introductory pharmacology- general principles of drug action (PH1) Flashcards
what is pharmacology
- the study of drugs- what they are, how they work, what they do at several different levels
- the study of the manner in which the function of living tissues and organs is modified by chemical substances
- comprises/ is made up of pharmacodynamics and pharmacokinetics
pharmacodynamics
-what a drug does to the body (biological effects and mechanism of action/ the biological effects of a drug and how the drug produces the effects)
pharmacokinetics
-what the body does to the drug (absorption, distribution, metabolism and excretion of drugs and their metabolites)
metabolites
- a substance formed in or necessary for metabolism
- aka substances that have been metabolised/changed etc by the liver
absorption
- the drug has to dissolve in the gut before being absorbed into the gastrointestinal lumen
- absorption = how the drug enters the body
elimination of a drug from the body
= metabolism followed by excretion
distribution
only drugs that get through the liver in unchanged form will be distributed (leave blood and enter tissues)
liver
- major metabolic organ of the body
- only drugs that pass through here in unchanged form will be distributed
general definition of a drug
any synthetic or natural substance used in treatment, prevention or diagnosis of disease
difference between a drug and a medicine
- a medicine may contain more than 1 drug (+ inert substances)
- drug has single molecular entity (a thing with distinct and independent existence)
- drugs and medicine are not identical
different types of drugs
- everyday substances (caffeine, nicotine, ethyl, alcohol)
- illicit substances (cannabis, heroin, cocaine)
- food additives (because drug definition = something that alters a chemical process)
drug specificity
- for a drug to be useful as a therapeutic agent, it must usually act with a degree of selectivity in its biological action (eg. a drug used to treat heart disease must specifically act on/target the heart)
- drugs act by binding to target molecules
- selectivity results from:
- > the chemical structure of the drug
- > the target recognising only ligands of a precise type
- drugs will only bind strongly to target if there is a complimentary shape
how do drugs act
most drugs act by binding to regulatory proteins (type of target)
regulatory proteins (type of target)
- enzymes (important type of target)
- carrier molecules (transporters and pumps)
- ion channels (anaesthetics used in dentistry block voltage gated sodium ion channels)
- receptors (eg. nicotinic acetyl choline receptors of neuromuscular junction, some drugs block these receptors to cause induced controlled paralysis)
other types of important targets
- RNA (target in bacteria)
- DNA
receptors
- receptors are macromolecules that mediate the biological actions of hormones and neurotransmitters
- typically protein or glycoprotein substances
- they mimic or block endogenous (having an internal cause or origin) substances
- > mostly protein macromolecules
2 types of drugs acting on receptors
- agonists
- antagonists
agonist
- an agonist (A) is a drug that binds to a receptor (R) to produce a cellular/biological response
- they bind to receptors to activate them
- eg. adrenaline
- agonists posses affinity (reversible binding step, A+R=AR) and efficacy (reversible activation step, AR=AR*)
antagonist
- an antagonist (B) is a drug that blocks the actions of an agonist
- an agonist can activate a receptor, an antagonist cannot (antagonists bind to receptors, R, but do not activate them)
- in the absence of an agonist, antagonist has no effect
- antagonists possess affinity (ability to bind, B+R=BR), but lack efficacy (ability to cause biological response) therefore there is no BR*
- antagonists
affinity
-characterises binding step
-transitional/short lived state
-measure of strength of binding to receptor depends on how quickly agonist binds in comparison to how quickly it unbinds (refers to the stickiness of agonist to receptor)
-affinity is the ‘strength of association’ between ligand and receptor (agonist spends different amounts of time on the receptor, they bind at the same rates but unbind at different rates)
-> an agonist with low affinity has a fast dissociation rate
->an agonist with medium affinity has a moderate dissociation rate
->an agonist with high affinity has a slow dissociation rate
(arrows between A+R and AR = rate constant)
-as affinity increases, the time the agonist spends with receptor increases
efficacy
- the ability to produce a desired or intended result
- activation step
- conformational change of receptor becoming activated shortly after binding step (affinity)
- efficacy is the ability to perform biological action/response
relationship between agonist concentration and receptor occupancy (as a % of total receptor population)
- hyperbolic relationship (not linear)
- as agonist concentration increases, as does the receptor occupancy (% of total receptor population occupied by agonist)
agonist concentration(dose) response relationship graph (linear plot/graph starting at zero) (concentration response curve)
- plots agonist concentration (dose) against response (as % of maximum response)
- relationship is hyperbolic
- EC50 is the concentration of agonist that elicits a half maximal response
- linear plot graph is not suitable for plotting a wide range of concentrations of agonists as it causes difficulty in determining EC50 value
agonist concentration(dose) response relationship graph (semi-logarithmic/logarithmic scale is used on the x axis aka scale constructed so that successive points along an axis, or graduations are an equal distance apart and represent values which are in an equal ratio) (concentration response curve)
- concentration is plot on logarithmic scale
- this semi-logarithmic plot is used over the linear plot by pharmacologists as it decreases the difficulty in determining an accurate value of EC50/ EC50 is found with a lot more precision
- the relationship between the concentration (dose) of agonist and response (as % of maximum response) is sigmoidal for this type of plot
- potency of an agonist is illustrated on semi-logarithmic plot
EC50
- effective concentration 50
- aka ED50 (referring to effective dose 50 not concentration)
- EC50 is the concentration of agonist at which 50% of maximum response is gained
- worked out from graph by determining the concentration of an agonist at which response is 50% of maximum (maximum value is specific to that agonist as not all agonists produce 100% response)
potency and efficacy
- if 2 agonists have the same efficacy but different potencies, they will have different EC50’s, therefore the one with the higher EC50 will require a higher concentration to produce the same degree of response
- if 2 agonists display the same potency (equipotent) but different efficacies, then they will both have the same EC50 values as they work over the same range of concentration of agonist, however their maximum response values will be different; the agonist with the lower efficacy will have a lower maximum response %)
full agonists
produce 100% maximum response
degree of potency
- describes range of concentration that an agonist works over
- EC50 is a measure of potency/ ability to effect
- therefore the lower the EC50, the higher the potency
- if two agonists are described as equipotent, they have equal potency
- if an agonist has a small potency, a much higher range of concentration is required to produce the same degree of response as an agonist with the same efficacy but higher potency
- the lower the potency, the higher the EC50 (concentration required to produce a half maximal response)
effect of degree of efficacy on response
-if an agonist has a high efficacy they can produce a higher response (as a % of maximum response)
partial agonists
- do not produce 100% maximum response
- have a lower efficacy than full agonists
antagonism
- antagonists can block the effect of agonist in two ways:
- > competitive antagonism
- > non-competitive antagonism
competitive antagonism
- situation is often between two extremes
- agonist (A) blocks binding site of antagonist (B) and antagonist blocks binding site of agonist
- binding of agonist and antagonist occur at the same (orthosteric) site and is thus competitive and mutually exclusive
- > when antagonist (B) binds to receptor site, the receptor is inactive
- > when agonist (A) binds to receptor site, the receptor is active
non-competitive antagonism
- binding site of agonist (A) and antagonist (B) are different
- agonist binds to orthosteric site and antagonist binds to separate allosteric site and thus is not competitive
- both may occupy the receptor simultaneously/at the same time, but activation can not occur when antagonist is bound
- > when antagonist binds to allosteric site, even when agonist is bound to receptor, receptor remains inactive (allosteric inhibition)
- > when antagonist binds to allosteric site, but agonist is not bound to receptor, nothing happens (as antagonists block effect of agonists)
effect of non competitive antagonist on agonist when plotted on curve of agonist concentration (dose) against response (% maximum) (agonist concentration response curve)
- agonist works over exactly same range of concentration
- maximal response produced by agonist is suppressed by non competitive antagonist
- if sufficient amount of non competitive antagonist binds, response (effect of agonist) can be blocked completely
- block cannot be overcome as it is non-competitive
- non competitive antagonists depress the slope and maximum of the concentration response curve but do not cause a rightward shift
effect of competitive antagonist on agonist when plotted on curve of agonist concentration (dose) against response (% maximum) (agonist concentration response curve)
- shifts agonist concentration response curve to the right (the greater the antagonist concentration that you add, the greater the shift)
- you can overcome competitive antagonist
- rightward shift of curve (decreased potency therefore increased EC50 value, greater concentration of agonist is required to produce half maximal response)
- no suppression of maximal
- parallel shift
