Pharmacodynamics

Pharmacodynamics

·        Study of drug/receptor interactions. Dimensions of time, concentration and effect (ie response intensity)

·        Types of „receptors‟ for drugs: enzymes, ion channels, receptors, carrier molecules. Most common targets are transmembrane receptors linked to G proteins

·        Receptor interactions:

o  Agonists:

§  Bind and produce a full effect

§  Partial agonists: bind and produce sub-maximal effect (ie lower dose-response curve)

§  Inverse agonists: bind and have opposite effect to that of agonists

§  Non-competitive agonists cannot be displaced

§  Competitive agonists reversibly interact, can be reversed by an antagonist.

o  Antagonists: bind and produce no effect. 

§  Competitive: maximal response is still possible with an ­ in dose of endogenous agonist (ie dose response curve shifts right). Eg ­adrenaline can over-ride b-blockers 

§  Non-competitive: don‟t allow a maximal response regardless (ie lower-dose response curve). Progressively lowers maximal response of agonist 

o  Agonist antagonist: has an agonist effect at one subtype of receptor and an antagonist effect at another

o  Specificity = effect produced by interaction with a single receptor

o  Ka = concentration required to occupy 50% of receptor sites at equilibrium 

o  Up-regulation/down-regulation: a very common response to an antagonist/agonist. Watch for rebound when it stops

·        Dose response curves:

o   Relationship between plasma concentration and drug‟s effect 

o   Efficacy: maximal ceiling of effect, regardless of dose. Effectiveness of drug once bound to a receptor

o   Potency: quantity required for maximal effect 

o   Affinity: if a drug has lower affinity, it can still produce a maximal effect but will require a larger dose (ie pushes dose response curve to the right). Higher affinity Þ higher potency. 

o   Individuals vary considerably in the efficacy, slope (difference between small and maximal effect) and potency of drugs. Eg with ­age have ¯receptors. So dependent on age, disease, environment, etc

·        Concentration vs. response: 

o   EC50 = drug concentration at 50% of maximal effect (describes affinity of the drug for the receptor)

o   Therapeutic index is the ratio of the Adverse Effect EC50 to the Therapeutic Effect EC 50 

o   Rise in response intensity is normally less than proportional to drug concentration. It reaches a point where further increases in concentration have no further effect (but may prolong effect – but to double time may need 10 fold ­ in concentration). Need to balance against ­ adverse effects 

o   Usually presented as Response vs log drug concentration – this linearises the central part of the curve 

o   Combining with another drug with a synergistic effect changes the dose response – often allows ¯dose (eg ACE + diuretic)

·        Dosing: 

o   „Usual dose‟: set at maximum profit for minimum toxicity. Always half New Ethicals starting dose! 

o   Objective in chronic disease management: use the lowest possible daily dose of the appropriate drug. Building up slowly, but this is usually impractical in general practice (requires lots of visits until therapeutic effect satisfactory, so back titration used) 

o   Loading dose dependent on volume of distribution

o   Infusion rate dependent on clearance 

o   Constant infusion ® gradually rising Cp. Bolus ® instantly high Cp, then declining. Both ® stable Cp

·        Factors in Failure to respond: 

o   Poor compliance: difficult dosage regimes, poor technique (eg inhalers), difficult to swallow, etc. Frequency critical. Increasing frequency ® more forgotten. But if T½ < 24 hours, will get better overall control (avoiding peaks and troughs in Cp) with > once a day 

o   Incorrect drug formulation 

o   Altered drug handling due to disease state (eg impaired absorption of oral frusemide due to mucosal oedema)

o   Drug tolerance or bacterial resistance

o   Disease state too severe (eg thiazide diuretic in heart failure)

o   Toxicity may prevent attainment of the therapeutic dose

Changes with Age

·        Blunted homeostatic reserve: 

o   ­Risk of postural hypotension with antihypertensives, neuroleptics, TCAs

o   Drugs have greater effect on postural control (eg sedatives)

o   Changes in neurotransmitters ® ­risk of drug induced confusion

·        Receptor changes.  Eg ¯response to b agonists and antagonists