Pharmacokinetics

Question 1

Pharmacokinetics

Answer 1

How the drug is processed by the body.

Question 2

LADME

Answer 2

Liberation
Absorption (to the blood stream)
Distribution (from blood stream to site of action)
Metabolism
Excretion

Question 3

Oral Administration

Answer 3

Safe, patients easily comply, economical.

Delay before uptake into blood stream.

Potential it could be metabolised before absorption.

Question 4

Intravenous Administration

Answer 4

No Absorption! - straight to the bloodstream

Typically immediate effects

Large volumes possible

Expensive, not suitable for lipophilic substances, potential for adverse effects.

Question 5

Liberation

Answer 5

pH dependent procedure.

Question 6

Lipinski’s Rule of 5

Answer 6

Failure to comply with 2 or more means the oral drug has poor bioavailability.

1. MW < 500
2. log P < 5
3. Less than 5-H bond donor groups
4. Less than 10 H-bond acceptor groups

Question 7

Volume of Distribution (Vd)

Answer 7

Relates the amount of drug in the body to the conc. of drug in blood plasma (IV administration)

Vd = total amount of drug in the body/ blood plasma concentration of drug = Db/Cp

High Vd = less soluble in water, will bind to tissue and macromolecules.

Question 8

Duodenum

Answer 8

Organic bases become neutral and are able to be absorbed by lipids, villi allow large total absorption of species with poor diffusion tendency.

Question 9

Passive Diffusion

Answer 9

From an area of high drug concentration to an area of low drug concentration.

Lipid soluble = pass through the cell membrane.

Water soluble = pass through aqueous channels or pores

Large molecules = transmembrane carrier proteins.

Question 10

Active Transport

Answer 10

Moves drugs against a concentration gradient, is an energy-dependent process and is driven by the hydrolysis of ATP.

Question 11

Partition Coefficient

Answer 11

‘Dual solubility’ of a drug is preferable so we take the ratio of a compounds equilibrium solubility in lipophilic solvents to its solubility in water.

log P = log (c in lipid/ c in water)

Question 12

Bioavailability

Answer 12

The extent or fraction to which a drug reaches a systemic circulation. It can be impacted by digestion of food, formulation, interactions with other drugs/food, enzyme activity, genetics etc.

Question 13

Blood Tissue Barriers

Answer 13

Drugs can become bound to serum proteins once they enter the blood stream, they act as a depot for maintaining sufficient concentration at the target site.

Since cell membranes are phospholipids (negative charge) they arrange into bilayers. Lipophilic bases tend to permeate these membranes and acids tend to be repelled.

Question 14

Blood Brain Barrier

Answer 14

Has tight junctions that are extremely resistant to the passage of drugs. Has a more rigid and resistant to passive permeation cell membrane structure. Requires the presence of metabolising enzymes.

Question 15

What are the 4 main pathways that endogenous ligands can bind to receptors?

Answer 15

1. Ligand-gated ion channels
2. G protein-coupled receptors
3. Enzyme-linked receptors
4. Intracellular receptors

Question 16

Dose Response Curves 101

Answer 16

Efficacy: is the maximal response or effect that can be achieved.

EC50: Concentration of a drug that produces 50% of the maximal effect.

Potency: a measure of the drug activity relative to the amount required.

Question 17

Agonist

Answer 17

Mimics the natural ligand to get the protein to action.

Full Agonists: bind to the receptor, maximal response possible

Partial Agonist: can’t reach Emax

Inverse Agonist: binds to same receptor but produces opposite effect, can make inactive

Irreversible Agonist: permanently bound, activates receptor.

Question 18

Antagonist

Answer 18

Do not cause or oppose a response.

Non-competitive: binds at the allosteric site and reduces agonist efficacy.

Competitive: binds at the receptor and competes with agonist for the site, will keep receptor inactive.

Question 19

Therapeutic Index

Answer 19

Ratio of the dose of a drug that causes a toxic effect versus the dose that produces the clinically desired effects in patients.

TD50/ED50

Question 20

Cytotoxic Drugs

Answer 20

Small drugs that will have direct access to DNA, large molecules that can manipulate the equilibrium of coiled and uncoiled DNA to the histone.

Question 21

What are the 3 main drug interactions with DNA?

Answer 21

1. Reversible DNA binders: external electrostatic interactions, groove binding or intercalation.
2. DNA alkylators: react as electrophiles to form stable covalent bonds, frequent reactions lead to mutations.
3. DNA strand breakers: intercalates with DNA to generate radicals, radicals abstract the H from the DNA bases = DAN strand scission

Question 22

Henderson - Hasselbalch Equation

Answer 22

pH = pKa + log[A-]/[HA]

Question 23

Xenobiotic Metabolism

Answer 23

The modification of foreign compounds, including drugs and toxins - the main metabolic strategy is to modify drugs to increase hydrophilicity.

Occurs mainly in the liver through enzymatic transformation

Will render metabolites inactive and allow them to be cleared by the kidneys.

Question 24

Oxidation

Answer 24

Enzymes: flavin-containing monooxygenases (eg. cytochrome P450)

Co-factor: NAD(P)H + NAD(P) (metal catalysis) FAD/FAD(H2) (non-metal catalysis)

Often occurs at the terminal or penultimate carbon, most exposed region of the molecule and acts to increase solubility.

Question 25

Reduction

Answer 25

Enzyme: reductases

Co-factors: NADPH

Occurs for aldehydes, ketones, azo and nitro functional groups.

Question 26

Hydrolysis

Answer 26

Esters and amides form carboxylic acids, alcohols and amines.

Enzymes: Esterases and amidases/peptidases

Question 27

Hydration

Answer 27

Addition of water turns epoxides to diols

Enzyme: epoxide hydrolase

Question 28

Phase II Metabolism

Answer 28

Conjugation reactions with the nucleophiles and electrophiles from phase I. Create larger and generally more water soluble products.

Drugs with -OH -NH2 and -COOh may directly undergo phase II.

Catalysed by transferases

Question 29

Glucuronidation

Answer 29

Sugar fragment is attached to metabolite

Enzyme: Glucuronyltranferase

Co-factor: Uridine triphosphate glucuronic acid.

Question 30

Sulfation

Answer 30

Enzyme: sulfotransferase

Co-factor: phosphoadenosyl phosphosulfate (PAPS -> PAP)

Attaches a sulfate group to metabolite.

Question 31

Amino-Acid Conjugation

Answer 31

• Co-factor: ATP/CoASH
• Enzyme: Acyl CoA synthetase and N-acyltransferase
• 3 steps:
  
  1. Activation of the RCOOH by ATP to the AMP ester
  2. This ester is converted to the coenzyme A thioester
  3. Condensation of amino acid and coenzyme A thioester to give the conjugated amino acid.

Question 32

Glutathione Conjugation

Answer 32

• Co-factor: glutathione
• Enzyme: glutathione S-transferase
  Undergoes Sn2, SnAr conjugation addition (Michael Addition) & reduction

Question 33

Acetylation

Answer 33

• Co-factor: acetyl CoA
• Enzyme: N-acetyltransferase
• 2 steps:
  
  1. Acetyl CoA acetylates amino acid residue of the enzyme
  2. Acetyl group is transferred to the substrate amino group

Question 34

Methylation

Answer 34

• Transfer of a methyl group, important for biosynthesis of endogenous compounds (melatonin), accepted by phenols, alcohols, amines and thiols.
• Co-factor: S-adenosyl methionine (SAM)
• Enzyme: methyltransferase