Drug Mech Exam 1

Dynamic equilibrium of receptors mean:

• -Receptors are being synthezied inside the cell
• -inserted into the cell membranes
• -sequestered out of the membranes
• -degraded at various rates

• -refers to up-regulation or down-regulation of receptors
• -receptors may also be reversibly inhibited by biochemical modifications

-by numbers, location, and sensitivity

-regulatory changes can occur over short times (min) or longer periods (days)

desensitization follows a frequent or continous exposure of the receptor to the agonist.

This is a rapid and reversible process that desensitizes the tissue to further receptor-agonist interaction for only a few minutes


"timeout", "reset" for the receptors

No, the mechanism is NOT KNOWN for many receptors.

• However, a mechanism is proposed for the desensitization of the B-adrenoreceptor
• This Mechanism rapidly and reversibly modulates the receptor's ability to interact with G-Proteins. (Common mechanism regulating many G-Protien-coupled receptors)

1. Phosphorylation of the -OH group of the intracellular part of the receptor by a GRK (G-protein receptor kinase)

2. B-arrestin "arrests" the phosphorylated area and forms a B-arrestin-Receptor complex (the G-Protein cannot access receptor) (secs to mins)

3. Reactivation of receptor by dissociation of B-arrestin and dephosphorylation (phosphatase)

Occurs following frequent or continous exposure of receptor to agonist over a rel. short time (mins to hours)

Receptor molecules are recycled intact to plasma membrane via endocytosis

Rapid cycling faciitates dephosphoylation of receptors and increases rate of restoring receptors to plasma membrane. "resensitizing"

Occurs ONLY after prolonged/repeated exposure (hours to days)

Decreases the number of receptor molecules in cell or tissue

Slower process than desensitization and less reversible

-degradation of receptor molecules via ligand-induced endocytosis and delivery to lysosomes

-biosynthesis of new receptor molecules for recovery

Down regulation

• No, numerous factors invovled:
• -genetic factors (diff # of receptor molecules, diff # of spare receptors)
• -disease states of diff patients

Tolerance is a decrease in the intensity (effect) of a response to a given dose of a drug, as a consequence of continued drug administration over time

Depletion of essential substrates required for downstream effects in the signal transduction pathway following continous activation of the receptor-effector system

Ex: depletion of thiol cofactors=tolerance to nitroglycerin, administering missing substrate may reverse tolerance

Occurs when receptor and agonist interaction is blocked for prolonged periods of time (usually several days) by a pharmacologic antagonist or denervations.

There will be increased synthesis of receptors in a cell

• Pharmacologic antagonists
• denervations

1. If patient is taking a "blocker" (pharmacologic antagonist)

2. Type of disease/disorder affecting signal transduction pathway

EX: Patients on Beta-blockers, Inc. synthesis of the B-adrenoreceptor in tissue. IF patient STOPS taking, there will be INC. binding of adrenaline to B-adrenoreceptor = MI, tachycardia, death (better to taper off dose, not all of sudden stop)

Efficacy is the ability of a drug to accomplish a specified effect.

Potency is the amount of drug (dose) required to cause an effect.

YES, and vice versa

- pharmacologic potency

-maximal therapeutic efficacy (in relation to desired effect)

-be able to distinquish between the two (potency and efficacy)

Potency is the concentration/dose of a drug required to produce 50% of its maximal therapeutic effect. (EC50)

Dec. EC50, INC Potency

1. Affinity (Kd) of a drug for binding to the receptor

2. Efficency of the occupancy-response coupling process (signaling pathway)

1. Maximal therapeutic efficacy (Emax)

2. Its ability to reach its site of action (pharmacokinetics, ADME)

Clinical effectiveness DOES NOT depend on its pharmacologic POTENCY

1. Relative effectiveness, NOT relative potency

the administered DOSE of the drug.

Potency of a drug is in dosage units, with respect to a therapeutic endpt.

