Pharmacokinetics and Pharmacodynamics

Question 1

Pharmacokinetics

Answer 1

Effect of the body on a drug

Question 2

Pharmacodynamics

Answer 2

What the drug does to the body

Question 3

What are the 4 processes of drug therapy?

Answer 3

Pharmaceutical (is drug getting to patient)

Pharmacokinetic (is drug getting to site of action)

Pharmacodynamic (is drug producing pharmacolgical effect)

Theraputic (is pharmacologic effect producing theraputic effect)

Question 4

Explain the pharmaceutical process of drug therapy

Answer 4

Compliance: drug will be ineffective if patients are non-compliant

Bioavailability: Proportion of administered drug that reaches the systemic circulation and is available for distribution to site of action

Formulation: physical factors affecting bioavailability e.g. tablet disintigration, drug dissolution, controlled release

site of administtation: affects drug delivery to target and duration of action.

Question 5

Name 4 sites of administation for drugs

Answer 5

Subcutaneous

Intramuscular

Sublingual

Buccal

Rectal

Vaginal

Inhalation

Transdermal

Question 6

Benefit of sublingual administration

Answer 6

Drugs pass into the venous circulation intact, avoiding first pass metabolism in the liver. Smaller doses required.

Question 7

Use of transdermal administration

Answer 7

Mostly patches that deliver small quantities of drug over a period of time.

Question 8

What are the four components of pharmacokinetics?

Answer 8

Absorption

Distribution

Metabolism

Excretion

Question 9

Factors affecting the rate of drug absorption

Answer 9

Drug absorption occurs mainly in the upper part of the small intesine. Affected by:

GI motility: delay in emptying may delay effects of painkillers. Increase in motility may mean enteric coated tablets pass through without being absorbed.

Malabsorptive sttes e.g. coeliacs

Food: can increase or decrease absorption of drugs

Question 10

What is first pass metabolism?

Answer 10

The extent of metabolism that occurs in the liver before the drug enters the systemic circulation.

Drugs are absorbed through the gut wall and delivered to the liver via the portal circulation where they are metabolised. This affects bioavailability.

Question 11

3 routes which by-pass first-pass metabolism

Answer 11

Sublingual

Rectal

Transdermal

Question 12

Extraction ratio

Answer 12

Measure of how much of a drug the liver removes by first pass metabolism before it reaches the systemic circulation.

High ratio = most of the drug is metabolised after absorption

Question 13

How can changes in plasma protein concentrations alter drug distribution?

Answer 13

Many drugs are bound to plasma proteins in solution. Drugs need to be unbound to be active - bind to cellular receptors pass into the tissue and enter the cells.

A fall in plasma protein will increase the percentage of unbound drug and therefore increase potency of the drug.

N.B. The effect this has is dependent on the % of drug that is normally bound.

Question 14

Factors that can decrease the levels of drug bound to protein

Answer 14

renal impairment - albumin exreted, levels decrease

3rd trimester pregnancy

Hypoalbuminaemia

displacement by other drugs e.g. sulphonamides and warfarin.

Question 15

Factors that affect tissue distribution

Answer 15

Plasma protein binding

Blood flow

Lipid solubility

Active transport

Diseases

Other drugs

Question 16

Name 4 organs that excrete drugs from the body

Answer 16

Kidney

Lungs

Breast milk

Sweat

Tears

Bile

Saliva

Question 17

Agonists

Answer 17

Bind to and activate the receptor. Can bring about the effect directly or indirectly.

Can be full or partial. Partial agonists produce a lower response at full receptor occupancy than full agonists.

Have maximum dose effect determined by tissue e.g. muscle shortening, once short will not get shorter even if [drug] increases

Question 18

Antagonists

Answer 18

Bind to the receptor without stimulating it, prevent binding of other molecules.

Can be competitive or non-competitive. Non-competitive bind at allosteric sites, competitive can be overcome by increasing [agonist].

Question 19

Potency

Answer 19

The concentration at which 50% of the maximum effect of the drug is acheived.

Question 20

Efficacy

Answer 20

The drug which has the biggest effect/response.

