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PCOL2011 > Module 2 - Pharmacokinetics & Drug Metabolism > Flashcards

Module 2 - Pharmacokinetics & Drug Metabolism Flashcards

1
Q

What are the two ways drugs cross the membrane?

A
  1. Passive Diffusion

2. Transporter-assisted uptake

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2
Q

What is passive diffusion?

A

A way drugs cross the membrane.

Drugs must be sufficiently hydrophobic to penetrate membranes. Must then pass through to the aqueous intracellular environment to reach drug target. Must not be trapped in membranes.

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3
Q

What is transporter-assisted uptake?

A

A ways drugs cross the membrane.

Specialised uptake transporters for physiologically important organic anions and cations. Can also accommodate many anionic and cationic drugs. Assists these drugs to enter cells and reach drug targets.

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4
Q

How is passive diffusion affected by drug ionization?

A

Ionization influences the extent of drug movement between aqueous and lipid environments.

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5
Q

How does tissue pH affect drug disposition?

A

pH varies in different biological fluids - stomach = 2-2.5; urine = 5-8; small intestine = 7.5-8

pH affects how much of a weak acidic or basic drug is absorbed because only the unionised form can cross membranes.

pH also affects drug excretion because membranes also have to be crossed.

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6
Q

What are solute carrier (SLC) transporters?

A

They play a physiological role in anion and cation transport across membranes and also mediate uptake of numerous drugs.

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7
Q

Structure of a solute carrier (SLC) transporter

A

Consist of 12 trans-membrane domains.

Several intracellular and extracellular loops orient the transporter in the membrane.

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8
Q

Approximately how much total blood volume is there in a 70kg human?

A

5-6 litres

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9
Q

Approximately how much total body water is there in a 70kg human?

A

32-40 litres

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10
Q

What do values of Vd close to blood volume reflect?

A

They reflect high degree of protein binding

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11
Q

Oral drug administration routes (3)

A

Tablets; capsules; suspensions (the state of a substance when its particles are mixed with but undissovled in a fluid or solid)

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12
Q

Injection drug administration route (3)

A

Intravenous (injected into the veins); intramuscular; intrathecal (injected into the spinal theca)

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13
Q

What is intraocular?

A

Injecting the drug into the eye

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14
Q

What are the less common routes of drug administration? (3)

A

Rectal; sublingual (applied under the tongue); subcutaneous injections (situated or applied under the skin)

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15
Q

What happens when a drug is administered orally?

A
  1. Drug released in the intestine is absorbed into the portal circulation.
  2. Portal blood is then delivered to the liver.
  3. The liver is the major organ of biotransformation.

However biotransformation soon after absorption means that the entire dose of a drug may not be available to act in the body.

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16
Q

Define first-pass effect (heptatic extraction?)

A

Is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.

Heptatic extraction is high when a drug is extensively metabolised.

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17
Q

Define relative bioavailability and what influences it

A

Relative bioavailability of an oral dose form is the fraction that reaches the systemic circulation intact.

Influenced by:
The amount of drug that is released form the oral dose form; the amount of the dose that is absorbed; how much is taken out by pre-systemic metabolism.

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18
Q

Name the three sites of oral absorption

A

Small intestine - this is a major site of absorption; has a large surface area

Large intestine - some molecules preferentially absorbed in large intestine; important for some delayed release dose forms

Stomach - small surface area; some drugs are ionised at stomach pH

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19
Q

How does food ingestion affect oral absorption of drugs?

A

Food slows gastric emptying and decreases absorption further down the intestine

Type of meal is important - solid meal is retained in the gut longer than a liquid meal

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20
Q

Define intravenous

A

Drug injected into the nerves therefore immediately available in the body; also means it is not reversible.

Does involve some risk of infection or embolism.

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21
Q

Define intramuscular

A

Drug injected into the muscle; is an oily injection and has a slow release (depot) where the effect is sustained over weeks/months

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22
Q

Define intrathecal

A

Drug injected directly into the cerebrospinal fluid. E.g. spinal anaesthesia

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23
Q

Why drug administration routes avoids first-pass effects? How?

