Pharmacokinetics

Question 1

What are some e.gs of routes of drug delivery?

Answer 1

Oral rectal - 50% first pass sublingual - rapid, no first pass transdermal - sustained effect intrathecal - CSF topical - local effect inhalation - rapid + targeted

Question 2

What does pharmacokinetics look at?

Answer 2

Looks at the ADME properties of the drug - absorption, distribution, metabolism, excretion

Question 3

How does a drug penetrate the various biological membranes to get to its site of action?

Answer 3

passive diffusion

Question 4

what is relevance of gastric emptying?

Answer 4

Gastric Emptying critical for drug absorption. The SA of the intestine is larger than the stomach. –> Most drugs are absorbed from intestine bc of this

Question 5

What is bioavailability?

Answer 5

Fraction of unchanged drug reaching the system circulation following any route of administration (intravenous injection = 100% bioavailability in circulation)

Question 6

What factors does bioavailability depend on?

Answer 6

Absorption First pass metabolism Food: can decrease the oral availability of sparingly lipid soluble drugs (i.e. atenolol oral availability decreased by 50% by food)

Question 7

How does the bioavailability differ between drugs?

Answer 7

Lidocaine 15% Propanolol 20% Morphine 30% Paracetamol 57% Theophilline 81% Diazepam 97%

Question 8

What modulates the distribution of the drug in the body? (2 main components)

Answer 8

Physiochemical properties of the drug, e.g: Molecular size, Oil/water partition coefficient, Degree of ionization that depends on pKa, Protein binding Physiological factors: Organ or tissue size Blood flow rate Physiological barriers (blood capillary membrane, cell membrane, specialised barriers)

Question 9

What do plasma proteins do? Give 2 examples of plasma proteins:

Answer 9

They’re involved in drug binding in blood e.g. albumin and α1-acid glycoprotein

Question 10

What is the main difference between albumin and α1-acid glycoprotein?

Answer 10

Acidic drugs will mainly bind to albumin. Basic drugs will mainly bind to α1-acid glycoprotein

Question 11

What happens when one acid drug is displaced by another acid drug?

Answer 11

Displacement of one acid drug by another acid drug results in transient increase of “free” drug concentration. Increase in the free drug concentration results in increase in the clearance of the free drug form the circulation Drug / drug protein interactions are rarely clinically significant.

Question 12

What are the 2 main factors that can modulate the RATE of drug distribution?

Answer 12

Perfusion-limited tissue distribution (only limited by blood flow) permeability rate limitations (or membrane barriers)

Question 13

What are some permeability rate limitations (membrane barriers)? (3)

Answer 13

BBB - blood-brain barrier BTB - blood-testis barrier Placenta

Question 14

What are some highly and poorly perfused tissue examples?

Answer 14

Highly perfused - liver, kidneys, lung, brain Poorly perfused - skin, fat, bone, muscle

Question 15

How do brain blood vessels differ to normal blood vessels?

Answer 15

Brain blood vessels don’t have pores - they have tight junctions . They are surrounded by glial brain cells to support the barrier. Things can’t leave by diffusion, it has to leave by carrier-mediated transport. acidic brain cells trap ionised weak bases (such as morphine)

Question 16

What does the placenta barrier allow? What can pass through and what is blocked?

Answer 16

Sugars, fats and oxygen diffuse from mother’s blood to fetus Urea and CO2 diffuse from the fetus to mother Maternal antibodies actively transported across placenta = this gives some resistance to disease (passive immunity) Most bacteria are blocked. Many viruses can pass including rubella, chickenpox, mono, sometimes HIV. Many drugs are toxins and can pass including alcohol, heroin, mercury

Question 17

Which type of drugs can pass the placenta barrier more easily?

Answer 17

Drugs that are lipid soluble and mostly un-ionised can easily pass the barrier to the foetus compared to the more polar and ionised ones.

Question 18

What are the two possible outcomes of drug metabolism?

