Introduction to pharmacokinetics

Question 1

Pharmacokinetics

Answer 1

The branch of pharmacology dedicated to determining the fate of chemical substances administered to a living organism- ‘what the body does to a drug’.

Question 2

4 stages of drug disposition

Answer 2

• absorption
• distribution
• metabolism
• excretion

ADME

Question 3

Pharmacokinetic data

Answer 3

Maps drug concentration over time. Plasma concentration of a drug is often used, as it reflects the concentration of the drug in extracellular fluid, where receptors/other targets are present. Drug concentrations in other body fluids (eg. urine, saliva, cerebrospinal fluid, milk) may also add useful information.

Question 4

Routes of administration

Answer 4

• enteral; oral, rectal
• parenteral; subcutaneous, intravenous, intramuscular, intraarterial, intrathecal, intraperitoneal, intravitreal
• percutaneous; inhalation, sublingual, topical/transdermal

Question 5

Absorption

Answer 5

Movement of a drug from its site of administration to the plasma.

Question 6

Factors affecting absorption

Answer 6

• site of administration; blood flow, surface area
• dose of drug
• drug solubility; hydrophilic/lipophilic
• pharmaceutical interventions; slow release capsules, dry powder inhalers

Question 7

Distribution

Answer 7

Reversible transfer of a drug from one location to another within the body.

Question 8

Factors affecting distribution

Answer 8

• blood flow
• lipid solubility
• diffusion barriers; blood brain barrier and placenta
• tissue binding
• plasma protein binding; albumin most common

Question 9

Albumin

Answer 9

A lipophilic protein with many binding sites. Drug binding establishes an additional equilibrium of the drug within the plasma, retaining higher concentrations in the blood.

Question 10

The one-component model

Answer 10

Treats the human body as a single vessel, measuring blood plasma concentration against time as a basic model of how much of a drug goes in vs how much goes out.

Question 11

Pharmacokinetic features of the human body

Answer 11

• fat (lipophilic) or no fat (hydrophilic)
• plasma membranes
• pH value
• active perfusion/pumping
• large SA or compact shape
• diffusion barriers
• inactivating enzymes

Question 12

Apparent volume of distribution

Answer 12

The theoretical volume of fluid required to dilute the absorbed dose to the concentration found in plasma.

AVD=dose/plasma concentration

Drugs that are heavily tissue bound or basic have a large AVD, whereas drugs that are heavily protein bound or acidic have a small AVD.

Question 13

Two-component model

Answer 13

Considers more complex mechanisms of drug disposition, like drug reservoirs and re-absorption.

Question 14

Modes of transport

Answer 14

• passive diffusion; through cells or intracellular pores
• facilitated diffusion
• active transport
• pinocytosis

Question 15

Lipid solubility

Answer 15

Lipophilicity determines whether a compound can pass through phospholipid cell membranes.

Question 16

Ionisation

Answer 16

Many drugs are weak acids or bases, whose degree of ionisation depends on local pH. They exist in an equilibrium between ionised and unionised forms. Only the unionised form is lipophilic enough to diffuse through membranes.

Question 17

Ion trapping

Answer 17

Drugs will tend to accumulate where ionisation is favoured, as the ions cannot be absorbed through membranes.

Question 18

Elimination

Answer 18

The irreversible loss of drug from the body, resulting from metabolism and excretion.

Question 19

Routes of excretion

Answer 19

• the kidneys
• the liver
• the lungs
• the salivary glands
• the mammary glands
• sweat glands

Question 20

Renal excretion

Answer 20

Low molecular weight substances (ie. most free drugs) are removed from the blood through glomerular filtration and tubular secretion. If the renal tubule is freely permeable to certain drugs, some will be passively reabsorbed, reducing the amount excreted.

Question 21

Biliary excretion

Answer 21

Liver cells transport various substances, including drugs, from plasma to bile. Some drugs are excreted fairly unchanged in bile, ending up in the faeces, while others have to undergo modification to prevent re-absorption.

Question 22

Enterohepatic circulation

Answer 22

Various hydrophilic drug conjugates (particularly glucuronides) are delivered in bile to the intestine, where they can be hydrolysed, activating the free drug, which can be reabsorbed. The cycle can then be repeated when the drug is returned to the liver, known as enterohepatic circulation.

Question 23

Phase I reactions

Answer 23

Involve ‘functionalisation’ of the drug via catabolic reactions (eg. oxidation, reduction, hydrolysis), which attach a functional group (eg. hydroxyl). Oxidation reactions mainly take place on the monooxygenase system, involving cytochrome P450 enzymes found in the liver. The products are more hydrophilic and often more reactive, and therefore can be more toxic/carcinogenic than the parent drug.

Question 24

Phase II reactions

Answer 24

Involve ‘conjugation’ of the intermediate molecule via anabolic reactions, attaching a conjugate group (eg. sulfate, glucuronyl, methyl, acetyl) to the functional ‘hook’. This usually renders the drug less reactive, and even more hydrophilic, so it can be excreted.

Question 25

Acid dissociation constant

Answer 25

pKa values are a quantitative expression of the strength of an acid or base.

Ka=(H+)(A-)/(HA)
pKa=-log(Ka)

The smaller the pKa value, the stronger the acid/base.

Question 26

Cytochrome P450 enzymes (CYP)

Answer 26

A superfamily of enzymes, found primarily as part of the monooxygenase system in the liver. They are involved in biotransformation phase I reactions during the metabolism of potentially toxic compounds, eg. drugs.