Pharmacokinetics

Question 1

Pharmacokinetics

Answer 1

The journey of a drug through the body (ADME):

Administration
Absorption
Distribution
Metabolism
Excretion
Removal

Question 2

Why is pharmacokinetics important?

Answer 2

Determines dose of drug available to tissues

Question 3

Administration of drugs

Answer 3

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Question 4

Systemic effect

Answer 4

The entire organism

E.g. cannabis, aspirin, nicotine (patch)

Question 5

Local effect

Answer 5

Restricted to one area of the organism

E.g. salbutamol, antacid, betnovate

Question 6

Enteral vs Parenteral

Answer 6

Enteral = gastro-intestinal admin

Parenteral = outside GI tract

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Question 7

Drug molecules move around the body in two ways:

Answer 7

Bulk flow transfer (i.e. in the bloodstream)
Diffusional transfer (i.e. molecule by molecule over short distances)

NOTE: drugs have to transverse both aqueous and lipid environment

Question 8

Compartments = aqueous (e.g. blood, lymph, ECF, ICF)

Barriers = lipid (i.e. cell membranes - epithelium, endothelium)

How can drugs cross these barriers?

Answer 8

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Also pinocytosis (drug embeds themselves into the membrane) - doesn’t happen very often

Question 9

Which of these three routes is least relevant for absorption of drugs?

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Answer 9

Diffusion across aqueous pores

The drugs have to be very small

Water soluble = small - diffuse through aqueous pore (but not many are that small)

Lipid soluble = just diffuse

Question 10

Drug via oral route

Answer 10

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Question 11

…..

Answer 11

Non-polar substances can freely dissolve in non-polar solvents. I.e. can penetrate lipid membranes freely.

Very important:
Most drugs are either weak acids or weak bases
Therefore drugs can exist in ionised (polar) and non-ionised (non-polar) forms - the ratio depends on the pH

Question 12

Henderson-Hasselbalch equation

Answer 12

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10^(pKa - pH) = [AH]/[A-] or [BH+]/[B]

Note: if the ratio is 1 = equilibrium

Question 13

TRUE OR FALSE:

PKa of drug does not change

Answer 13

TRUE

pH of different body compartments do change

Question 14

….

Answer 14

Acids = if pH is below pKa = more unionised

Bases = if pH is below pKa = more ionised

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Question 15

What is ion-trapping?

Answer 15

Drugs can be very localised within certain compartments

E.g. aspirin can easily transport from the stomach (lower pH than pKa)m but there are lots of ionised aspirin in the blood due to the pH

Question 16

Why might treatment with intravenous sodium bicarbonate increase aspirin excretion

Answer 16

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IV sodium bicarbonate will increase urine pH
High pH = more ionised drug
Excretion needs high ionisation (otherwise it’s lipid soluble and diffuses back into the bloodstream)

E.g. people who overdose are given bicarbonate to facilitate excretion of drug

Question 17

Factors influencing drug distribution

Answer 17

Regional blood flow
Extracellular binding (plasma-protein binding)
Capillary permeability (tissue alterations - renal, hepatic, brain/CNS, placental)
Localisation in tissues

Question 18

Regional blood flow

Answer 18

The more blood goes to a particular tissue, the more drug reaches that tissue

Highly metabolically active tissues = denser capillary networks

NOTE: eating a meal = more blood directed to the gut, exercise = more blood directed to skeletal muscle

Question 19

Extracellular binding (plasma-protein binding)

Answer 19

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If a drug is bound to plasma protein, it’s not leaving the blood.

E.g. warfarin is heavily plasma-protein bound (well over 90%). Therefore, adjust dose

NOTE: acidic drugs are heavily plasma-protein bound (e.g. aspirin = 50-80% bound)

Multiple drugs = if two of them are bound to plasma proteins, they can displace each other (e.g. 5% of unbound warfarin —> 10% unbound warfarin)

Question 20

Capillary permeability

Answer 20

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Most capillaries = continuous structure (H2O filled gap junction)

Water soluble drugs = need some mechanism to get across membrane (especially blood brain barrier with tight junctions)

Question 21

Localisation in tissues

Answer 21

Some drugs can just sit in the tissue (mostly adipose tissue - very little blood supply)

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Really fat-soluble drugs = vast amounts are distributed into adipose tissue
It will slowly leak back into the blood, but it will take a long time

E.g. general anaesthetic = very lipid-soluble (after 24 hours, you suddenly feel very drowsy - drugs are leaking out of adipose tissue)

Question 22

Two major routes of drug excretion

Answer 22

Kidney - eliminate drug in urine
Liver - secreted into bile and lost in faeces

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Question 23

Excretion in kidney

Answer 23

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Mostly active secretion (kidney has hundreds of transporters for drugs)

If drug remains lipid-soluble it will diffuse across again into the bloodstream

Question 24

Excretion in liver

Answer 24

Biliary excretion (large molecular weight molecules can concentrate)
Active transport systems for water soluble drugs - into bile (bile acids and glucuronides)

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Question 25

Enterohepatic cycling - why is it a problem for excretion?

Answer 25

Drug/metabolite excreted into gut (via bile) then reabsorbed, taken to liver and excreted again

This leads to drug persistence

Question 26

Other routes of excretion (usually of little quantitative importance)

Answer 26

Lungs, skin, GI secretions, saliva, sweat, milk, genital secretions

E.g. breathalyser

Question 27

Consider all of. The pharmacokinetic processes acting simultaneously:

Answer 27

Can predict time course of drug action

Question 28

Bioavailability

Answer 28

Linked to absorption

Proportion of the administered drug that is available within the body to exert its pharmacological effect

Question 29

Apparent volume of distribution

Answer 29

Linked to distribution
The volume in which a drug appears to be distributed - an indicator of the pattern of distribution (e.g. in adipose tissue)

Fatsoluble drugs can distribute more so than water-soluble

Question 30

Biological half-life

Answer 30

Linked to metabolism/excretion

Time taken for the concentration of drug (in blood/plasma) to fall to half its original value

Question 31

Clearance

Answer 31

Linked to excretion
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time.
(Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes)