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Pharmacology (Pharmacodynamics & kinetics) (Pharmacodynamics (Binding,…
Pharmacology
(Pharmacodynamics & kinetics)
Pharmacodynamics
Binding
increased by number of receptors, concentration of ligand and affinity
Occupation theory: effect proportional to fraction of receptors occupied b agonist and max effect of agonist, max response independent of number of receptors, irreversible antagonism causes reduced max effect, efficacy consists of intrinsic efficacy and total number of receptors
Intrinsic efficacy: amount of effect you get when binding occurs, higher for full agonist, partial agonist can be more potent than full agonist by having higher affinity
vary affinity (Kd) get rightward shift of curve vary intrinsic efficacy (e) get change in max , vary receptor concetration get decrease in max ,
Affinity: higher affinity, lower concentration of drug needed for any level of occupancy -affinity constant (Ka) is ratio of forward and backwards reaction rate -higher affinity drugs occupy receptors at lower concentrations than low affinity drugs
binding determined by affinity & biophase cocentration -activation determined by intrinsic effiacy and receptor density -response determined by tissue stimulus, response coupling
Non-equilibrium processes
receptors can desensitise to stimulus eg. low conc, response stays at steady level- medium conc, response fades - higher conc, larger response but higher fade
Antagonism
Competitive antagonism (Reversible) - max unchaged, slope unchanged, get a rightward shift - more agonist needed to have an effect)
Shift determined by Schild equation log(r-1)=log[B]-logKb where r=ratio of EC50s -when r=2, concentration effect is shifted 2 times by antagonist
Antagonist potency (pA2)- neg log of concentration of antag required to cause a 2 times rightward shift of agonist concentration response curve
Non-competitive:
pathway inhibition: any agent acting at a recpetor that uses the pathway eg nifedipine antagonsm of NA induced vasoconstriction
functional: antagonist acts at separate receptor, initiating effects that are functionally opposite of agonist
Constitutive activity and inverse agonism
Agonist selective change in affinity
receptors may be active in absence of agonist ligands (constitutively active receptors) and active receptors 'prefer' to bind to receptors
basally active receptors, sufficient receptor numbers means large basal activation in absence of agonist, antagonists can have neg efficacy
in constitutively active system, agonists will activate but most antagonists will turn off completely - turning off partially or rarely wont lower constitutive activity (neutral antag)
Two state model
this model allows for contitutively active receptors and can deal with inverse antagonism
R
active, R inactive -initially more R than R
, if ligand binds to R
and creates LR
, amount of R* is less because it's used up to maintain equlibrium
receptors can be active in absence of ligand -mutant receptors with basal activity or WT receptors in excessive density
antagonists can turn off constitutively active properties (have inverse agonist properties)
Allosteric modulation
receptor subtype selectivity: subtypes generally simillar in aa structure, for drug to be selective, need to target specifics of indivdidual molecule
GABAa receptor - two binding sites, one for GABA, one for benzodiazepines - when benz binds with GABA, it increases affinity of receptor for GABA
competitive modulation- if drug reaches asymptote (non linear) on a schild plot you likely have allosteric antagonist
Advantages: once concentration that occupies all allosteric sites has been reached, more compound has no effect -positive modulation of endogenous agonist effect rather than continuous effect of exogenous agonist
Pharmacokinetics
Administration & absorption: local -access to limited tissues -systemic:drug enters blood stream, access many tissues , rapid IV admin (reach distribution eq)
Distribution
driven by circulation, rarely uniform, generally rapid
affected by mol size, plasma binding, lipid solubility, blood brain barrier
drug resevoir: sites where drug accumulates,can prolong action or terminate action, can lead to slow distribution (eg plasma proteins, cells, fat)
Volume of distribution- Vd=X/C - small if bound to plasma proteins, large if widely distributed
Metabolism
increases water solubility to facilitate excretion
metabolites can be: inactive, active, new activity, toxic
phase I: creates chem functional group on drug, cytochrome p450
phase II: conjugation of water soluble molecule to functional group
any drug administered orally goes through liver before circulation - first pass hepatic metabolism-amount of drug entering circulation/form of drug may be different
Elimination
Renal excretion
glomerular filtration - drug out of blood, only free drugs, limited by GFR, PEGylation(attach big proteins to drug so cant get filtered) - prolong action of drug
Tubular secretion: actively remove drug from blood, can remove protein bound drug, can be competitively inhibited
tubular reabsorption: drug back in blood, passive movement across tubule and peritubular capillary, pH dependent - acid in low pH (well reabsorbed)
First order elim
renal excretion/drug metabolism dependent on concentration of drug in blood
rapid IV admin:
rapid rise, drug has half life, peak concentration related to dose and Vd , if you log y axis should get straight line
short term iv infusion: drug in at constant rate, conc increases, elimination gets faster so curve flattens, when infusion stops, sharp fall in conc then exponential decay
Long term IV infusion: reach steady state, steady state proportional to infusion rate -multiple dosing: give dose every half life, 7 half lives to reach steady state, may need loading dose
Oral admin
concentration increase because lots of drug in intestine, as it decreases, rate of absorption decreases, faster elim
bioavailability - calculated by area under curve (time-concentration curve) -proportion of active drug which enters systemic circulation -important when calculating dose
Unusual drug behaviour
drugs w small therapeutic index - need to monitor plasma concentration, therapeutic effect
low bioavailability - variability from patient will have greater consequence, need to administer other way that avoids FPHM
slow distribution - tends to have large Vd, drug absorbed into fat/muscle), rapid IV admin causes initial fast distribution, then slow peripheral -peak concentration is higher than predicted from Vd
Zero order elimination
drug in high concentration, saturates elimination process, steady state never reached- increasing dose leads to disproportionate increase in concentration eg aspirin
Interpatient variability : age, genetic factors, disease, drug-drug interactions