Pharmacokinetics

Front 1

what are the ways in which drugs can be transported across membranes? (4) which of these require energy & which of these require a carrier?

Back 1

passive diffusion
facilitated diffusion (carrier)
aqueous channels
active transport (energy & carrier)

Front 2

what drives passive diffusion of a drug across a membrane? (2)

Back 2

concentration gradient across membrane
lipid:water partition coefficient of the drug (greater cooefficient, high conc drug in membrane & faster diffusion)

Front 3

what drives passive diffusion of ionic compound? why?

Back 3

its pKa
pH gradient across the membrane

very small compounds can be carried in bulk water flow (molecular weight less than 200)


since they are not soluble in lipid

Front 4

how are drugs passed across most capilliary endothelial membranes? with which exception & why

Back 4

bulk flow through intercellular pores

tight junctions in CNS capillaries limit this intercellular diffusion

Front 5

what defines facilitated diffusion?

Back 5

carrier - mediated transport process that does not require energy (ie movement of substance is not against an electrochemical gradient)

Front 6

when is facilitated diffusion useful?

Back 6

when the rate of movement across the membrane by simple diffusion would otherwise be too slow

Front 7

how does active transport differ from facilitated diffusion?

Back 7

it is identical except that ATP powers the drug transport against a concentration gradient

Front 8

what, generally speaking, is pharmacokinetics?

Back 8

what the body does to the drug

Front 9

what is the definition of drug absorption?

Back 9

the rate at which a drug leaves site of administration & extent to which this occurs

Front 10

what concept is more clinically useful than drug absorption?

Back 10

bioavailability - proportion of administered dose reaching the systemic circulation

Front 11

what does drug absorption ultimately depend on, regardless of site?

Back 11

drug solubility

Front 12

what are drug factors influencing absorption? (5)

Back 12

ionization state
molecular weight
solubility (lipophilicity)
formulation (solution versus tablet)
concentration (increased conc absorbed more rapidly)

Front 13

what patient factors influence drug absorption?

Back 13

- local conditions at site of absorption
- pH local anaesthetic
- presence of food in gastro tract
- circulation to site of absorption

- surface area of absorbing surface
(determined by route of admin)

Front 14

what features of a drug favour absorption in the GI tract? why?

Back 14

non ionized & lipophilic

since most GI absorption occurs via passive process

Front 15

why is the stomach a poor absorber of drugs?

Back 15

thick mucous membrane
low surface area
increased electrical resistance

Front 16

why does gastric emptying increase drug absorption?

Back 16

intestine has a thin, low resistance membrane & a high surface area

so pushing drug from low absorbing stomach to high absorbing intestine increases drug absorption rate

Front 17

how does enteric coating influence drug absorption in the GI tract? (2)

Back 17

prevents drugs being destroyed by gastric contents

HOWEVER may also resist dissolution in the intestine -> low absorption

Front 18

why is the sublingual route effective for GTN? (4) why would we think it wouldn't be so?

Back 18

GTN - non ionic & high lipid soluble
- is very potent - need relatively few molecules for therapeutic effect
- venous drainage from mouth is to SVC, so limited 1st pass metabolism
- first pass metabolism would destroy GTN if swallowed as tab

the sublingual route has a low surface area which theoretically would decrease absorption

Front 19

what are two negatives and two positives for using the rectal route of drug administration?

Back 19

-ve:
- often irregular & incomplete absorption
- often irritates rectal mucosa

+ve
- ~50% absorption bypasses liver first pass
- useful when pt vomiting/unconscious

Front 20

what kind of first pass metabolism are parenteral methods subject to?

Back 20

lung
especially weak bases & those not ionized @ blood pH

Front 21

how are SC & IM drugs absorbed?

Back 21

simple diffusion along gradient

Front 22

what factors limit SC/IM absorption (2)

Back 22

SA of absorbing capillary membrane
solubility of substance in interstitial fluid

Front 23

what are the positive features of IV route of admin (3)?

Back 23

- circumvents absorption problems
- allows accuracy & immediacy not otherwise possible
- suitable for large volumes

Front 24

what are the negative features of IV admin? (3)

Back 24

can't go back
can't use for oily/insoluble drugs (WHY)
need a patent vein

Front 25

what happens if we use an irritating drug via SC route?

