Pharmacodynamics - ODonnell Flashcards
Receptor/drug target
Cellular of macromolecular complex with which a drug interacts to elicit a cellular response
Pharmacodynamics
biochemical and physiological effects of drugs on the body, and their mechanisms of action
Types of receptors
Neurotransmitters Autocoids Hormones Ion channels (Na/K, ATPase) Transport Proteins
Physiological Receptors
drug receptors that consist of proteins that serve as a receptor for endogenous regulatory ligands
Agonist
Drugs that bind to physiologic receptors and mimic the regulatory effects of endogenous signaling compounds
Primary agonist
drug that binds to the SAME recognition site as the endogenous agonist (primary or orthosteric site)
Allosteric (allotropic) agonist
Drug that binds to a different region on the receptor than the primary site, referred to an allosteric and allotropic site
Antagonists
Drugs that block or reduce the action of the agonist
Chemical antagonism
An antagonist that works by binding to the agonist, rendering it ineffective
Functional antagonism
An agonist that works by indirectly inhibiting the cellular or physiological effects of the agonist.
Partial agonist
Agents that are only partially functional as agonist regardless of concentration
Inverse drug
Drug that stabilizes a receptor in an inactive state when bound (receptor usually causes some kind of activity when unbound)
Affinity
The pull of a drug to be bound to a specific receptor/target. Determines the concentration of a drug required to form a significant number of drug receptor complexes.
Specificity
The concept of a drug or ligand interacting only with a particular target/ receptor or class of receptors.
competative/reversible antagonists
Binds to a receptor but does not activate them. Competitive antagonist progressively inhibit the agonist response, high antagonist concentrations can prevent response completely. However, high concentrations of the agonist can eventually overcome the effect of the antagonist, that is, the Emax (maximum response) of the agonist remains the same for any fixed CON of the antagonist. Because the antagonism is competitive the presence of antagonist increases the agonist CON required for a specific response and so the CON-effect curve is shifted to the right.
Irreversible antagonists
Bind to a receptor in an irreversible or near irreversible fashion either covalently, or so tight that the receptor cannot bind to another ligand. After some portion of receptors are bound to an irreversible antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit a response comparable to the previous Emax. If spare receptors are present however, a lower dose of an irreversible antagonist may leave enough receptors unoccupied to allow achievement of a maximum response, tho a much higher CON may be required.
Disadvantages/Advantages: once an irreversible antagonist has bound to receptors, it need not be present in an unbound form to inhibit agonist responses. Therefore the duration of an irreversible antagonist is relatively independent of its own rate of elimination and more dependent on the rate of receptor turn-over.
Partial agonists
Drugs that produce a lower response at full receptor capacity. Their CON-effect curves resemble those of full agonists in the presence of an agonist that irreversibly blocks some of the receptor sites. This is not due to lower affinity. Partial agonists can compete for receptor sites with full agonists, and be used in conjunction with full agonists to lower the effect of the full agonist.
3 variables of drug-receptor interactions
DOSE
EFFECT
TIME
Potency
The measure of the amount of drug necessary for a given response. Refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the Emax (maximum effect).
EC50
Median Effective Concentration - 50%, the concentration of a drug required to create an effect in 50% of subjects
ED50
Median Effective Dose - 50%, the dose amount required to cause an effect in 50% of subjects.
LD50
Median lethal Dose, dose at which 50% of subject reach lethal toxicity (die).
TD50
Median Toxic Dose, the smallest dose required to cause a given toxic symptom in 50% of the population
TI
Therapeutic Index - TD50/ED50 , ratio of median toxic dose over median effective dose. Commonly used to compare the toxicity of two drugs. The smaller the TI, the more toxic the drug.
Physiological Receptors
2 functions: ligand binding, and message propagation. Two functional domains: a ligand-binding domain and an effector domain.
Digoxin
A competitive inhibitor of Na/K ATPase. Competes with K, stops the exchange of Na/K. Increases the Ca levels in intracellular space resulting in stronger heart contraction
Benzodiazepine
Positive agonist of GABAaR, results in increased affinity of GABA to GABAaR = increase in frequency of Cl channel activation
*Used as a sedative, anxiolytic, anticonvulsant, muscle relaxant (opposite to Bicuculline)
Buprenorphine
Partial agonist of opioid receptors - safer than morphine because it produces less respiratory depression in cases of an overdose.
*Effectively analgesic when administered to morphine-dependent individuals, however my precipitate a drug withdrawal symptom due to competitive inhibition of morphine’s agonist action
Heparin
Agonist, binds to Anti-Thrombin III, activating it. AT then inactivates Thrombin resulting in anti-clotting effects. Is present as an endogenous protein. Ex: Chemical Agonism
Lidocaine
Local anesthetic that block VG Na channels preventing depolarization and transmission of pain signals to the brain
Naloxone
Opioid antagonist, does not possess agonist or “morphine-like” characteristic of other opioid antagonists.
*Competitive, reversible antagonist for the mu-opioid receptor site.
Phenoxybenzamine
Non-selective, Irreversible alpha antagonist. Blocks alpha receptors which lead to muscle relaxation of vessels, vasodialation, and lower BP
Protamine
Antagonist, highly basic complex that binds with the acidic molecule Heparin in the blood, resulting is a complex which has no anti-coagulant effects. Used for Heparin overdose
Ex: Chemical Antagonism