Answer 18

De-activation: decrease of pharmacological effect and decrease of toxicity. Activation: increase of pharmacological effect and increased toxicity (i.e. chemical carcinogenesis)

Question 19

Explain the phase I and II reactions of drug metabolism?

Answer 19

Drugs can either go to phase I or phase II metabolism.

phase I reactions:

Introduction, or exposure, of a polar group by oxydation, reduction or hydrolysis (catalised by CYP450)

At this point if the metabolites are sufficiently polar can be excreted

A C-H group can be turned into a C-OH converting non pharmacological active compound into active. DANGER: Toxic compound can be created as well

phase II reactions:

Attachment of an endogenous molecule to a drug or Phase I metabolite, glucoronide, sulphate, acetyl

The outcome products are heavier in molecular weight, so tend to be less effective.

MAJOR DIFFERENCE between Phase I and Phase II reaction is that Phase I predominantly produces more active compounds while Phase II produces less active

Question 21

What enzymes are involved in the phase I and II reactions of drug metabolism?

Answer 21

Phase I – oxidation = Cytochrome P450

This is the major drug-metabolising enzyme system found in the liver. From a super family of several form i.e. multiple forms of cytochrome

Cytochromes possess varying substrate specificity. Catalytic activities show large inter-individual differences

Phase II – conjugation = Transferases: Glucoronyl- Sulpho- Acetyl- Methyl-

Question 22

What is quetiapine used for? What enzyme does it use?

What do inhibitors and inducers for this enzyme do?

Answer 22

Used for schizophrenics - uses cytochrome 3A4 (CYP3A4)

When administering a drug to patients on quetiapine you need to make sure it doesnt interfere with the CYP3A4.

Question 23

How can drugs be eliminated once metabolised?

Answer 23

Question 24

How does biliary excretion / elimination work?

Question 25

What factors influence secretion in bile?

Answer 25

Molecular weight (i.e. > 300)

Polarity (higher polarity more bile excretion)

Nature of biotransformation

Also gender, diseases, drug interactions

Some drugs and metabolites excreted by the liver cells into bile, pass into the intestine. Reabsorption from the gut during the process of enterohepatic recycling may prolong the pharmacological effect of a drug

Question 26

Which are the 2 major organs for drug elimination from the body?

Answer 26

Kidney and liver.

Drugs high in water or ionised will be excreted unchanged in the kidney, whereas drugs very lipid soluble or largely unionised will be processed by the liver.

Question 27

How does elimination in the kidneys work regarding the nephrons?

Answer 27

Only unbound proteins filter from the Bowman’s capsule into the proximal tubule.

Several pumps in the nephron facilitate the filtration.

Question 28

What is renal clearance?

Answer 28

GFR = glomerular filtration rate

The net contribution of filtration, secretion and reabsorption will determine the renal clearance of a drug, an index of the efficiency of the renal excretion processes.

Renal diseases may interfere with drug elimination

Question 29

What is the therapeutic index?

Answer 29

The margin between the therapeutic dose and the toxic dose. Higher the therapeutic index is safer the drug is.

Question 30

How does blood level affect metabolism?

Answer 30

HIGH blood level: excessive dosing and/or decreased clearance risk of TOXICITY

Decreased clearance:

Normal variation, saturable metabolism, genetic enzyme deficiency, renal failure, liver failure, age (neonate or elderly), enzyme inhibition.

LOW blood level: dose to low or clearance to high risk of NO EFFECT Increased clearance: Normal variation, poor absorption, high first pass metabolism, non compliance, enzyme induction

Question 31

What are some general factors affecting drug metabolism?

Answer 31

environmental, disease, genetic, age, drug interaction

Question 32

What is genetic polymorphism?

Answer 32

The occurrence of a variant form of an enzyme/receptor through the inheritance of drug-metabolising enzymes.

most clinically studied: CYP2C9, CYP2C19, CYP2D6