Back 25

severe pain, necrosis, slough

Front 26

what features of SC route lead to sustained effect? how can this be prolonged?

Back 26

constant & slow absorption

prolonged by adding vasoconstrictor or by using insoluble preparation

Front 27

what human factor greatly increases absorption via IM route?

Back 27

blood flow to area

Front 28

how does presence of subcutaneous fat influence rate of absorption?

Back 28

decreases, since poorly perfused

Front 29

what characteristic of the lungs facilitates rapid absorption of volatile /atomized drugs?

Back 29

large surface area

Front 30

when is systemic absorption the goal of topical nasal therapy? when is it an unwanted side effect?

Back 30

ADH therapy (desired)

Local anaesthesia (not desired)

Front 31

which of the epidermis vs dermis acts as a barrier to topical absorption of drugs to skin? when is this clinically relevant

Back 31

epidermis

dermis freely permeable to solutes

relevant when skin barrier has been disrupted (abraded, burned, denuded skin)

Front 32

what is inunction?

Back 32

suspending skin drugs in oily vehicle to increase absorption

Front 33

how are eye drugs usually absorbed & when is this clinically important?

Back 33

through the cornea
corneal infection/trauma results in rapid absorption

Front 34

what is bioequivalence?

Back 34

same active ingredients
identical in strength/concentration, dosage form & route of admin
same rate & extent of bioavailability of active ingredient

Front 35

where would a drug with Vd = 3L be distributed? how about Vd = 16L? Vd >46L?

Back 35

3L - plasma only (plasma vol 3L)
16L - extracellular H20 (3L plasma plus 10-13L interstitial fluid)
>46 likely sequestered in depot as body only contains 40-46L fluid

Front 36

what kinds of organs receive most of a drug during the first few minutes after absorption?

Back 36

heart, liver, kidney, brain & other well perfused organs

Front 37

how long does delivery of a drug to muscle, most viscera & fat take after absorption?

Back 37

several minutes to hours before steady state

Front 38

what factors, as well as blood flow, determine rate of distribution? (4)

Back 38

- highly permeable capillary endothelium means distro is rapid into interstitium, except in brain

- lipid insoluble drugs can't permeate membranes easily -> limited distro

- drug binding to plasma proteins eg albumin acid drugs limits access to cellular sites of action

- accumulation in tissues in higher conc than expected due to pH gradients, binding to intracellular contituents or partitioning into lipid

Front 39

what lesson does thiopental teach us about distribution?

Back 39

successive doses of thiopental accumulate in fat & can become thiopental reservoirs.

Thiopental, on first dose, has a rapid onset of anaesthetic but also of termination, since it doesn't actually bind to anything in the brain. Thiopental diffuses into other tissues eg muscle, so plasma conc falls.

Fat reservoirs can maintain plasma concentration and therefore brain concentration at/above anaesthetic threshhold -> can become long acting

Front 40

how does the CNS pose problems to drug distribution?

Back 40

tight junctions predominate & aqueous bulk flow is therefore severely restricted -> less drugs can get in

highly lipid soluble drugs can get into CNS

but strongly ionized agents are usually unable to enter CNS from circulation

Front 41

what plasma proteins bind acidic drugs? basic drugs?

Back 41

albumin - acidic

a1-acid glycoprotein - basic

Front 42

what normal drug processing activities are prevented by plasma protein binding? (2)

Back 42

- limits concentration of drug at tissues & locus of action (only unbound drug is in equilibrium across membranes)

- glomerular filtration (conc of free drug in plasma not immediately changed)

Front 43

what renal drug processing function is not limited by binding to plasma protein & why?

Back 43

renal tubular secretion/biotransformation since these processes lower free drug concentration, leading to dissociation of drug - protein complex

Front 44

what kinds of molecules do drugs normally bind to in tissues & is tissue binding of drugs generally reversible/irreversible?

Back 44

proteins/phospholipids/nucleoproteins

generally reversible

Front 45

why is fat a stable drug reservoir?

Back 45

relatively low blood flow

Front 46

how does bone act as a drug reservoir?

