A.D.M.E

Question 1

what is pharmacokinetics

Answer 1

the study and characterisation of drug absorption, distribution, metabolism and excretion

Question 2

what is pharmacodynamics

Answer 2

what the body does to the drug as opposed to what the drug does to the body

Question 3

what does knowledge of pharmacokinetic properties of a particular drug tell us

Answer 3

what dose to give, how often to give it, how to change the dose in certain medical conditions, how some drug interactions occur

Question 4

what is absorption

Answer 4

the movement of a drug from the site of administration to the bloodstream

Question 5

3 mechanisms by which drugs may cross membranes

Answer 5

passive diffusion, facilitated diffusion, active transport

passive diffusion most common

Question 6

distribution

Answer 6

process of reversible transfer of the drug from the bloodstream to other areas of the body. if the drug does not return to the blood, it has been eliminated.

Question 7

what is the rate and extent of distribution determined by

Answer 7

• how well perfused the organs/tissues are
• binding of the drug to plasma proteins and tissue components
• permeability of tissue membranes to the drug
• ion trapping
• P-glycoproteins (efflux mechanism)
• pKa

Question 8

volume of distribution

Answer 8

convenient method of describing how well a drug is removed from the plasma and distributed to the tissues. however, it doesn’t provide any specific info about where the drug is concentrated in a particular organ.
a large Vd implies wide distribution, or extensive tissue binding, or both. conversely, ionised drugs that are trapped un plasma will have small Vd

definition; amount of fluid that would be required to contain the drug in the body at the same concentration as in the blood or plasma.

Question 9

bioavailability

Answer 9

the proportion if a dose that reaches the systemic circulation in a chemically unaltered form

Question 10

elimination half life

Answer 10

t1/2
the time required to reduce the plasma concentration to one half of its initial value
can be used to estimate for how long a drug should be stopped if a patient has toxic drug levels

Question 11

clearance

Answer 11

Cl; volume of plasma in the vascular compartment cleared of drug per unit time by the process of metabolism and excretion

drug can be cleared by renal excretion or by metabolism or both

Question 12

drug metabolism

Answer 12

drugs are detoxified by a set of xenobiotic-metabolising enzymes;
-cytochrome P450 oxidases, primarily found in the liver

enzymatic action may also convert prodrugs (inactive) to active state
availability of these enzymes is more than sufficient to efficiently metabolise most drugs

exceptions
small number of drugs where concentrations seen in real life use are high enough o saturate the eliminating enzymes e.g. phenytoin, salicylates and ethanol

Question 13

excretion

Answer 13

elimination of the molecule in its unchanged form, mainly via kidney.

1) glomerular filtration
2) tubular secretion/reabsorption

Question 14

drug interactions

Answer 14

occur when the effect of the drug is modified by presence of another agent

modifying agents- other drugs, diet, smoking, alcohol
most drug interactions involve changes to the absorption, distribution, metabolism or excretion of drugs

Question 15

pharmacokinetic vs pharmacodynamic interactions

Answer 15

pharmacokinetic; amount of drug in blood is altered

pharmacodynamic; amount of drug in blood remains the same, but its effect is altered

Question 16

drug absorption interactions

Answer 16

one drug make the absorption of another drug;
faster or slower, less or more complete

mechanisms;
pH, gastric emptying and intestinal motility, physiochemical interactions

Question 17

drug distribution interactions

Answer 17

displacement e.g. drug A and B both compete to bind to the same plasma protein

Question 18

drug metabolism interactions

Answer 18

one drug changes the rate of metabolism of another drug
induction; A increases the rate of metabolism of B, blood concentrations of B fall below normal therapeutic levels. B becomes ineffective

inhibition; A reduces the rate of metabolism of B, blood concentrations increase above that which is safe, B becomes toxic

Question 19

drug excretion interactions

Answer 19

Drug A increases or reduces the excretion of drug B

blood levels of B fall below or rise above normal therapeutic range
becomes either ineffective or toxic

Question 20

absorption requirements for passive diffusion

Answer 20

water solubility- almost all drugs are sufficiently water soluble to undergo passive diffusion
lipid solubility- some do lack necessary lipid solubility . in practise, diffusion depends mainly on lipid solubility

Question 21

efficient molecules of passive diffusion

Answer 21

hydrocarbons, anaesthetics, alcohols, lipids, most drugs

Question 22

inefficient drugs for passive diffusion

Answer 22

carbohydrates, proteins. ionised molecules

Question 23

facilitated diffusion

Answer 23

selective gateway allows entry of one group of molecules, but excludes all others

Question 24

active transport

Answer 24

structurally selective, energy requiring, can operate against concentration gradient

Question 25

patient characteristics which could effect distribution

Answer 25

oedema, dehydration, obesity, pregnancy - dose needs to be modified accordingly

Question 26

what compartments can drugs distribute into

Answer 26

plasma, interstitial fluid, intracellular fluid

Question 27

incomplete oral bioavailability

Answer 27

1. failure of disintegration or dissolution 2. chemical, enzymatic or bacterial attack 3. failure of absorption and p-gp efflux 4. first pass metabolism in gut wall or liver

