Drug Receptor Concepts Flashcards
what is pharmacology?
study of interaction between drugs + living body
what is pharmacokinetics?
study of how body deals with/handles drugs
what is pharmacodynamics?
study of effects of drugs on living body + how effects = produced
what is pharmacotherapeutics?
study of use of drugs in treatment + prevention of disease
what are the 2 types of drug action?
- non specific
- specific
non-specific drug action
- some drugs act in simple physical/chem way (e.g. osmotic diuretics, antacids + chelating agents)
- lack specific structure - activity relationship
- needs large doses of drug for effect
specific drug action
- most drugs act in highly specific way - e.g. phenylephrine, salbutamol, atropine, digoxin
- interact with/bind to specific macromolecular/ cellular targets in body (receptors)
- show clear cut structure -activity relationship
- produce effects at v low doses
what is the drug receptor concept?
most drugs produce their biological effects by interacting with specific macromolecules in body called receptors
what is a receptor?
specialised component of cell/organism that interacts with drug + initiates chain of biochem events leading to drugs observed effects
what are drug receptors mainly?
protein / glycoprotein mol
give examples of drug receptors located on cell membrane?
- atenolol
- chlorphenamine
- cimetidine
- codeine
give examples of drug receptors located on inside of cell?
- oestrogen
- testosterone
- vitamin D
what are the different types of drug targets / receptors?
- classical - neurotransmitter, hormones
- ion channels - lidocaine, diazepam, amiodarone
- enzymes - NSAIDs, statins, ACE inhib
- carrier/transport proteins - PPIs, digoxin, SSRIs
what law is the drug-receptor interaction governed by?
law of mass action
can relate drug conc + effect to fraction of receptors occupied
what do a drug + receptor interacts to form and how?
D-R complex
via reversible chemical interaction
what is the lock and key relationship based on?
selectivity of drug
- chem selectivity
- biological / tissue selectivity
the fraction of receptors occupied by the drug is a function of what?
- conc of drug in biophase
- equilib dissociation constant (Kd) for d-r complex
what are the assumptions of the receptor occupancy theory?
- drug effect = proportional to FRACTION of receptors occupied
- max drug effect (Emax) happens when ALL receptors in systems = occupied
what are the possible outcomes of a drug-receptor interaction?
drug may mimic natural, endogenous chemical messenger —> prod same effect as natural chemical messenger (AGONIST)
drug may block access of natural, endogenous chemos messenger to receptor site —> prod no effect (ANTAGONIST)
drug may bind to site near binding site near binding site for natural, endogenous chem messenger + influence its binding —> inc + dec effect of chem messenger (ALLOSTERIC MODULATOR)
drug may bind to site normally occupied by natural, endogenous chemical messenger —> produce opposite effect to chem messenger (INVERSE AGONIST)
what does an agonist drug to?
produces same effect as natural chemical messenger
what does an antagonist do?
produces no effect
what is an allosteric modulator?
inc/dec effect of chemical messenger
what is an inverse agonist drug?
produce opposite effect to chem messenger
what do agonist and antagonist drugs both have?
affinity for their receptors
what is affinity?
measure of probability that drug mol = interact with receptor to form d-r complex
what is affinity measured by?
Kd of drug
affinity = 1/Kd
differentiate between agonist drugs and antagonist drugs?
agonist drugs have efficacy whilst antagonist drugs have NO efficacy
what is efficacy?
measure of biological effectiveness of drug-receptor complex
also = measure of ability of d-r complex to couple/ transduce drug binding into biological response
what may efficacy (e) be?
0, low + v. high
what is an agonist?
drug that binds to its receptor, activates receptor + elicits biological response
what are the 2 types of agonist?
