Pharmocodynamics- receptors

Question 1

What is pharmacodynamics?

Answer 1

What a drug does to a body/ pharmacological effects

biochemical and physiological effect, mechanisms of drug action, relationship between drug concentration and drug effect

Question 2

What are the general principles of drug therapy?

Answer 2

Normal physiology depends on structure and function of cells
Pathophysiology underlying disease progression involves cell disorder
Drugs are exogenous molecules intended to restore endogenous systems by increasing/decreasing activity of key regulatory pathways

Question 3

How do drugs exert their effects?

Answer 3

Initiate new events/ blocking action of endogenous substances
Mostly interactions between drugs and endogenous receptors

Question 4

What are the biological responses of drugs?

Answer 4

Changing ion content of cells
Promoting secretion of hormones
Reducing the electrical signalling by excitable cells
Reducing contractile activity
Stimulating synthesis of proteins

Question 5

What are receptors?

Answer 5

Glycoproteins situated in cell membrane/ intracellular site

Recognise and bind ligands

Question 6

What are ligands?

Answer 6

Exogenous compounds

Question 7

What is signal transduction?

Answer 7

When ligands bind to receptors, initiate conformational change in receptor protein that transmits biochemical signal into cell, triggering secondary messenger response/ cascade to biological response

Question 8

What is the drug-receptor complex?

Answer 8

Usually reversible, biological response proportional to fraction of receptors bound

Question 9

Name the main types of receptors

Answer 9

Channel-linked
G-protein-coupled
Kinase-linked
DNA-linked

Question 10

Describe channel-liked receptors

Answer 10

Coupled directly to an ion channel, activation opens channel, cell membrane more permeable to ion
Ligand-gated ion channels because receptor binding operates them vs voltage-gated membrane potential

Question 11

Describe G-protein-coupled receptors

Answer 11

Coupled to intracellular effector mechanisms via G proteins that participate in signal transduction by coupling receptor binding to intracellular enzyme activation or the opening of an ion channel

Question 12

Examples of G-protein-coupled receptors

Answer 12

muscarinic cholinergic receptor, adrenoreceptors, opioid receptors

Question 13

Examples of secondary messenger systems

Answer 13

enzymes adenylate cyclase generate cyclic AMP- relaxation of smooth bronchiole muscle
enzyme guanylate cyclase generate cyclic GMP

Question 14

Describe Kinase-linked receptors

Answer 14

Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions
insulin receptor

Question 15

Describe DNA-linked receptors

Answer 15

Intracellular/nuclear receptors, binding of ligand promotes or inhibits synthesis of new proteins, takes hours or days to promote biological effect- steroids, thyroid and growth hormones

Question 16

What are other types of ‘receptors’?

Answer 16

Voltage-sensitive ion channels in excitable tissues (Na+ ion channels blocked by lidocaine local anaesthetic)
Enzymes that catalyse biological reactions (cyclo-oxygenase inhibited by aspirin)
Transporter proteins that facilitate movement of molecules and ions across membranes (serotonin reuptake transporter inhibited by fluoxetine)

Question 17

Describe enzyme targets

Answer 17

Drugs interfere with active site/ affect cofactors required by enzyme for activity
cyclo-oxygenase and aspirin, angiotensin- converting enzyme and lisinopril, xanthine oxidase and allopurinol

Question 18

Describe transporter targets

Answer 18

Drugs inhibit specialised protein transporter activity/ act as false substrates to prevent transport of normal biological substrate- diuretics

Question 19

What is receptor affinity?

Answer 19

Expression of the strength of the drug-receptor binding/ how tightly ligand is bound to receptor
Drugs dissociate from drug-receptor complex at varying rates

Question 20

What is the difference between high and low affinity drugs?

Answer 20

Low- allow rapid fine modulation because changes in drug concentration around the receptor are quickly reflected in changes in drug-receptor binding (Ach)
High- well bound at low concentration producing prolonged biological responses that continue even when concentration has fallen- growth hormone

Question 21

What is an agonist?

Answer 21

Ligand that binds to a receptor protein to produce a conformational change (mostly reversible binding)
As free ligand concentration increases, proportion of receptors occupied inc. so biological response inc.

Question 22

What is an antagonist?

Answer 22

Ligand that binds to a receptor but does not cause conformational change that initiates intracellular signal
Competitive- occupies and prevents agonist
Non-competitive- alters signal transduction/ second messenger cascade permanently

Question 23

What is a partial agonist?

Answer 23

Able to activate a receptor after it binds but unable to produce maximum signalling effect even when all available receptors occupied- poor molecular fit
Partial compete/block with full so antagonise effect of full agonist

Question 24

What is an inverse agonist?

Answer 24

Ligand that produces the opposite effect to the full agonist when they bind to a receptor

Question 25

How can inverse agonists be identified?

Answer 25

Relevant endogenous receptor must show some degree of activation even in the absence of the ligand binding (constitutive activity)- receptors coupled to low level response, inverse agonists switch this off (antagonists)

Question 26

What is the relationship between drug dose and drug response?

Answer 26

Linear scale= hyperbolic curve
Clinical responses= heart rate/ blood pressure…
Non-clinical= enzyme activity/ membrane potential…
Emax= max response, ED50- half max response

Question 27

What is the dose-response curve?

Answer 27

Logarithmic scale- sigmoidal curve
Useful as expands the dose scale in region where drug response is changing rapidly and compresses scale at higher doses where large changes have little effect on repsonse
Assumes drug dose and ligand concentration closely linked

Question 28

What are the basic features of a dose response curve?

Answer 28

Progressive increases in drug dose produce increasing drug effects- occur over relatively narrow part of overall concentration range
Effective dose range= spanning the straight line segment of the log dose-response curve (20-80% Emax)
Max tolerated dose= highest dose of a drug that can be administered without adverse effects

Question 29

Describe the effect of competitive antagonists on the dose-response curve

Answer 29

Shift curve to the right (higher agonist concentrations required to achieve given percentage receptor occupancy/ to achieve same proportional response
Surmountable- reversible to overcome by giving agonist at sufficiently high concentration

Question 30

Describe the effect of non- competitive antagonists on the dose-response curve

Answer 30

Antagonise in ways other than direct competition for receptor binding so impossible to achieve max response (not surmountable)
Shift agonist curve right and decrease Emax
Antagonism that persists (aspirin, omeprazole) only disappears when new enzymes/proteins synthesised

Question 31

Describe the effect of partial agonists on the dose-response curve

Answer 31

Activate receptors, not full effect of complete agonists
Reduced Emax compared to full agonist- effective dose range similar
Increase biological response when receptors not fully occupied so does not displace full agonist
Decrease biological response when competing with full