Question 28

phases of metabolism

Answer 28

phase 1- functionalisation chemical change-addition of a new functional group most frequently oxidation, but also reduction renders the drug more conductive to phase 2 phase 2- conjugation conjugative or synthetic addition off a polar molecule drug becomes water soluble and amenable to renal excretion

Question 29

cytochrome P450

Answer 29

phase 1 oxidative reactions typically involve a cytochrome P450 monooxygenase (CYP) nomenclature based on nucleic acid and amino acid homology (nomenclature is genetically based; no functional implication) CYPs have family, sub family and specific gene e.g. CYP2D6

Question 30

first pass metabolism in the gut wall

Answer 30

intestinal epithelium is rich in drug metabolising enzymes (CYPs, mainly CYP3A4) ``` CYP450 activity in intestinal epithelium relative to liver duodenum 50% jejunum 30% ileum 10% colon 25 ```

Question 31

kidneys and excretion

Answer 31

excretion irreversibly removes drugs or metabolites from the body the kidneys are the principal organ of excretion, but the liver, GI tract and lungs also may play important roles ``` excretion by the kidney;1. glomerular filtration - glomerular structure, size constraints, protein binding 2. tubular reabsorption/secretion acidification/alkalisation active transport, competitive/saturable organic acids/bases protein binding ```

Question 32

biliary excretion

Answer 32

bile formed in large volumes in the liver->most of the water reabsorbed->concentrated bile stored in the gall bladder->bile excreted into the upper small intestine

Question 33

drug interactions-changes in pH

Answer 33

stomach-pH is variable antacids pH^, alcohols and some foods cause acidic secretion pH to decrease small and large intestine pH always near neutral no significant changes seen

Question 34

gastric emptying and intestinal motility

Answer 34

drug absorption from small intestine is much more efficient than from the stomach, however if drug A alters rate of gastric emptying - rate of absorption of drug B also altered

Question 35

physio chemical interactions

Answer 35

two drugs bind together within GI contents and then neither is absorbed. e.g. polyvalent cations, cholestyramine, charcoal

Question 36

CYP450

Answer 36

gradual onset and offset; onset--accumulation of inducing agent and increase in enzyme production offset- elimination of inducing agent and decay of enzymes. result in reduction of plasma concentration of substrate drugs

Question 37

withdrawal of inducer

Answer 37

patient taking barbiturates and warfarin, barbiturates cause induction-warfarin clearance increased]warfarin dose titrated above normal dose, blood levels now normal barbiturate suddenly withdrawn and replaced by valproate warfarin clearance falls- blood levels rise above normal- patient dies

Question 38

beneficial use of induction

Answer 38

new born infants have poorly developed hepatic metabolic enzymes conjugate bilirubin inefficiently-some become jaundiced small doses of barbiturates can be used to induce the liver enzymes and clear the bilirubin

Question 39

inhibition

Answer 39

not just opposite of induction: induction- additional CYP450 in the liver inhibition-no reduction in quantity of CYP450 -existing CYP450 made less effective probably most significant of all interactions-potentially fatal

Question 40

fruit juices

Answer 40

grapefruit juice contains antioxidants that inhibit CYP3A4 in the gut wall and liver. leads to increased blood levels of terfenadine and some calcium channel blockers cranberry juice contains various antioxidants including flavonoids which are known to inhibit CYP450- warfarin levels may rise significantly

Question 41

drug excretion interactions

Answer 41

mechanism of urinary excretion ; dimple filtration, active secretion (have limited capacity) mechanism for active secretion; acids, bases,, saturation of mechanisms by one of the competing drugs -other is secreted less efficiently

Question 42

most important physio-chemical properties

Answer 42

solubility in water, solubility in lipids, electrical charge, size

Question 43

physiological factors

Answer 43

nature of barriers/membrane blood supply site of action rate of removal

Question 44

patient factors

Answer 44

age, size/weight, gender. pregnancy, medical condition, ethnicity

Question 45

benefits of drugs by passing the liver

Answer 45

will not get metabolised by liver (many drugs get therapeutically altered while being metabolised by the liver) ways you can do this is by giving the drug rectally

Question 46

factors effecting bioavailability

Answer 46

formulation, physio-chemical properties, physiological factors, patient factors

Question 47

what is the therapeutic index

Answer 47

ratio of the minimum toxic concentration to the median effective concentration

Question 48

how to calculate Vd

Answer 48

Vd (L)=dose (gr)/C (gr/L) | or C=dose/Vd

Question 49

blood brain barrier

Answer 49

``` specialist cells (glial and endothelial) separate the blood vessels from the cerebrospinal fluid (CSF) exact nature varies depending on location provides additional protection to CNS while regulating transport of essential; molecules ad maintaining a stable environment (homeostasis) ```

Question 50

how would weight gain effect Vd

Answer 50

increase in fat (e.g.), depending on drugs solubility, the above may contribute to an increase in Vd, which in tur will require increasing the dose to maintain drug concentration within effective range

Question 51

excreting organs in the body

Answer 51

kidneys, skin, lungs liver

Question 52

what may direct a molecule towards excretion by kidney rather than liver

Answer 52

polar molecules get readily filtrated out by the kidney. amphiphilic drugs are more likely to get excreted by the liver into the bile,

Question 53

how do CYPs differ from one another

Answer 53

substrate, substrate affinity and enzymatic activity | genetic makeup