Back 46

tetracycline antibiotics & heavy metals can adsorb onto the bone crystal surface & be incorporated into the lattice, thus bone can become a reservoir for slow release of toxic agents for a long time after exposure has ceased

Front 47

what is the major transcellular reservoir?

Back 47

GI tract

Front 48

what is redistribution of a drug?

Back 48

when drug effect terminates because the drug has been redistributed from its site of action to other tissues/sites

esp when a highly lipid soluble drug acting on CNS/CVS administered rapidly IV/inhaled

Front 49

how do drugs cross the placenta?

Back 49

simple diffusion esp lipid soluble, non ionized drugs

Front 50

when is the volume of distribution much larger than the animal itself?

Back 50

when a drug binds preferentially to tissues at the expense of plasma

Front 51

what size volume of distribution would an ionized molecule trapped in plasma have?

Back 51

small

Front 52

what is the usefullness of volume of distribution?

Back 52

hypothetical measure of how well a drug is removed from the plasma and distributed to the tissues

Front 53

how would the volume of distribution distinguish between drugs that are not highly bound to plasma but don't enter the cell vs those which enter the cell freely?

Back 53

Vd in non cell entering would be volume of extracellular fluid (0.2L/kg) whereas those entering cells freely would be total body water volume (0.55L/kg)

Front 54

how does the one compartment model limit our evaluation of the volume of distribution?

Back 54

drugs will not be distributed to all the tissues evenly, this only looks at whether drug is in plasma or not

Front 55

how does volume of distribution relate dose and concentration

Back 55

a low volume of distribution means the concentration > dose ie H20 soluble, highly bound to plasma protein

a high vol of distribution means dose>concentration ie lipid soluble, highlhy bound to tissues

Front 56

give example of 3 drugs with low volume distribution

Back 56

warfarin
amoxycillin
gentamicin

Front 57

give example of 4 drugs with high volume of distribution

Back 57

diazepam
digoxin
amitryptiline
chloroquin

Front 58

what is the formula for calculating volume of distribution?

Back 58

Vd = dose (amount of drug in body)
____________

concentration in plasma

Front 59

how does volume of distribution affect our calculation of drug loading doses?

Back 59

if you know the desired drug concentration in plasma & the volume of distro (in L/kg) & the pts weight, you can change the equation around to:

dose = Vd x target concentration

Front 60

how does Vd affect our calculation of top up doses if the drug is present but the concentration too low?

Back 60

loading dose = (target conc - measured conc) x Vd

Front 61

why is drug biotransformation necessary? (2)

Back 61

because most active drugs are non polar and polar drugs are more easily excreted

also because duration of action would be very long if left polar vs changed into (usually less active) metabolite

Front 62

what are the two main categories of drug biotransformation and what distinguishes them?

Back 62

phase I = NONSYNTHETIC - drugs are oxidised/reduced to a more polar form

phase II = SYNTHETIC
polar group is conjugated to a drug

drugs undergoing phase II conjugation may have already undergone phase I transformation (& vice versa)

Front 63

where does drug biotransformation mainly occur? where else may it occur (5)

Back 63

liver

also GI, lungs, skin, kidneys, brain

Front 64

give 4 examples of drugs which are more extensively metabolised in the intestine than the liver

Back 64

clonazepam
chlorproazine
cyclospine
midazolam (50% intestinal metabolism)

Front 65

what in the lower gut is capable of many biotransformation reactions?

Back 65

microbes

Front 66

give an example of a drug that can be metabolised by gastric acid

Back 66

penicillin

Front 67

give an example of a drug that can be metabolised by digestive enzymes

Back 67

polypeptides eg insulin

Front 68

give an example of a drug that can be metabolised by enzymes in intestinal wall

Back 68

sympathomimetic catechoamines

Front 69

where are biotransformations catalysed at the subcellular level (4)

Back 69

ER, mitochondria, cytsol, lysossomes

occasionally nuc envelope/plasma membrane

Front 70

what are microsomes and which kind are full of oxidative drug metabolism enzymes?

Back 70

microsomes are vesicles formed from leftover endoplasmic reticulum

the ones formed from smooth ER contain the enzymes

Front 71

?? how much detail do we need on the P450 system ??

