introductory pharmacology- general principles of drug action (PH1)

Question 1

what is pharmacology

Answer 1

• 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

Question 2

pharmacodynamics

Answer 2

-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)

Question 3

pharmacokinetics

Answer 3

-what the body does to the drug (absorption, distribution, metabolism and excretion of drugs and their metabolites)

Question 4

metabolites

Answer 4

• a substance formed in or necessary for metabolism

- aka substances that have been metabolised/changed etc by the liver

Question 5

absorption

Answer 5

• the drug has to dissolve in the gut before being absorbed into the gastrointestinal lumen
• absorption = how the drug enters the body

Question 6

elimination of a drug from the body

Answer 6

= metabolism followed by excretion

Question 7

distribution

Answer 7

only drugs that get through the liver in unchanged form will be distributed (leave blood and enter tissues)

Question 8

liver

Answer 8

• major metabolic organ of the body

- only drugs that pass through here in unchanged form will be distributed

Question 9

general definition of a drug

Answer 9

any synthetic or natural substance used in treatment, prevention or diagnosis of disease

Question 10

difference between a drug and a medicine

Answer 10

• 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

Question 11

different types of drugs

Answer 11

• everyday substances (caffeine, nicotine, ethyl, alcohol)
• illicit substances (cannabis, heroin, cocaine)
• food additives (because drug definition = something that alters a chemical process)

Question 12

drug specificity

Answer 12

• 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

Question 13

how do drugs act

Answer 13

most drugs act by binding to regulatory proteins (type of target)

Question 14

regulatory proteins (type of target)

Answer 14

• 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)

Question 15

other types of important targets

Answer 15

• RNA (target in bacteria)

- DNA

Question 16

receptors

Answer 16

• 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

Question 17

2 types of drugs acting on receptors

Answer 17

• agonists

- antagonists

Question 18

agonist

Answer 18

• 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*)

Question 19

antagonist

Answer 19

• 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

Question 20

affinity

Answer 20

-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

Question 21

efficacy

Answer 21

• 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

Question 22

relationship between agonist concentration and receptor occupancy (as a % of total receptor population)

Answer 22

• hyperbolic relationship (not linear)
• as agonist concentration increases, as does the receptor occupancy (% of total receptor population occupied by agonist)

Question 23

agonist concentration(dose) response relationship graph (linear plot/graph starting at zero) (concentration response curve)

Answer 23

• 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

Question 24

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)

Answer 24

• 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

Question 25

EC50

Answer 25

- 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)

Question 26

potency and efficacy

Answer 26

- 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 %)

Question 27

full agonists

Answer 27

produce 100% maximum response

Question 28

degree of potency

Answer 28

- 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)

Question 29

effect of degree of efficacy on response

Answer 29

-if an agonist has a high efficacy they can produce a higher response (as a % of maximum response)

Question 30

partial agonists

Answer 30

- do not produce 100% maximum response | - have a lower efficacy than full agonists

Question 31

antagonism

Answer 31

- antagonists can block the effect of agonist in two ways: - >competitive antagonism - >non-competitive antagonism

Question 32

competitive antagonism

Answer 32

- 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

Question 33

non-competitive antagonism

Answer 33

- 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)

Question 34

effect of non competitive antagonist on agonist when plotted on curve of agonist concentration (dose) against response (% maximum) (agonist concentration response curve)

Answer 34

- 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

Question 35

effect of competitive antagonist on agonist when plotted on curve of agonist concentration (dose) against response (% maximum) (agonist concentration response curve)

Answer 35

- 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