S2 - Pharmacokinetics and Pharmacodynamics

Question 1

Define Pharmacokinetics

Answer 1

study of movement of a drug into and out of the body

what the body does to the drug

Question 2

Define Pharmacodynamics

Answer 2

study of drug effect and mechanisms of action

what the drug does to the body

Question 3

Define Pharmacogenetics

Answer 3

the effect of genetic variability on the pharmacokinetics or dynamics of a drug on an individual

Question 4

what is the therapeutic window

Answer 4

the range of plasma concentrations over which drug exerts its therapeutic effects without causing significant adverse reactions

Question 5

what does ADME stand for

Answer 5

Absorption
Distribution
Metabolism
Elimination

Question 6

Define bioavailability

Answer 6

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

Question 7

what is bioavailability affected by ?

Answer 7

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)

Question 8

what is distribution ?

Answer 8

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)

Question 9

once in circulation, are drugs bound ?

Answer 9

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

Question 10

what is protein binding affected by

Answer 10

hypoalbuminaemia
pregnancy (decreased binding as GFR and protein excretion increases)
Renal failure
Displacement by other drugs

Question 11

how does changes in protein binding affect drug distribution ?

Answer 11

affect if there is high binding, low VD and a narrow therapeutic ratio

Question 12

Define Volume of Distribution Vd

Answer 12

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

Question 13

what is the relationship of Vd and half life

Answer 13

half life is proportional to Vd, longer half-life greater distribution. Tissue distribution can be affected by blood flow, lipid solubility and disease states

Question 14

describe metabolism in terms of pharmacokinetics

Answer 14

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)

Question 15

describe phase 1 enzymes

Answer 15

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

Question 16

describe phase 2 enzymes

Answer 16

by hepatic enzymes which catalyse sulphation and methylation.

Question 17

what is metabolism affected by

Answer 17

metabolism is different in many individuals ; lower in kids and elderly, women are slow ethanol metabolisers, size of human

Question 18

describe elimination in terms of pharmacokinetics

Answer 18

main route is through kidney and is determined by glomerular filtration, passive tubular reabsorption, Active tubular secretion

Question 19

define clearance

Answer 19

rate of elimination of drug from the body (usually=GFR)

half life is inversely proportional to clearance so a reduction shall increase T1/T2

Question 20

what is first order kinetics ?

Answer 20

Linear ; rate of elimination is proprotional to drug conc,a constant fraction of drug is eliminated in unit time
half life can be defined

Question 21

what is zero order kinetics ?

Answer 21

non-linear rate of elimination is a constant

most drugs initially exhibit first order then zero order kinetics at high doses

Question 22

why is drug monitoring essential ?

Answer 22

zero order drugs are more likely to result in toxicity as small dose changes can produce large increments in plasma conc.

Question 23

what is a steady state and why is it important

Answer 23

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

Question 24

what is loading dose and why are they useful

Answer 24

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

Question 25

describe elimination half lives

Answer 25

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)

Question 26

what are agonists

Answer 26

binds to receptor and changes its conformation to activate it and generate a response . Has affinity, intrinsic efficacy and efficacy. activate endogenous proteins

Question 27

what are antagonists ?

Answer 27

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

Question 28

where do drugs work

Answer 28

cell surface receptors, transport inhibitors and enzyme inhibitors

Question 29

describe some mechanisms of drug action

Answer 29

disruption of structural proteins, being enzymes and reacting chemically

Question 30

define affinity

Answer 30

tendency of a drug to bind to a specific receptor(Kd- a lower value indicates a higher affinity)

Question 31

define intrinsic efficacy

Answer 31

ability of a drug to bind to a receptor and activate it

Question 32

Define efficacy

Answer 32

ability of a ligand to generate a response as a result of the receptor or receptors being occupied

Question 33

Define potency

Answer 33

Does required to produce the desired biological response

Question 34

define Emax

Answer 34

max response we can measure

Question 35

Define EC50

Answer 35

conc of drug which causes 50% max response

Question 36

Define Bmax

Answer 36

max binding capacity

Question 37

Define KD

Answer 37

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

Question 38

what are competitive antagonists and non- competitive antagonists ?

Answer 38

competitive compete w the agonists but non comp bind to the allosteric site which reduces the effects of an agonist

Question 39

Whats IC-50

Answer 39

conc of antagonist giving 50% inhibition

Question 40

what is drug selectivity

Answer 40

the more the selective a drug for its target, the less chance it will interact

Question 41

define some drug -drug interactions

Answer 41

interactions can either enhance/reduce therapeutic outcome through actions on receptors. Drug interactions can occur via different receptors or different tissues

Question 42

what is enzyme induction ?

Answer 42

increasing the amount of enzyme present for a specific action

Question 43

what are examples of Cp450 inducers or CP450 inhibitors

Answer 43

inducers : Phenytoin, Carbamazepine

Inhibitors : omeprazole, disulfiram

Question 44

what are some drug - disease interactions

Answer 44

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

Question 45

describe a drug - food interaction

Answer 45

grapefruit juice inhibits many CP450 isoenzymes reducing clearance of many drugs - Simvastation
Amiodarone (Long QT), terfenadine (Long QT)

Question 46

what is an ADR ands its causes

Answer 46

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