- full agonist
- partial agonist
what is a full agonist?
binds to its receptor + is capable of eliciting the max poss response from receptor system
has HIGH efficacy
e.g. dobutamine, salbutamol
what is a partial agonist?
binds to its receptor + is capable of eliciting LESS than max poss response from receptor system
intermediate efficacy (e)
reduces response elicited by full agonist
e.g. buprenorphine, oxymetazoline
what is an antagonist? (pharmacological)
drug that binds to its receptor but fails to activate receptor, + so fails to elicit a response
has efficacy of 0
an antagonist competes with…
agonist drug (or natural chem messenger) for binding to receptor
where does an antagonists biological effect result from?
preventing agonist drug from binding to its receptor
e.g. atenolol, chlorphenamine, naloxone
what is the ‘spare receptor’ / ‘receptor reserve’ concept?
- exceptions to ‘receptor occupancy theory’
- full agonists elicit max response WITHOUT full receptor occupancy
- system has spare receptors
what does the spare receptor concept enable?
- economy of hormone / transmitter secretion
- allows low affinity drugs to elicit max poss response
characteristics of the graded dose-response curve
potency
measures amount of drug needed to elicit specified response
- reflected in location of D-R curve along dose axid
- expressed as ED50 / EC50
- clinically expressed as ABSOLUTE / RELATIVE potency
- NOT critical characteristics
e.g morphine vs diamorphine
what is maximal efficacy?
maximal response / effect produced by drug
characteristics of graded dose-response curve
maximal efficacy
- reflected as plateau in log D-R curve
- MOST imp characteristic of drug
e. g. paracetamol vs morphine
- may = determined/limited by onset of adverse side effects
characteristics of graded dose-response curve
slope
- reflects magnitude of change in response with unit of change in dose
- imp consideration under certain circumstances
characteristics of graded dose-response curve
biological variability
- DIFF responses to same dose of drug in DIFF people
- DIFF responses to same dose of drug in SAME people
- sources of variation in response: age, genes, gender, poly pharmacy, pathological state
define drug antagonism?
interaction between 2 drugs so that the effect of 1 is diminished/completely abolished in presence of other
what are the types of drug antagonism?
- competitive (pharmacological/receptor)
- non- comp
- chemical
- pharmacokinetic
- physiological / functional
competitive antagonism
agonist + antagonist drugs compete for same receptor binding site
- antagonist binding reduces chance of agonist binding —> dec agonist effect
- 2 subtypes, depending on nature of antagonist-receptor interaction
what are the 2 subtypes pithing competitive antagonism?
- reversible/surmountable
- irreversible/insurmountable
reversible competitive antagonism?
- antagonist + agonist bind REVERSIBLY to receptor
- fraction of receptors occupied depends on drugs’ relative AFFINITIES + CONC
- antagonism can = overcome by inc conc of agonist drug
what are the 2 effects on the agonist log D-R curve for reversible competitive antagonism?
- parallel shift to right
- no reduction in maximal response
irreversible competitive antagonism?
- antagonist drug binds IRREVERSIBLY to receptor (high affinity/cov bonding)
- fraction of receptors = permanently unavailable for agonist drug binding
- antagonist NOT OVERCOME by inc conc of agonist drug
what are the 2 effects on the agonist log D-R curve for irreversible competitive antagonism?
- reduction in slope of curve
- reduction in maximal response
non-competitive antagonism?
- antagonist drug DOESNT compete with agonist drug for same receptor binding site
- antagonist drug may bind to diff site on receptor/interfere with response coupling
- antagonism CANT = overcome by inc conc of agonist drug
what are the 2 effects on the agonist log D-R curve for non-competitive antagonism?
- reduction in slope of curve
- reduction in maximal response
chemical antagonism?
- direct interaction between agonist and antagonist drugs
- ‘antagonist’ drug binds to/combines with active drug (agonist) in sol
- active drug = inactive/unavailable to interact with target receptors
what are the typical examples of chemical antagonism?
- protamine vs heparin
- dimercaprol vs heavy metals (Cd, Pb)
pharmacokinetic antagonism?
‘antagonist’ drug acts to reduce effective conc of active drug (agonist) at site of action
what are the possible mechanisms for pharmacokinetic antagonism?