A

Injections - Because the drug is injected directly into the systemic circulation so bypasses presystemic metabolism in enterocytes or liver. In comparison with an oral dose form, a lot of dissolution occurs in the gut (liver)

Intraocular and intranasal - because they act locally, this generally minimizes systemic effects

Creams, ointments, rectal administration, sublingual

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24
Q

Which drug administration route has the lowest blood concentration?

A

Oral

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25
Q

Define xenobiotic metablism

A

Xenobiotic is a synonym for a foreign or exogenous chemical. Therefore is a set of metabolic pathways that modify the chemical structure of xenobiotic.

This includes drugs, dietary chemicals, environmental pollutants, industrial chemicals and other poisons.

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26
Q

Define endobiotic

A

Or or relating to an organism that exists as a parasite or symbiont entirely within the tissues of a host organism.

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27
Q

What happens when unchanged drug and drug metabolites exit the liver?

A

The drug enters the systemic circulation and is delivered to tissues where it exerts its pharmacological effect.

Drug metabolites in blood may be excreted in the kidney.

Other metabolites may be excreted in bile and are deposited in the intestine.

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28
Q

What are the major class of phase 1 biotransformation enzymes?

A

Cytochromes P450

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29
Q

How many Cytochrome P450 are there?

A

There are 57 human P450 genes; about 12 mediate drug oxidation

30
Q

Define Cytochrome P450

A

Cytochrome P450 enzymes are haem proteins, comprising a large family of related but distinct enzymes, each referred to as CYP followed by a defining set of numbers and a letter.

Lipophilic xenobiotics and endobiotics are oxidised by cytochrome P450s

31
Q

Define CYP3A4

A

Is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.

Role in metabolism of 60% of drugs and 50% of all P450s

32
Q

What drug inhibits CYP3A4?

A

The increase in blood levels of felodipine is consistent with inhibition of CYP3A4, which metabolises felodipine.

Blood levels of felopdipine after grapefruit juice were much higher. Grape juice inhibits intestinal metabolism so more drug is absorbed.

33
Q

What is grapefruits interaction with CYP3A4

A

Grapefruit juice contains bergamottin that inactivates intestional but not liver CYP3A4. Drugs that undergo pre-systemic oxidation in the intestine are susceptible to the grapefruit juice effect.

34
Q

How are CYP activated?

A

By exposure to certain drugs and chemicals.

35
Q

Define induction

A

The process of increasing the amount or the activity of a protein.

36
Q

Define P450 Enzyme Induction

A

Induction can cause marked increases in P450 composition and chemical clearance or bioactivation.

As a result, induction can increase tolerance to some toxicants while enhancing the toxicity of others.

Induction can decrease the therapeutic effect of drugs by increasing the rate and pattern of metabolism.

37
Q

St Johns wort relationship with CYP3A4

A

Is a CYP3A4 substrate

38
Q

Role of CYP1A2 in the body

A

Approximately 15% of total in P450 in liver.

Role in metabolism of few drugs

39
Q

Induction of CYP1A2

A

You see much higher levels of CYP1A2 in smokers than non-smokers. The CYP1A2 gene is inducible by chemicals in cigarette smoke and other environmental pollutants like dioxins

40
Q

CYP1A2, smoking and clozapine

A

CYP1A2 is inducible by cigarette smoke.

The antipsychotic drug clozapine may be the only effective agent in some patients. Clozapine is metabolised by CYP1A2.

Some patients may be stablised on clozapine and a high level of cigarette use; higher maintenance doses of clozapine required in smokers.

41
Q

Define Prodrug

A

Prodrugs are inactive precursors that are metabolised to active metabolites.

42
Q

ABC efflux transporters

A

Facilitate the initial phase of polar metabolite removal from cells (exports polar drug conjugates from cells)

43
Q

Inhibition of ABC transporters and its role with cancer

A

Pharmaceutical companies have searched for inhibitors of ABC-transporters because of their role in anticancer drug efflux.

ABC-transporters are often over-expressed in cancer cells; this enables cancer cells to efficiently eliminate drugs; cancer cells are then resistant to these drugs.

44
Q

What are the major routes of elimination for a drug?

A

Once a drug has undergone phase 1 and 2 metabolism it is ready for elimination.

Transporters can direct the drug metabolite back into the systemic circulation (for elimination in urine) or bile (elimination in faeces)

45
Q

What are the minor routes of elimination for a drug?