Back 71

...

Front 72

what are the two microsomal enzymes that are key in microsomal biotransformation? which is more important? why?

Back 72

NADPH-cytochrome P450 reductase

cytochrome P450 which is more important - it is more abundant in the liver, so P450 heme reduction is a rate limiting step in hepatic drug oxidation

Front 73

why is P450 so named?

Back 73

in its reduced (ferrous) form it binds CO to give a complex that maximally absorbs light at 450nm

Front 74

what is required for microsomal drug oxidation? (4)

Back 74

p450
p450 reductase
NADPH
molecular oxygen

Front 75

what is the common structural feature of drugs metabolised in the p450 system?

Back 75

high lipid solubility

Front 76

how do P450s compare with many other enzymes in terms of speed?

Back 76

sluggish & reactions are slow

Front 77

?? HOW MUCH DETAIL DO WE NEED TO KNOW FOR PHASE I reactions??

Back 77

???

Front 78

what is the significance of CYP3A4?

Back 78

is the P450 isoform responsible for metabolising >50% prescription drugs metabolised by the liver

Front 79

?? how much detail about enzyme inducers & inhibitors?

Back 79

...

Front 80

what is required for increased P450 synthesis?

Back 80

increased transcription/translation (mediated by cell receptors for the inducer) & increased synthesis of heme (prosthetic cofactor)

Front 81

what is a cruciferous vegetable?

Back 81

spinach/kale/tatsoi etc
induce CYP1A p450 genes

Front 82

what is the common mechanism of inhibiting p450 enzymes?

Back 82

binding or interact with the P450 heme iron -> inactivate enzyme/competitively inhibit binding etc

Front 83

what distinguishes phase II reactions?

Back 83

they are synthetic

vs nonsynthetic phase I reactions

Front 84

are phase I or phase II reactions generally faster?

Back 84

phase II

Front 85

what are the general characteristics of conjugates formed by phase II reactions?

Back 85

polar, readily excreted, often inactive

Front 86

what are the most dominant phase II enzymes?

Back 86

UGTs

uridine 5'-diphosphate - glucuronosyl transferases

Front 87

?? need to know metabolism of paracetamol to hepatotoxic metabolites in detail?

Back 87

katzung fig 4-5

Front 88

what percentage of paracetamol metabolism is phase II vs phase I? why is this important

Back 88

95% phase II

the remaining 5% phase I becomes important at very high doses as P450 pathway becomes increasingly important

Front 89

what hepatic compound is necessary for safe phase I metabolism of paracetamol?

Back 89

GSH (glutathione)

is depleted faster than it can be regenerated with time, leading to accumulation of reactive toxic metabolite

Front 90

which enzymes do charcoal broiled foods & cruciferous vegetables induce?

Back 90

CYP1A

Front 91

what does grapefruit juice inhibit?

Back 91

CYP3A metabolism of coadministered drug substrates

Front 92

what affect does cigarette smoke have on enzyme induction?

Back 92

increases in some drugs

Front 93

which drugs are enzyme inducing? (5)

Back 93

various sedative hypnotics
antipsychotics
anticonvulsants
rifampicin (anti TB)
insecticides

Front 94

how do sedatives and certain antipsychotics affect warfarin levles?

Back 94

routine use of these may lead to considerably higher doses of warfarin required & cessation of these may lead to reduced anticoagulant metabolism & bleeding

Front 95

what is the inductive explanation for drug tolerance?

Back 95

an inducer may enhance not only the metabolism of other drugs but its own metabolism

Front 96

apart from liver, what other system disease can impair drug metabolism & how?

Back 96

cardiac - by preventing blood flow to liver of very rapidly metabolised drugs

thyroid (esp hypo)

bacterial/viral infections -> inflamm mediators/cytokines & NO release

Front 97

what is drug clearance?

Back 97

the factor that predicts rate of elimination in relation to drug concentration

Front 98

what is the formula for clearance?

Back 98

C = rate of elimination/concentration

Front 99

how is drug clearance additive?

Back 99

drug elimination may involve processes occuring in kidney, lung, liver & other organs. total systemic clearance equals CL kidney + CLliver + CLother

Front 100

what are the two main sites of drug elimination?