- reduced absorption from GIT: ferrous salts vs tetracycline antibiotics
- inc metabolic degradation: phenobarbitone vs warfarin
- inc renal excretion:
NaHCO3 vs aspirin
physiological/functional antagonism?
- interaction of 2 opposing agonist effects in single biological system —> cancelling out of each others effect
- 2 drugs elicit OPPOSING responses by acting on diff receptors
what are the typical examples of physiological/functional antagonism?
- Ach vs noradrenaline (heart rate)
- glucocorticoids vs insulin (blood sugar levels)
what is summation?
combined effect of 2 drugs elicits same overt response, regardless of mechanism of action = algebraic sum of individual effects
what is additivity?
combined effect of 2 drugs, acts by same mechanism = to what is expected by simple addition of individual effects
what is synergism/potentiation?
conjoint effect of 2 drugs = greater than algebraic sum of individual effects
what may a synergist act to do?
- inc conc of other drug at receptor sites: tyramine + MAO inhib
- inc responsiveness of other drugs receptor - effector protein: benzodiazepines + GABA (gaba A receptor)
what does the binding of GABA cause?
Cl- ion channels to open —> hyperpolarisation of cell
what does the binding of GABA and benzodiazepine cause?
- entry of Cl- hyperpolarises the cell —> more difficult to depolarise —> reduces neural excitability
- binding of GABA = enhanced by benzodiazepine —> greater entry of Cl- ions
variation in drug responsiveness - scope?
- inter patient variation
- intra patient variation
variation of drug responsiveness - poss consequences?
- lack of efficacy
- unexpected side effects
variation in drug responsiveness - poss mechanisms?
- pharmacokinetic
- pharmacodynamic
variation in drug responsiveness - poss types of variation?
- qualitative
- quantitative
variation in drug responsiveness - quantitive variations?
- hyper - responsiveness
- hypo - responsiveness / tolerance
variation in drug responsiveness tolerance?
- innate vs acquired tolerance
- tolerance vs tachyphylaxis
what is acquired tolerance?
acquired state of progressively dec responsiveness to drug as a result of prior repeated exposure to the drug / another drug with similar action
what are the mechanisms for acquired tolerance?
- pharmacodynamic
- metabolic
- exhaustion / depletion of mediators
- physiological adaptation
mechanism of acquired tolerance - pharmacodynamic?
- receptor down regulation
reduction in receptor density e.g. Beta 1 adrenergic receptor - receptor uncoupling
uncoupling of receptors from effector systems e.g. Beta 2 adrenergic receptor
mechanism of acquired tolerance - metabolic?
- enhanced metabolism of drug
- due to induction of metabolising enzymes
e. g. alcohol, barbiturates
mechanism of acquired tolerance - exhaustion/ depletion of mediators?
- common with indirectly-acting drugs
- due to depletion of endogenous stores of mediators of drugs action
e. g. amphetamine, nitrates
mechanism of acquired tolerance - physiological adaptation?
- evoked compensatory / homeostatic mechanisms
- blunts / cancels drugs effects
e.g. diuretics, nitrates
what are the 2 types of clinical selectivity?
absolute + relative
what 2 effects do u get?
- therapeutic / desirable
- adverse/ undesirable/ side effects
absolute vs relative selectivity?
- no drug has one single specific effect
- produces spectrum of effects
define relative selectivity?
degrees to which drug acts upon given site relative to all possible sites of interaction
therapeutic vs undesirable effects?
undesirable effects may = minor/serious
how may undesirable effects come about?
- both effects mediated via same receptor effector mechanism - e.g. nitrates, insulin, warfarin
- both effects mediated via identical receptor in diff tissues e.g. haloperidol, verapamil
- both effects mediated via diff types receptors e.g. salbutamol, propranolol
what is therapeutic index determined by?
ratio of toxic to therapeutic dose
formula for therapeutic index?
median toxic dose (TD50) / median effective dose (ED50)
what does therapeutic index provide a useful measure of?
- margin of safety of drug
- benefit to risk ratio of drug
e.g. penicillin vs warfarin
