

tolerance

Back 39

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

Front 40

Hyperreactive

Back 40

If a drug produces its usual effect at a very LOW dosage

Front 41

Hyporeactive:

Back 41

If unusually LARGE doses of the drug are required to produce the effect.

Front 42

Tolerance:

Back 42

Hyporeactivity that develops as a result of continued EXPOSURE to the drug.

Front 43

Tachyphylaxis

Back 43

Hyporeactivity that develops RAPIDLY after administration of only a few doses of a drug-- “ ACUTE TOLERANCE”

Front 44

desensitization

Back 44

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.

Front 45

“downregulation”

Back 45

an actual decrease in number of receptors.

Front 46

“up-regulation”

Back 46

synthesis of additional receptors.

Front 47

selectivity

Back 47

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

Front 48

risk-to benefit ratio

Back 48

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.