Back 100

kidneys & liver

Front 101

what represents renal clearance?

Back 101

clearance of unchanged drug in urine

Front 102

how are drugs cleared in liver? (3)

Back 102

biotransformation to metabolites

excretion of unchanged drug into bile

both

Front 103

how does rate of drug elimination compare to concentration?

Back 103

directly proportional

clearance is constant over concentration range

Front 104

what is first order elimination? how can it be calculated?

Back 104

when rate of elimination = clearance x concentration

estimated by calculating the area under the curve of time/concentration profile after a dose?

Front 105

how can clearance be related to area under the curve?

Back 105

clearance = dose/AUC

Front 106

how does first order elimination clearance relate to capacity-limited (or saturable/non linear/ Michaelis-Mentin elimination)?

Back 106

first order elimination is not saturable & the rate of drug elimination is directly proportional to concentration

capacity limited elimination means that clearance will vary depending on the concentration of drug achieved & is saturable

Front 107

which are the three drugs for which clearance has no real meaning & why?

Back 107

aspirin, ethanol, phenytoin

concentration will keep rising as long as dosing continues (if dosing rate exceeds elimination capacity, steady state cannot be achieved)

Front 108

what is the equation to relate rate of elimination in capacity limited elimination?

Back 108

rate of elimination = Vmax x C
________

Km + C

where V max is max elimination capacity
Km is drug concentration where rate of elimination is 50% of Vmax

Front 109

how does flow dependent elimination relate to capacity limited elimination?

Back 109

flow dependent - some drugs cleared so readily by organ that most of drug is eliminated on first pass ie blood flow determines rate of elimination

capacity limited drug elimination has no relevance to blood flow & can be saturated by drug concentration

Front 110

what is the formula for half life in a single compartment?

Back 110

t1/2 = log2 x Vd / CL

nb log2 approx equal to 0.7

Front 111

when does the "true" half life exceed that from the half life formula?

Back 111

in multicompartment models (most drugs)

Front 112

what is the accumulation factor? what does the accumulation factor equal for a drug given every half life?

Back 112

an index of accumulation

accumulation is inversely proportional to the fraction of the dose lost in each dosing interval

ie AF = 1/1- fraction remaining

so for dose every half life

AF = 1/0.5 = 2

Front 113

what are the 3 primary processes of pharmacokinetics?

Back 113

absorption
distribution
elimination

Front 114

what is volume of distribution?

Back 114

the measure of apparent space in the body available to contain the drug

Front 115

what links pharmacokinetics & pharmacodynamics?

Back 115

concentration

Front 116

what is steady state?

Back 116

pseudo zero order elimination
elimination rate almost independent of concentration

average total amount of drug in the body does not change over multiple dosing cycles

Front 117

what is first pass effect?

Back 117

elimination of drug occuring after administration but before it enters systemic circulation

Front 118

how do we calculate loading dose?

Back 118

target conc (mg/L) x vol distribution (L/kg)

Front 119

how do we calculate IV maintenance dose?

Back 119

Infusion rate
= target steady state conc x clearance rate

divided by salt & molar correction factor

Front 120

how do we calculate oral maintenance dose?

Back 120

avg target steady state x clearance x dosage interval

divided by

bioavailability x salt corr x molar corr

Front 121

when do ionizable forms of drugs cross membranes best?

Back 121

when they are in their non ionized form

Front 122

when would a weak acid be in its best form to cross the lipid membrane? a weak base?

Back 122

weak acid - non ionized at more acid pH

weak base - non ionized at more alkaline pH

Front 123

how can we use pH to trap drugs in the urine for excretion?

Back 123

by adjusting urine pH to make sure drug is in ionized state & hence can't be reabsorbed from the tubule

Front 124

give a clinical example of how we could possibly use urine to excrete a drug?

Back 124

methamphetamine, a weak base, is freely filtered at the glomerulus but can be rapidly reabsorbed at the renal tubule

ammonium chloride acidifies the urine which converts a larger fraction to charged form, poorly absorbed & thus rapidly eliminated

however there is a risk of renal damage with forced diuresis & urinary pH manipulation