Pharmacodynamics Flashcards
What is the concept of “drug selectivity”? What is it dependent on?
The ability of a drug to “target” one receptor vs. another at any given clinical dose range. It is dependent on the relative affinities of a drug (KD) for various receptors.
For ANY drug, how does selectivity change with drug dose?
selectivity DECREASES as drug dose INCREASES
What is the dose-response relationship?
The correspondence between the amount of drug and the magnitude of the effect; increasing the dose increases the effect in a graded manner.
What is drug potency?
The concentration or dose of drug needed to produce 50% of the drug’s maximal response (ED50).
What does drug potency depend on? (2 things)
1) affinity of a drug for its receptor
2) efficiency with which receptor activation is coupled to response
Maximal efficacy is used synonymously with the term _____________.
intrinsic activity
Describe the intrinsic activity (max. efficacy) of full agonists vs. partial agonists vs. neutral antagonists vs. negative antagonists.
- Full agonists: activity=1
- Partial agonists: activity <1
- Neutral antagonists: activity=0
- Negative antagonists: activity <0
A negative antagonists is also known as an ____________.
inverse agonist; can reduce the constitutive activity of receptors
Does the clinical effectiveness of a drug depend on maximal efficacy (Emax) or potency (ED50)?
maximal efficacy!
easy way to remember: clinical effectiveness=efficacy
Describe a system that would be considered to have “spare receptors,” or “receptor reserve.”
systems in which maximal response is achieved by doses of agonists that occupy only a small percentage (Fraction) of receptors
In terms of receptors, what is required for a drug to achieve a maximal response?
- all receptors must be equally functional
- not all receptors must be occupied
The magnitude of receptor reserve is most likely due to what?
the degree of response amplification following any given drug-receptor interaction
What are the 3 effects of competitive antagonists on pharmacodynamics?
1) shift to right in dose response curve
2) increase in ED 50
3) no change in Emax
(inhibition is effectively overcome by
What are the 2 main effects of non-competitive antagonists on pharmacodynamics?
1) decrease in Emax
2) NO change in ED50
What are some non-pharmacological means to antagonizing drug effects?
- chemical inactivation
- physiologic use of opposing pathways
- biologic interactions (one drug may affect metabolism/pharmacokinetics of another)
For ligand-regulated transmembrane enzyme receptors, what can intensify/prolong the duration of receptor activation?
autophosphorylation of tyrosines on the receptor’s cytoplasmic side (ex: autophosphorylation of insulin receptor persists long after insulin dissociates from receptor)
How are transmembrane receptors subject to downregulation?
via endocytosis
What are examples of endogenous substances that utilize tyrosine kinase receptors?
EGF, insulin, ANF
What is the difference between tyrosine kinase receptors and cytokine receptors?
Cytokine receptors utilize a separate protein tyrosine kinase that binds non-covalently and is NOT intrinsic to the receptor.
With cytokine receptor activation, what is the final product that dissociates, travels to the nucleus, and regulates gene transcription?
a dimer of STATs (phosphorylated by JAKs)
Describe some signaling characteristics of the nicotinic cholinergic receptor (a ligand-gated receptor)
- pentamer consisting of 4 types of glycoprotein subunits that form a membrane channel
- ACh binding to alpha subunits produces a conformational change and transient opening of the channel
- open channel allows Na+ ions to pass from ECF into the cell
- time b/t binding and response is in milliseconds, allowing for very rapid transfer
What are examples of neurotransmitters that signal via ligand-gated receptor mechanisms?
ACh, GABA, excitatory amino acids (glutamate and aspartate)
In GPCRs, which side of the polypeptide chain is extracellular vs. intracellular?
amino terminus is extracellular; carboxy terminus is intracellular
GPCRs are used by which neurotransmitters?
A variety, including dopamine, NE, serotonin, ACh.
Activation of adenylyl cyclase produces ______.
cAMP, a second messenger that goes on to affect other cellular processes
Describe the activation of the phosphoinositide hydrolysis pathway.
Agonist binding results in the G prot. subunit activating phospholipase C (PLC), which cleaves PIP2 into IP3 and DAG. IP3 increases intracellular Ca2+, while DAG activates protein kinase C (PKC).
What is the quantal dose response curve?
it describes the relationship b/t drug dose and a specified effect in a population of individuals; it is obtained from the cumulative frequency distribution of drug doses that produce a specified (quantal) effect in a patient population
What does the ED50 on a quantal dose-response curve represent?
It represents the dose of drug producing a specified endpoint (ex: therapeutic effect vs. lethal effect) in 50% of the population
Can drug safety be better assessed from the therapeutic window or therapeutic index?
Therapeutic window; ideal is for the window to be broad and not narrow
What can be determined from quantal dose-response curves?
1) Median effective dose (ED50)
2) Index of selectivity of drug actions (by comparing ED50 for different specified effects, like decongestion vs. sedation)
3) Estimate of the degree of safety of a drug for a therapeutic effect
What is the therapeutic index?
It is a ratio used to describe the relative safety of a drug. Thus, it is the ratio of the dose of drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED50).
What is the therapeutic window?
A clinically relevant index of drug safety that represents the dosage range b/t the minimum effective therapeutic dose and the minimum toxic dose.
List some variations in drug responsiveness.
- Idiosyncratic drug response (unusual response not normally observed in the majority of patients)
- Quantitative variations (intensity of effect for a given dose may be greater/less in comparison to most patients; intensity of response may vary during the course of therapy)
List the two main variations in receptor responsiveness to drugs (compensatory responses).
- receptor desensitization (in response to over-stim.)
- receptor supersensitivity (in response to under-stim.)
What are the 2 types of desensitization?
- homologous
- heterologous
What is tachyphalaxis?
the rapid development of diminished responsiveness to a drug
What are the 3 main mechanisms that account for reduced responsiveness to a drug?
1) Agonist-induced phosphorylation (activated receptor is phosphorylated and β-arrestin binds)
2) Receptor down-regulation (loss of membrane-bound receptors)
3) Post-receptor adaptations (receptors “functionally uncoupled” from post receptor components due to modification of G-proteins or 2nd messenger enzymes)
For mechanisms that cause reduced responsiveness to a drug, how is the dose-response curve affected?
These mechanisms will cause a right shift in the agonist dose-response curves (increased ED50) but no change in Emax, unless the receptor reserve is exceeded.
What are 2 things that might explain desensitization-induced reduction in Emax?
1) Receptor reduction exceeding receptor reserve
2) Post-receptor defects (changes in reserve of G proteins, enzymes, etc. required to maintain original Emax)
Describe the difference between homologous and heterologous desensitization.
With homologous desensitization, kinases will only recognize and phosphorylate sites on the agonist-occupied receptor. Thus, there is loss of activity ONLY to agonists interacting with this modified receptor. With heterologous desensitization, agonist activation of one receptor subtype results in a decreased responsiveness of other receptor subtypes (specifically, receptors that were not directly activated by the agonist).
Why does receptor supersensitivity occur?
A loss of activity on receptors, which leads to increased receptor density and/or enhanced receptor-effector coupling. (left shift)
What are the protein kinases capable of promoting heterologous desensitization?
PKA and PKC
