Drug receptros and pharmacodynamics week 1 Flashcards
physiological receptors
agonist
primary vs allosteric agonist
A major group of drug receptors consists of proteins that normally serve as receptors for endogenous regulatory ligands. These drug targets are termed physiological receptors. Many drugs act on physiological receptors and are particularly selective because physiological receptors have evolved to recognize and respond to individual signaling molecules with great selectivity. Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds are termed agonists. If the drug binds to the same recognition site as the endogenous agonist (the primary or orthosteric site on the receptor) the drug is said to be a primary agonist. Allosteric (allotopic) agonists bind to a different region on the receptor referred to as an allosteric or allotopic site.
antagonist
allosteric antagonist
chemical antagonist
functional antagonist
partial agonist
inverse agonist
Drugs that block or reduce the action of an agonist are termed antagonists. Antagonism most commonly results from competition with an agonist for the same or overlapping site on the receptor , but can also occur by interacting with other sites on the receptor (allosteric antagonism), by combining with the agonist (chemical antagonism), or by functional antagonism by indirectly inhibiting the cellular or physiological effects of the agonist. Agents that are only partly as effective as agonists regardless of the concentration employed are termed partial agonists. Many receptors exhibit some constitutive activity in the absence of a regulatory ligand; drugs that stabilize such receptors in an inactive conformation are termed inverse. The figures below depict the site, agonists, partial agonists, antagonists , and log dose response (LDR) curves.
State what kind of compound (agonist, antagonist, etc.) is bound for each of the lines in the attached graph.
Full agonist: produces maximum level of response-highest efficacy
partial agonist: produces same response as full agonist with lesser efficacy
inactive compound: antagonist. blocks action of agonist at receptor. key is there is NO ACTION at the receptor
inverse agonist: has OPPOSITE action of agonist at the receptor
State what kind of compound (agonist, antagonist, etc.) is shown in each of graphs.
State the functions and effects of the following drugs:
digoxin
lidocaine
There are numerous examples of drugs that work through a discrete action, but have effects throughout the body. These include the inotropic drug digoxin, which inhibits the ubiquitously expressed enzyme Na+/K+ -ATPase), and the antifolate anticancer drugs such as methotrexate that inhibit dihydrofolate reductase, an enzyme required by all cells for the synthesis of purines and thymidylate. The Na+ channel blocker lidocaine has effects in peripheral nerves, the heart, and the central nervous system (CNS) because Na+ channels are highly expressed in all these tissues.
tachyphylaxis
Define and explain why it occurs.
The pharmacological properties of many drugs differ depending upon whether the drug is used acutely or chronically. In some cases, chronic administration of a drug causes a down-regulation or desensitization of receptors that can require dose adjustments to maintain adequate therapy. Chronic administration of nitrovasodilators to treat angina results in the rapid development of complete tolerance, a process known as tachyphylaxis. To avoid tachyphylaxis, it is necessary to interrupt nitrovasodilator therapy every night for at least 18 hours.
pharmacological antagonism
physiological antagonis
chemical antagonism
a. pharmacological antagonism (1 receptor) – both the agonist and antagonist compete for the same receptor.
b. physiological antagonism (2 receptors) – two agonists bind to two different receptors. Each agonist elicits a physiological response. Those responses tend to oppose each other. Although glucocorticoids and insulin act on quite distinct receptor-effector systems, the clinician must sometimes administer insulin to oppose the hyperglycemic effects of a glucocorticoid hormone.
c. chemical antagonism (0 receptors) – the antagonist directly interacts with the agonist, e.g. antacids neutralizing HCl, or chelating agents
What is the function of phenoxybenzamine? Why is it used? Explain its action at its receptor.
Explain the issues with this type of drug.
Therapeutically, irreversible antagonists present distinct advantages and disadvantages. Once the irreversible antagonist has occupied the receptor, it need not be present in unbound form to inhibit agonist responses. Consequently, the duration of action of such an irreversible antagonist is relatively independent of its own rate of elimination and more dependent on the rate of turnover of receptor molecules.
Phenoxybenzamine, an irreversible adrenoceptor antagonist, is used to control the hypertension caused by catecholamines released from pheochromocytoma, a tumor of the adrenal medulla. If administration of phenoxybenzamine lowers blood pressure, blockade will be maintained even when the tumor episodically releases very large amounts of catecholamine. In this case, the ability to prevent responses to varying and high concentrations of agonist is a therapeutic advantage. If overdose occurs, however, a real problem may arise. If the adrenoceptor blockade cannot be overcome, excess effects of the drug must be antagonized “physiologically,” i.e., by using a pressor agent that does not act via the same receptors.
Explain the function of protamine.
protamine, a positively charged protein, neutralizes negatively charged heparin, thus making the heparin unavailable for interactions with proteins involved in blood clotting. (more about this in the CV/Resp Block)
Explain the mechanism of action of benzodiazepines.
benzodiazepines bind noncompetitively (allosteric modulator) to ion channels activated by the neurotransmitter -aminobutyric acid (GABA), enhancing the net activating effect of GABA on channel conductance.
What is the cause for the lesser response of partial agonist binding as compared to full agonists?
Partial agonists produce concentration-effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blocks some of the receptor sites). It is important to emphasize that the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist’s inability to cause a maximal pharmacologic response, even when present at high concentrations that saturate binding to all receptors, is caused by the fact that the binding of an individual partial agonist to a receptor produces less of a response than a full agonist would.
Because partial agonists compete with full agonists to bind receptors, partial agonists can inhibit the responses produced by full agonists. Many drugs used clinically as antagonists are actually weak partial agonists. Partial agonism can be useful in some clinical circumstances.
Explain the function of buprenorphine. What is its clinical use?
buprenorphine, a partial agonist of opioid receptors, is a generally safer analgesic drug than morphine because it produces less respiratory depression in overdose. Buprenorphine is effectively analgesic when administered to morphine-dependent individuals, however, and may precipitate a drug withdrawal syndrome due to competitive inhibition of morphine’s agonist action.
potentcy
EC50, ED50
Potency is the measure of the amount of drug necessary for a given response. The less drug needed to elicit a response, the more potent the drug. It is important not to equate greater potency with therapeutic superiority since other factors like side effects have to be considered.
Potency of a drug depends in part on the affinity (Kd) of receptors for binding the drug and in part on the efficiency with which drug-receptor interaction is coupled to response. Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect. Relative potency, the ratio of equi-effective doses (0.2, 10, etc), may be used in comparing one drug with another. (morphine 7 mg = hydromorphone 1 mg).
Explain how therapeutic index is calculated.
ED50 - median effective dose – the smallest dose required to obtain a given response in 50% of the test population.
LD50 - median lethal dose – the smallest dose required to kill 50% of the test population.
TD50 - median toxic dose – the smallest dose required to cause a given toxic symptom
For humans: TI (therapeutic index)=TD50/ED50
• The higher the TI, the safer the drug
with most drugs, you can give 1000 fold of ED50 with no toxicity
• But a high TI does not guarantee a normal therapeutic response
TI is lower in NTI drugs
Answer the following questions:
Name the physiological ligands of B-adrenergic receptors
What structural famility of receptors to muscarinic receptors belong to? What are physiological ligands? Name a drug that binds to muscarinic receptors
Name two drugs that bind to voltage gated ion channels.
- NE, E, Dopamine
- Muscarinic receptors are GPCRs (G-protein coupled receptors). ACh is a physiological ligand for muscarinic receptors. Atropine binds to muscarinic receptors (as an antagonist).
- Verapamil (Ca2+ channel blocker) and lidocaine (Na+ channel blocker) both bind to voltage gated ion channels