A

Pulmonary; breast milk; sweat; hair; saliva.

46
Q

3 important components of renal elimination

A
  1. Glomercular filtration (removal of free drug, not bound to plasma protein, at the glomerulus)
  2. Active tubular secretion (drug is transported from blood into urine by tubular transporter protein
  3. Tubular reabsorption (passive process in which drug in urine diffuses back into the blood)

Filtration, secretion and reabsorption.

47
Q

Alkaline

A

Having a pH of greater than 7. Used in urine.

48
Q

2 major mechanisms that drugs can appear in faeces

A
  1. By not being absorbed into the systemic circulation (so the drug remains in intestine)
  2. By being absorbed, excreted in bile and then being deposited back into the intestine
49
Q

Can drug conjugates be excreted in bile?

A

YES, deposited in intestines.

50
Q

Physiological role of bile

A

Excretion of cholesterol; absorption of lipids; stimulation of intestinal motility.

51
Q

Enterohepatic recycling

A

Re-absorption of the drug or metabolite can boost blood levels again; this may produce a secondary phase of the therapeutic effect.

52
Q

Can drugs be excreted through breast milk?

A

YES, a large number of drugs are excreted this way.

In particular, cytotoxic agents used in cancer chemotherapy, lithium etc. However, risks appear to be minor

53
Q

Define half-life

A

Time to halve drug amount in body

54
Q

Define T(max)

A

The time taken to reach peak (minutes, hours)

55
Q

Define C(max)

A

The peak plasma concentration

56
Q

Define bioavailability

A

Difference between plasma concentrations following single oral dose and single injection of same amount.

Generally: F = AUC(oral) / AUC (IV)

57
Q

Define oral absorption

A

Net rate of change of drug in body is rate of absorption minus rate of elimination.

58
Q

Define Therapeutic Drug Monitoring (TDM)

A

The clinical practice of measuring specific drugs at designated intervals to maintain a constant concentration in a patient’s bloodstream, thereby optimising individual dosage regimens.

59
Q

Define Genome

A

Total of all genetic information in a cell.

60
Q

Estimated number of human genes

A

Between 20,000 and 25,000

61
Q

Define single-nucleotide polymorphism (SNP)

A

A DNA sequence variation occuring when a single nucleotide adnine (A), thymine (T), cytosine (C) or guanine (G) in the genome differs between members of a species or paired chromosomes in an individual.

62
Q

Allele

A

Each of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome.

63
Q

Phenotype

A

Set of observable characteristics of an individual resulting from the interaction of its genotype with the environment.

64
Q

Determinants of the drug response

A

Genetic variation in the drug target can influence response (pharmacodynamics).

Genetic variation that alters the activity of enzymes and transporters (pharmacokinetics).

65
Q

Why is pharmacogenetics is important?

A

The efficacy of drugs can vary significantly between individuals even when used at standard doses.

Standard doses of some drugs produce toxicity in some individuals.

We would like to be able to predict whether drugs will be efficacious in individuals and not produce toxicity.

66
Q

Define acetylation polymorphism

A

Individuals who were defective in acetylation experienced peripheral neuropathy with isoniazid.

Individuals with adequate acetylation did not experience toxicity.

67
Q

Which countries show a high incidence of defective alleles (slow acetylators)?

A

High incidence of defective alleles (slow acetylators) in mediterranean, caucasian and sub-saharan populations

68
Q

What is CYP2D6?

A

A debrisoquine hydroxylase

69
Q

List the 4 CYP2D6 phenotypes

A
  1. Extensive metaboliser (EM) phenotype - shows “normal” activity.
  2. Intermediate metaboliser (IM) phenotype - carry one active and one inactive allele or two low-activity alleles.
  3. Poor metaboliser (PM) phenotype - carry two inactive alleles and lack CYP2D6 altogether.
  4. Ultrarapid (UM) phenotype - multiple copies of active alleles (3-13) rather than 2.
70
Q

Define Irinotecan

A

Irinotecanis is in topoisomerase inhibitor family of medication. It works by blocking topoisomerase 1 which results in DNA damage and cell death.

71
Q

Define UGT1A1

A

Polymorphism that has seven ‘TA’ repeats instead of six

*28 variant alleles

PCOL2011 (4 decks)

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