Pharmacodynamics 2 Flashcards
Which of the following initiates the quickest response? G-protein coupled receptor Ligand gated ion channel Intracellular receptor Tyrosine kinase receptor
Ligand gated ion channel
Explain the concepts of drug selectivity and specificity
Many drugs act PREFERENTIALLY on particular receptors or subtypes (selectivity)
No drug is specific i.e. 100% selective for only one receptor subtype.
Specificityof drug action relates to the number of different mechanisms involved.
Assessment of degree of selectivity is important for dosage calculation
e.g. Salbutamol is ~10x more effective in stimulating b2 receptors in airways than b1 receptors in heart
Define the term ‘therapeutic index’
The therapeutic index is a comparison of the amount of atherapeuticagent that causes thetherapeutic effect to the amount that causes toxicity
Describe the phenomena of desensitization and tolerance
Toleranceis the reduction in response to a drug after repeated administration
An antagonist is a drug which _________ the action of an agonist ___________ in the absence of an agonist
inhibits
but has no effect
An antagonist is a drug which blocks the response to an agonist. Pure antagonists do not by themselves cause any ‘action’ by binding to the receptor.
What effect does this have on efficacy?
Antagonists have no efficacy.
Antagonists can be of two types:
- receptor antagonists
a. active site binding (reversible - competitive // irreversible - non-competitive)
b. allosteric binding ((reversible // irreversible - both non-competitive)) - nonreceptor antagonists
a. chemical antagonist
(inactivate an agonist before it has the opportunity to act (e.g., by chemical neutralization))
b. physiologic antagonist eg antibodies (physiologic antagonistscause a physiologic effect opposite to that induced by the agonist.)
competitive antagonism ________ be overcome by ______________. same maximal response (same Emax) __________ be achieved.
can
by increasing [agonist].
can
In the presence of a competitive antagonist - agonist curves features:
Agonist curves have 1. the same form
- displaced rightwards
- same maximal response = Emax
- The linear portion of the curves are parallel
Non-competitive //irreversible antagonism ________ be overcome by ______________. Same maximal response (same Emax) __________ be achieved.
cannot
by increasing [agonist]
cannot - even with very high agonist doses
In the presence of a irreversible antagonist - agonist curves features:
Agonist curves:
- do not have the same form
- Agonist curves have a reduced maximal response (lowered Emax)
Examples of Competitive versus irreversible antagonists
competitive:
examples include
bisoprolol at the b1 adrenoceptor
irreversible:
phenoxybenzamine at the a1adrenoceptor.
Because no drug is _______ as dose increases the desired response in a patient rises to a maximum beyond which further increases elicit no more benefit but induce unwanted effects (toxic effects)
specific.
you want a SELECTIVE drug so it prevents unwanted side effects
Explain difference between graded and quantal dose-response relationships
GRADED
In an individual
Response of a particular system (isolated tissue, animal or patient) measured against agonist concentration
QUANTAL
In a population
Drug (agonist or antagonist) dose required to produce a specified response determined in each member of a population
Percent of a population that responds to a given dose of a drug
(plotted against the drug dose)
Used to determine the effective therapeutic (recommended) dose for a population
Therapeutic window (TW) =
= range of doses of a drug that elicits an effective therapeutic response, without unacceptable adverse effects (toxicity)
Therapeutic index =
comparison of the amount of atherapeuticagent that causes thetherapeutic effect to the amount that causes toxicity
TI = TD50/ED50
TI =
(dose of drug that causes a toxic response in 50% of the population)
/
(dose of drug that is therapeutically effective in 50% of the population)
TI is a measure of a drug’s ________ because _____________
safety
because a larger value indicates a wide margin between doses that are effective and doses that are toxic
Drugs with a low therapeutic index (small TW) can be difficult to use unless therapeutic dose monitoring is in operation (e.g. warfarin)
Drugs with a large therapeutic index are generally safe and easy to use (e.g. penicillin)
Tolerance is ________
Toleranceis the reduction in response to a drug after repeated administration
The two different types of tolerance are:
- Pharmacokinetic (e.g. altered drug metabolism)
- Pharmacodynamic:
a. Receptor internalisation
b. Receptor down-regulation
c. Decreased activity of intracellular signalling pathways and ion channels
all of these are tried to be fixed in desensitization.
The following are characteristics of drug tolerance:
It is reversible,
the rate depends on the particular drug,
dosage and frequency of use,
differential development occurs for different effects of the same drug.
Summary
Antagonists have affinity but NO efficacy
Competitive antagonists:
- Bind reversibly to the receptor
- Antagonism can be overcome by increasing the concentration of the agonist i.e. the same maximal response is achievable
- The agonist dose response curves are shifted to the right in parallel
Irreversible antagonists:
- Bind irreversibly to the receptor
- Antagonism cannot be overcome by increasing the concentration of the agonist i.e. the same maximal response is not achievable
No drug is 100% specific for a particular receptor, so increasing the dose will cause unwanted side effects
The therapeutic index is a measure of a drugs safety; the larger the TI the easier and safer a drug is to use
