Pharmacodynamics Flashcards
What is pharmacodynamics?
Pharmacodynamics describes the relationship between drug level and effect.
OR ‘What a drug does to the body’
What are dose-response curves?
Dose-response curves enable us to quantify biological effect of drugs on both molecular and physiological processes
What is hysteresis?
The phenomenon in which the value of a physical property lags behind changes in the effect causing it.
– i.e. relationship between drug concentration and
effect is not direct
What is counter-clockwise hysteresis?
the process in which effect can increase with time for a given drug concentration
What is clockwise hysteresis?
the measured effect decreases with time for a given drug concentration
How does counter-clockwise hysteresis work?
Sensitisation (up regulation of receptors) Distribution delay to site of effect Generation of agonist metabolite Slow receptor kinetics Time-dependent protein binding
Give an clinical example of a drug that shows counter-clockwise hysteresis.
Isosorbide dinitrate
How does clockwise hysteresis work?
Tolerance (down regulation of receptors) Disequilibrium between arterial and venous conc. Generation of antagonistic metabolite Feedback regulation Time-dependent protein binding
Give an clinical example of a drug that shows clockwise hysteresis.
Temazepam
Most drugs act by binding to a target. Name some exceptions. (4)
– osmotic diuretics
– antacids and chelating agents
– bile sequestrants
– certain anti-microbials and anti-tumour
What are enzymes?
Globular proteins that catalyse reactions through binding of substrate in an active site. They speed up time to reach equilibrium and allow a lower activation energy for reaction.
Enzymes may be extracellular or intracellular.
Give an example of the former, and two of the latter.
angiotensin converting enzyme
carbonic anhydrase, xanthine oxidase
How does allopurinol work?
Inhibits the oxidation of xanthine to uric acid
How does streptokinase work?
activates human plasminogen
What are ion channels?
Ion channels allow ions to travel across an otherwise
impermeable membrane, passively down the
electrochemical gradient, at a high rate.
What is the typical function of ion channels?
Typical function is to maintain resting membrane potential, to shape electrical signals including action potentials, and to regulate cell volume.
Drugs may act to increase the probability of closed channels - give an example.
CCBs such as nifedipine
Drugs may act to increase the probability of open channels - give an example.
Benzodiazepines
Ion carriers/pump - what do these do?
Ion carriers / pump - actively moves ions across a plasma membrane against their concentration gradient. This requires energy from various sources, including ATP (e.g. Na+/K+ ATPase) and potential energy stored in an electrochemical gradient (e.g. Na+/Ca2+ exchanger).
Ion carriers/pump - what are the three types?
uniporters (only one ion transported)
sympoters (ions going in same direction)
antiporters (in opposite directions)
Receptors relay _____ _____ from ___________.
Relays chemical signals from outside to inside a cell.
What are the main classifications of receptors? (3)
– G protein-coupled receptors
– Kinase linked
– Nuclear receptors
Receptors may be membrane bound cell surface receptors, _________, or in the ______.
cytoplasmic, or in the nucleus.
Which classification of receptors may have a longer-lasting effect?
Nuclear receptors
Define affinity. What does this determine?
The strength of forces attracting ligand and receptor together. This determines the degree of association and dissociation of the drug and the receptor.
The affinity of a drug for an individual receptor describes…?
how avidly the drug binds to the receptor (ie, the dissociation constant, Kd)
Covalent binding of drug to receptor (e.g. fluoroquinolones acting on bacteria) leads to…?
formation of an irreversible link
Aspirin irreversibly binds to its target enzyme. What is it called?
COX
What is Kd?
Kd is the equilibrium dissociation constant and provides a mathematic measure of affinity (1/Kd).
If the receptors have a high affinity for the ligand, the Kd will be…?
Why?
low, as it will take a low concentration of ligand to bind half the receptors
The ‘Law of Mass Action’ is a simple model of receptor ligand interactions with a number of assumptions.
What are they? (5)
– All receptors are equally accessible to ligands
– Receptors exist in one of two states: free or bound to ligand
– Bindings does not alter ligand or receptor
– Binding is reversible
– Receptors numbers are fixed
Ligand-receptor interaction requires spatial interaction i.e…?
‘lock and key’
Certain drugs exhibit stereospecific interactions where
different stereoisomers bind to different targets.
Give an example.
S(-) carvedilol binds to alpha- and beta-adrenoceptors, but R(+) cavedilol binds selectively to alpha adrenoceptors.
Affinity is determined by the strength of receptor ligand
interaction.
What are the three types?
– Electrostatic interactions (most common)
– Hydrophilic interactions
– Covalent bonds (least common)
Define selectivity.
a drug’s ability to preferentially bind to certain receptors.
E.g. COX-2 selective NSAIDs are without significant effect on COX-1
Define specificity.
Specificity of drug action relates to the number of different mechanisms involved. Non-specific = several mechanisms.
Give an example of two specific drugs.
atropine (muscarinic receptor antagonist)
salbutamol (β2-adrenoceptor agonist)
Give an example of a non-specific drug.
chlorpromazine causes blockade of D2-dopamine,
α-adrenergic, and muscarinic receptors.
Define potency.
the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drug’s maximal effect
Define median inhibitory concentration (IC50).
the concentration of an antagonist that reduces a specified response to 50% of the maximal possible effect
Define efficacy.
the maximum effect (Emax) of a drug
What are agonists?
drugs that bind to receptors, converting it to the
active conformation, resulting in a biologic response
Full agonists result in a _____ by occupying all or a fraction of receptors.
Partial agonists results in a …. even when the drug occupies all of the receptors.
maximal response
less than maximal response
How can partial agonists act as competitive antagonists in the presence of a full agonist?
as it competes for receptor occupancy, thereby producing a net decrease in the receptor activation as compared to that observed with the full agonist alone
Partial agonists - their usefulness is derived from…?
E.g.?
their ability to enhance deficient systems while simultaneously blocking excessive activity (e.g.
methadone).
Describe antagonists in terms of affinity and efficacy.
Antagonists have affinity (i.e. they bind) but no efficacy (i.e. have no effect) for their receptors, therefore binding will disrupt the action of an agonist at the receptors.
What is an inverse agonist?
E.G.?
an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.
E.g. naloxone
What are competitive antagonists?
reversibly bind to receptors as the agonist, but without
activating the receptor, therefore “competing” for the same binding site
What are non-competitive antagonists?
reduce the magnitude of the maximum response
attained by any amount of agonist
What are allosteric modulators?
they indirectly influence (modulate) the effects of an agonist by binding to a site distinct from the agonist
they usually induce conformational change within the target
What are positive allosteric modulators?
E.g.?
induces an amplification of the agonist’s effect, either by enhancing the affinity or the functional efficacy.
Benzodiazepines
What are negative allosteric modulators?
reduces the effects of the agonist, but is inactive in the absence of the orthosteric ligand.
Define chemical antagonism.
involves chemical interaction between a drug and either a chemical or another drug leading to a reduced or nil response.
Define physiologic antagonism.
occurs when two drugs acting on different receptors and pathways exert opposing actions on the same physiologic system.
Define pharamcokinetic antagonism.
the result of one drug suppressing the effect of a second drug by reducing its absorption, altering its distribution, or increasing its rate of elimination
What are biological therapies?
engineered macromolecule products like protein and
nucleic acid–based drugs.
Often highly targeted, especially in monoclonal
antibodies.
Typically more specific and high potency / efficacy.
Typically act as antagonists (e.g. anti-inflammatory)