Emax-upper limit of the dose-response curve relation to the response axis (x axis)

a maximal therapeutic effect a drug can produce

1. The mode of interactions of the drug with the receptor (ex: partial agonists)

2. by Characteristics of the receptor-effector system ( ex: diuretics act on one part of nephron, produce greater effect than duiretics that act on a diff part of nephron)

3. a host of other factors

The drug's tendency to cause a TOXIC EFFECT

The percentage of individuals (or lab animals) under the study who exhibit a specified drug effect (therapeutic effect, side effect, lethal effect, etc.) plotted as a function of log drug dose.

-Illustrates the potential variability of responsiveness to the drug among individuals in a given human population.

The drug dose at which 50% of individuals exhibit the specified effect.

Drug dose required to produce a toxic effect in 50% of individuals/lab animals.

If the "toxic" effect is Death.

Drug dose to kill 50% of lab animals.

Dose of a drug to produce a desired effect to the dose of drug which produce an undesirable effect.

• Therapeutic Index = TD50/ED50
• (only in lab animals)

-clinically acceptable risk of toxicity depends on severity of disease state

Describes the dosage range between the minimum effective therapeutic concentration or dose and the minimum toxic concentration or dose of a drug in humans.

MORE clinically useful index of SAFETY

MEC - MTC = Therapeutic Window

MEC=minimal effective concentration of a drug

MTC=minimal toxic concentration of a drug

the specific toxic effect used in the determination

Narrow ranges (windows) means the drug is NOT SAFE.

This is the basis for therapeutic drug monitoring.

[Wider range=safer]

age, sex, body size, disease states, genetic factors, simultaneous administration of other drugs.

Yes, there are great variations.

Variations of drug response has been shown in a single individual at different times during the course of treatment by same drug.

1. Alteration in Drug Concentration at the Receptor Site

2. Variation in Concentration of an Endogenous Receptor Ligand

3. Alterations in the Number or Function of Receptors

4. Changes in Components of Response Distal to the Receptor

The differenece in pharmacoKINETICS (ADME) in patients can lead to variable clinical response.

The different concentrations of an endogenous agonist different patients have can affect drugs which are antagonists/partial agonists, leading to variations in clinical response.

EX: Levels of endogenous catecholamines differ in patients and affect clinical response to the B-adrenoceptor antagonist propranolol.

-Alterations (INC or DEC) in number of receptor sites

-Alterations in the efficiency of the occupancy-response coupling

-Both can lead to variable clinical responses

1. Other Hormones (thyroid hormone inc both number of b-adrenoceptor and cardiac sensitivity to catecholamines)

2. Agonist ligand (induce decrease in number or coupling efficiency of receptor sites)

3. Genetic factors (different genetic variant receptors can confer an increase risk for a disease state, EX: CHF by variant adrenoceptor)

• Drug response depends not only on the drug's ability to bind to receptor but also (post-receptor events):
• 1. Efficiency of biochemical process
• 2.Physiologic regulation by interacting organs

Post-receptor events: biochemical processes, physiologic regulation

(Changes in components of response distal to receptor)

age, general health, severity and pathophysiologic mechanism of disease state (Most IMPT)

Can be attributed by the physiologic conpensatory mechanism that respond to and oppose the effects of a drug

(EX: compensatory vasocontrictiion and fluid retention by kidney cause tolerance to antihypertensive, effects of vasodilator)

-Needs additional DRUGS to treat patient.

• 1. Beneficial or therapeutic effects
• 2. Toxic effects (side effects)

1. Therapeutic and Toxic effects mediated by the same receptor-effector Mechanism - Much of serious drug toxicity is result of direct pharmacologic extention of the therapeutic actions of the drug (drug toxicity=prolonged drug exposure or action of drug)

2. Therapeutic and toxic effects mediated by Identical Receptors in Different Tissues (or via different Effector Pathways)- Many drugs exert therapeutic and toxic effects by acting on a single receptor type in diff tissues. (ex: glucocoticoid hormones, digitalis, glycosides, methotrexate)

3. Therapeutic and Toxic Effects Mediated by Diff Types of Receptors