What does it mean when receptors exist in a dynamic equilibrium?
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
How are receptors constantly being "dynamically" regulated?
-by numbers, location, and sensitivity
-regulatory changes can occur over short times (min) or longer periods (days)
What is Desensitization?
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
Is the Mechanism for desensitization "known" for all 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)
How does Desensitizaton of some G-Protiens work?
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)
What is Internalization?
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"
What is Down Regulation?
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
What is invovled in Down Regulation?
-degradation of receptor molecules via ligand-induced endocytosis and delivery to lysosomes
-biosynthesis of new receptor molecules for recovery
What may cause Tolerance?
Does all patient experience Tolerance as a result of Down regulation?
- No, numerous factors invovled:
- -genetic factors (diff # of receptor molecules, diff # of spare receptors)
- -disease states of diff patients
What is Tolerance?
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
What may also occur as a result of Tolerance?
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
What is Upregulation?
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
What can block the activation of a receptor in Up-Regulation?
- Pharmacologic antagonists
How does receptor and agonist interaction lead to Up-Regulation?
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)
What does Efficacy refer to?
Efficacy is the ability of a drug to accomplish a specified effect.
What does Potency refer to?
Potency is the amount of drug (dose) required to cause an effect.
Can a drug have a HIGH EFFICACY, but LOW POTENCY?
YES, and vice versa
What factors should be considered to determine a appropriate dose of drug for a particular therapeutic effect in a patient?
- pharmacologic potency
-maximal therapeutic efficacy (in relation to desired effect)
-be able to distinquish between the two (potency and efficacy)
Where is Potency on a dose-response curve?
Potency is the concentration/dose of a drug required to produce 50% of its maximal therapeutic effect. (EC50)
Dec. EC50, INC Potency
What factors also affects Potency?
1. Affinity (Kd) of a drug for binding to the receptor
2. Efficency of the occupancy-response coupling process (signaling pathway)
What does the Clinical Effectiveness of a drug depend on?
1. Maximal therapeutic efficacy (Emax)
2. Its ability to reach its site of action (pharmacokinetics, ADME)
What does the clinical effectiveness of a drug NOT depend on?
Clinical effectiveness DOES NOT depend on its pharmacologic POTENCY
One must make the selection of a drug for a patient based on what?
1. Relative effectiveness, NOT relative potency
What does the pharmacologic potency largely determine?
the administered DOSE of the drug.
Potency of a drug is in dosage units, with respect to a therapeutic endpt.
What is Maximal Therapeutic Efficacy?
Emax-upper limit of the dose-response curve relation to the response axis (x axis)
a maximal therapeutic effect a drug can produce
What is DRUG EFFICACY determined by?
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
What can LIMIT the practical clinical efficacy of a drug?
The drug's tendency to cause a TOXIC EFFECT
What does the Quantal Dose-Response CUrve represent?
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.
What is the Median Effective Dose (ED50) on a quantal dose-response curve?
The drug dose at which 50% of individuals exhibit the specified effect.
What is the Median Toxic Dose (TD50)?
Drug dose required to produce a toxic effect in 50% of individuals/lab animals.
What is the Median Lethal Dose (LD50)?
If the "toxic" effect is Death.
Drug dose to kill 50% of lab animals.
What is the Therapeutic Index of a drug?
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
What is the Therapeutic Window (Therapeutic Range)?
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
How do you determine the Therapeutic Window of a drug?
MEC - MTC = Therapeutic Window
MEC=minimal effective concentration of a drug
MTC=minimal toxic concentration of a drug
Both the Therapeutic Index and Therapeutic Window depend on what?
the specific toxic effect used in the determination
If the therapeutic window is narrow, what does that mean?
Narrow ranges (windows) means the drug is NOT SAFE.
This is the basis for therapeutic drug monitoring.
What factors affect the variability of drug responsiveness?
age, sex, body size, disease states, genetic factors, simultaneous administration of other drugs.
Is there great variability of responsiveness of a drug among individuals?
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.
What are the mechanisms that contribute to variation in drug responsiveness?
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
Explain the mechanism that contribute to variation in drug responsiveness: Alteration in Drug Concentration at the Receptor Site
The differenece in pharmacoKINETICS (ADME) in patients can lead to variable clinical response.
Explain the mechanism that contribute to variations in drug responsiveness: Variation in Concentration of an Endogenous Receptor Ligand
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.
Explain the mechanism that contribute to variations in drug responsiveness: Alterations in the Number or Function of Receptors
-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
What can cause an Alterations in the Number or Function of Receptors?
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)
Explain the mechanism that contribute to variations in drug responsiveness: Changes in components of Response Distal to the Receptor
- 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
What is the most important mechanism that causes variation in responsiveness to drug therapy?
Post-receptor events: biochemical processes, physiologic regulation
(Changes in components of response distal to receptor)
What Factors influence these post-receptor events to cause variation to drug response?
age, general health, severity and pathophysiologic mechanism of disease state (Most IMPT)
What can attribute to an unsatisfactory therapeutic response?
-In such cases, what needs to be done?
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.
What two categories determine the clinical selectivity of a drug?
- 1. Beneficial or therapeutic effects
- 2. Toxic effects (side effects)
What are the three mechanisms for mediating the beneficial and toxic effects of drugs?
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