Clinical effectiveness of a drug depends on efficacy

Question 21

Theraputic window

Answer 21

[drug] needed to produce an effect relative to the [drug] which has a harmful/toxic effect.

Question 22

Drug variability

Answer 22

Variability between patients in the dose needed for benefit vs. harm.

Can be due to genetic factors (metabolism, target sensitivity) or acquired factors (receptor expression, other diseases, [ligand])

Single individual may respond differently to the same drug at different times during treatment.

Question 23

Factors that affect drug absorption

Answer 23

Lipid solubility: Ability to move from aq. to lipid varies with pH of medium. Most drugs are weak acids/bases and cross membranes when unionised.

Surface area: required to efficently absorb drugs, majority occurs in the small bowel

Blood flow: required for access to the tissues. Reduced flow affects the absorption.

Question 24

Bioavailbility

Answer 24

The proportion of a dose that gets from the point of delivery to the systemic circulation unchanged.

Note: not always an indicator of activity, some drugs are precursors which are metabolised to active products.

Bioavailability affects how some drugs are delivered. If metabolised before it reaches systemic circulation then it is ineffective.

Question 25

Tissue distribution

Answer 25

Well-perfused organs (heart, kidney, liver) accumulate drugs to a greater extent that poorly perfused tissue.

Cells with leaky junctions e.g. muscle, endothelial cells allow water-soluble substances to diffuse through easily. The BBB has tight junctions and pumps to restrict water soluble molecules. Lipid soluble drugs cross easily.

Question 26

Hepatic drug metabolism

Answer 26

Converts lipid soluble drugs into more water soluble molecules. Usually terminates activity

Phase 1: oxidation, reduction, deamination, hydrolysis. Metabolite may retain activity. Oxidation most common, controlled by cytochrome P450 isoenzymes. Enzymes can be induced or inhibited by certain drugs

Phase 2: conjugation (glucoronate, acetate, sulphate). Metabolite lacks activity

Some drugs undergo both phase 1 and 2, some just 1 or 2.

Question 27

Briefly outline renal drug excretion

Answer 27

Glomerular filtration: Only the free unbound drug is filtered. Extent of filtration depends upon GFR

Active secretion: Some strong acids/bases actively pumped into PCT

Passive tubular absorption: Some drugs are reabsorbed in the PCT. This is dependent on pH and lipid solubility. e.g. aspirin is a weak acid - less reabsorbed in alkaline urine.

Question 28

Pharmacokinetic parameters

Answer 28

Half life: time required to change to amount of drug in the body by 1/2. Guide to time it takes for drug to be eliminated form the body. (In renal failure half life is prolonged). Used to measure time to steady state (5 half-lives) and loading dose

Volume of distribution: Measure of the degree to which a drug is in the circulation or tissues. Drugs with high VD are mainly in the tissues, cannot be easily removed from the body.

Clearance: Volume of blood cleared of a compund per unit time. Measure of the ability of the body to tlimate the drug.

Question 29

What determines intensity of a drug’s action following parenteral administration?

Answer 29

Volume of distribution (governed by body composition and regional blood flow)

Question 30

What determines a drug’s plasma concentration after oral administration?

Answer 30

Bioavailability

Rate of systemic clearance (hepatic metabolism/renal excretion)

Question 31

Factors that affect oral bioavailability?

Answer 31

Destuction in the GIT

Absorption across the gut epithelium

First pass metabolism (avoided by iv, im or sublingual)

Question 32

How does half-life affect loading dose?

Answer 32

Drugs with long half-lives take a long time to reach strady state (constant blood level) and have theraputic effect, therefore a a higher dose (loading dose) may be required to get a patient to have a response

Drugs with short half-lives may need a loading dose in emergencies e.g. lignocaine in arrhythmia.

Question 33

Types of pharmacological action of drugs

Answer 33

Via a receptor to have a pharmacological effect

Via an indirect alteration of aan endogenous agonist e.g. SSRI, ACEi

Inhibition of transport processes

Enzyme inhibition e.g. NSAIDs, warfarin

Enzyme activation

Question 34

How to determine choice of treatment

Answer 34

Consider:

Efficacy

Evidence

Adverse Effects

Effectiveness (cost)