Pharmocodynamics- receptors Flashcards
What is pharmacodynamics?
What a drug does to a body/ pharmacological effects
biochemical and physiological effect, mechanisms of drug action, relationship between drug concentration and drug effect
What are the general principles of drug therapy?
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
How do drugs exert their effects?
Initiate new events/ blocking action of endogenous substances
Mostly interactions between drugs and endogenous receptors
What are the biological responses of drugs?
Changing ion content of cells Promoting secretion of hormones Reducing the electrical signalling by excitable cells Reducing contractile activity Stimulating synthesis of proteins
What are receptors?
Glycoproteins situated in cell membrane/ intracellular site
Recognise and bind ligands
What are ligands?
Exogenous compounds
What is signal transduction?
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
What is the drug-receptor complex?
Usually reversible, biological response proportional to fraction of receptors bound
Name the main types of receptors
Channel-linked
G-protein-coupled
Kinase-linked
DNA-linked
Describe channel-liked receptors
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
Describe G-protein-coupled receptors
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
Examples of G-protein-coupled receptors
muscarinic cholinergic receptor, adrenoreceptors, opioid receptors
Examples of secondary messenger systems
enzymes adenylate cyclase generate cyclic AMP- relaxation of smooth bronchiole muscle
enzyme guanylate cyclase generate cyclic GMP
Describe Kinase-linked receptors
Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions
insulin receptor
Describe DNA-linked receptors
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
What are other types of ‘receptors’?
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)
Describe enzyme targets
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
Describe transporter targets
Drugs inhibit specialised protein transporter activity/ act as false substrates to prevent transport of normal biological substrate- diuretics
What is receptor affinity?
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
What is the difference between high and low affinity drugs?
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
What is an agonist?
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.
What is an antagonist?
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
What is a partial agonist?
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
What is an inverse agonist?
Ligand that produces the opposite effect to the full agonist when they bind to a receptor
How can inverse agonists be identified?
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)
What is the relationship between drug dose and drug response?
Linear scale= hyperbolic curve
Clinical responses= heart rate/ blood pressure…
Non-clinical= enzyme activity/ membrane potential…
Emax= max response, ED50- half max response
What is the dose-response curve?
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
What are the basic features of a dose response curve?
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
Describe the effect of competitive antagonists on the dose-response curve
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
Describe the effect of non- competitive antagonists on the dose-response curve
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
Describe the effect of partial agonists on the dose-response curve
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
