S2 - Pharmacokinetics and Pharmacodynamics Flashcards
Define Pharmacokinetics
study of movement of a drug into and out of the body
what the body does to the drug
Define Pharmacodynamics
study of drug effect and mechanisms of action
what the drug does to the body
Define Pharmacogenetics
the effect of genetic variability on the pharmacokinetics or dynamics of a drug on an individual
what is the therapeutic window
the range of plasma concentrations over which drug exerts its therapeutic effects without causing significant adverse reactions
what does ADME stand for
Absorption
Distribution
Metabolism
Elimination
Define bioavailability
the relative amount fo a drug that reaches systemic circulation once the drug molecules have gone through their first hepatic circulation
Bioavailability ( for oral) = amount of drug reaching systemic circulation(AUC oral) / total amount of drug administered (AUC IV) AUC= Area under the curve
thus, all drugs administered IV have 100% bioavailability , if there is less, the drug has undergone absorption/first pass metabolism
what is bioavailability affected by ?
Absorption (drug formulation, age, food ; lipids soluble > water soluble, vomiting ) and first pass metabolism ( metabolism that occurs before the drug enters systemic circulation e.g. in gut lumen/wall or liver)
what is distribution ?
ability to dissolve in the body and occurs in arteries, capillaries, interstitial fluid, cell membranes and then target tissues. affected by lipophilicity ( freely moves across memb) and by hydrophilicity (movement depends on SA and pKA)
once in circulation, are drugs bound ?
many are bound to proteins E.g albumin and globulins .
Only free drugs have a pharmacological effect - bind to cellular receptors, pass tissue membrane and gain access to cellular enzymes
what is protein binding affected by
hypoalbuminaemia
pregnancy (decreased binding as GFR and protein excretion increases)
Renal failure
Displacement by other drugs
how does changes in protein binding affect drug distribution ?
affect if there is high binding, low VD and a narrow therapeutic ratio
Define Volume of Distribution Vd
measure of how widely a drug is distributed in body tissues
summaries the movement out of plasma -> interstitial –> intracellular components
Small Vd- less penetration of intracellular components
Large Vd - more penetration
Vd(L) = dose(mg)/[drug(mg/L)] at time=0 or peak plasma concentration
what is the relationship of Vd and half life
half life is proportional to Vd, longer half-life greater distribution. Tissue distribution can be affected by blood flow, lipid solubility and disease states
describe metabolism in terms of pharmacokinetics
occurs in liver via phase 1 and phase 2 enzymes which increases ionic charge and eventually form water soluble products which are easily eliminated. Can involve metabolism of a pharmacologically inactive or active compound to other active compounds (pro-drugs e.g codeine –> morphine)
describe phase 1 enzymes
carried out by CP450 which involves redox reactions. CP450 mainly present in liver and metabolise toxins such as carcinogens and pesticides
CP450 induction shall reduce plasma levels of a drug. CP450 inhibition shall increase it
describe phase 2 enzymes
by hepatic enzymes which catalyse sulphation and methylation.
what is metabolism affected by
metabolism is different in many individuals ; lower in kids and elderly, women are slow ethanol metabolisers, size of human
describe elimination in terms of pharmacokinetics
main route is through kidney and is determined by glomerular filtration, passive tubular reabsorption, Active tubular secretion
define clearance
rate of elimination of drug from the body (usually=GFR)
half life is inversely proportional to clearance so a reduction shall increase T1/T2
what is first order kinetics ?
Linear ; rate of elimination is proprotional to drug conc,a constant fraction of drug is eliminated in unit time
half life can be defined
what is zero order kinetics ?
non-linear rate of elimination is a constant
most drugs initially exhibit first order then zero order kinetics at high doses
why is drug monitoring essential ?
zero order drugs are more likely to result in toxicity as small dose changes can produce large increments in plasma conc.
what is a steady state and why is it important
situation where the overall intake of a drug is in dynamic equilibrium with its elimination. During repeated drug administration a new steady state is achieved in 3-5 half lives irrespective of dose or frequency of administration
for e,g digoxin has a large Vd and half-life is 40 hours, 5 half lives to steady state will be >1 week so need loading doses achieve a rapid therapeutic effect
what is loading dose and why are they useful
an initial higher does of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose.
useful when you want a drug with a long half life to have an immediate effect rather an effect in a week or so. these drugs require a low maintenance dose to maintain the steady state
loading dose = Vd X [Drug} target
describe elimination half lives
slope of the curve = elimination rate constant (K)
k= ratio of clearance (Cl) to VD
t1/2= Vd/Cl or t1/2 is proportional to VD or inversely proportional to Cl
In chronic kidney disease
Clearance (kidney) is proportional to renal function (GFR)
t1/2 is proportional to 1/clearance (GFR)
what are agonists
binds to receptor and changes its conformation to activate it and generate a response . Has affinity, intrinsic efficacy and efficacy. activate endogenous proteins
what are antagonists ?
binds to receptor and inhibits the binding of endogenous agonists. Has affinity but no intrinsic efficacy and no efficacy . antagonise, block or inhibit endogenous proteins
where do drugs work
cell surface receptors, transport inhibitors and enzyme inhibitors
describe some mechanisms of drug action
disruption of structural proteins, being enzymes and reacting chemically
define affinity
tendency of a drug to bind to a specific receptor(Kd- a lower value indicates a higher affinity)
define intrinsic efficacy
ability of a drug to bind to a receptor and activate it
Define efficacy
ability of a ligand to generate a response as a result of the receptor or receptors being occupied
Define potency
Does required to produce the desired biological response
define Emax
max response we can measure
Define EC50
conc of drug which causes 50% max response
Define Bmax
max binding capacity
Define KD
conc of drug which gives 50% occupancy of available receptors.
Full agonists give 100% response while partial agonists give 50% response but allow a controlled response and work in low levels of ligand
what are competitive antagonists and non- competitive antagonists ?
competitive compete w the agonists but non comp bind to the allosteric site which reduces the effects of an agonist
Whats IC-50
conc of antagonist giving 50% inhibition
what is drug selectivity
the more the selective a drug for its target, the less chance it will interact
define some drug -drug interactions
interactions can either enhance/reduce therapeutic outcome through actions on receptors. Drug interactions can occur via different receptors or different tissues
what is enzyme induction ?
increasing the amount of enzyme present for a specific action
what are examples of Cp450 inducers or CP450 inhibitors
inducers : Phenytoin, Carbamazepine
Inhibitors : omeprazole, disulfiram
what are some drug - disease interactions
Renal disease - low GFR so reduced clearance of some renally excreted drugs - digoxin
hepatic disease - reduced clearance of hepatic metabolised drugs, Reduced CYP 450 activity, much longer half lives . Examples - opiates in cirrhosis
cardiac disease - falling cardiac output leads to excessive response to hypotensive agents and reduced organ perfusion
describe a drug - food interaction
grapefruit juice inhibits many CP450 isoenzymes reducing clearance of many drugs - Simvastation
Amiodarone (Long QT), terfenadine (Long QT)
what is an ADR ands its causes
an unwanted or harmful reaction which occurs after administration of a drug
Risks : reckless prescribing, extreme ages
Drug response varies based on weight, size, ages, genetics, health, placebo effect and method of administration E.g dose or frequency
