1 Introducing Pharmacokinetics and Pharmacodynamics Janice Davies Pharmacist Room 23 Maudland Building [email protected].

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Introducing Pharmacokinetics and

Pharmacodynamics

Janice DaviesPharmacist

Room 23 Maudland [email protected]

eLearn

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DVD Any problems / questions?

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Learning outcomes

Define and discuss pharmacokinetic factors Discuss the factors that affect absorption,

distribution, metabolism and excretion-how they affect drug therapy

Define and discuss pharmacodynamic mechanisms of drug actions

Apply pharmacokinetic and pharmacodynamic concepts to patient scenarios.

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Definitions

Pharmacokinetics is what the body does to the drugs, for almost all drugs the magnitude of pharmacological effect depends on its concentration at its site of action.

Pharmacodynamics is what the drug does to the body, ideally including

the molecular mechanism (s) by which the drug acts

PHARMACOLOGY

PHARMACODYNAMICS(SPECIFIC TO DRUG OR DRUG

CLASS)

PHARMACOKINETICS(NON-SPECIFIC, GENERAL

PROCESSES)

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Arrange the phrases!!! Factors determining response of a patient to a drug

1) Drug interactions

2) Duration of effect

3) Unwanted effects

4) Reduction in symptoms

5) Modification of disease progression

6) Accumulation on repeat dosage

7) Absorption from the site of administration

8) Elimination from the body

9) Delivery to the site of action

10) Effects at the site of action

11) Interaction with cellular component

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Pharmacokinetics:considering such terms as

Route Absorption Distribution Hepatic Metabolism Metabolic products Protein Binding Renal Excretion Half-life Toxicity

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Distribution

Metabolism

Excretion

Absorption

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Absorption

Route

EnteralParenteral

IVTopical

transdermal inhalationoral sublingual

Distribution

Systemic circulation

Absorption Absorption

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Absorption

Process of drug movement from the administration site to the systemic circulation.

The amount and rate of absorption are determined by several factors: Physical nature of the dosage form Presence or absence of food in the stomach Composition of the GI contents Gastric or intestinal pH Mesenteric blood flow Concurrent administration with other drugs

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Bioavailability “Bioavailability is the proportion of the administered

dose that reaches the systemic circulation.”Dale and Haylet, Pharmacology Condensed. 2004

Refers to the amount and the rate of appearance of the drug in the blood after administration in its initial dose form

Orally administered drug bioavailability is directly related to the individual solubility in body fluids.

Poor solubility = low bioavailability

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Effect of Food

Bioavailability of some drugs is affected by the presence of food. E.g penicillin's, erythromycin, rifampicin, thyroxine

Some drugs are taken before meals to allow time for drug to act before food is taken

Gastric irritation can be caused by drugs taken on an empty stomach

Effect of food on the absorption of drugs

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First Pass Effect

Drugs that are absorbed via the GIT are

circulated to the liver first via

the hepatic portal vein Liver then acts as a filter Only part of the drug is

circulated systemically The combination of

processes is termed

the ‘First Pass’ effect

Absorption animation

http://www.youtube.com/watch?v=xiuWdJYyIKs

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Distribution

Factors affecting

Absorption Metabolism

Low albumin Problems with:Heart

CirculationDiabetes

Bound drugs are pharmacologically inactive because the drug-protein complex is unable to cross cell membranes.

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Metabolism

Drugs are metabolised in the liver, lungs,kidneys, blood and intestines. In order for drugs to pass across the lipid cell

membrane they must be lipophilic The higher the solubility in lipids compared to

water, the more rapid the tissue entry Metabolic rate determines the duration of the

action of the drugs

Which BNF appendix relates to patients’ ability to metabolise?

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Excretion

Drugs are primarily excreted by the kidneys In order for drugs to be excreted

they need to become hydrophilic Excretion of drugs can be affected

by the urinary pH How the drug is excreted can

influence prescribing decisions

Which BNF appendix relates to patients’ ability to excrete?

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Half Life of Drugs

Drug excretion is commonly expressed in terms of half life (t1/2)

This is the time required for the concentration of the drug in the plasma to decrease by one-half of it’s initial value

Drug half life is variable and can be long or short Subsequent doses are given to raise the

concentration levels to a peak In theory, the optimal dosage interval between drug

administration is equal to the half-life of the drug

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Example

Drug 100mgs with a 6 hour half life

1st dose 100 mgs2nd dose 100mgs + 50 mgs still present = 150mgs3rd dose 100mgs + 75 mgs still present = 175mgs4th dose 100mgs + 88mgs still present = 188mgs5th dose 100mgs + 94mg still present = 194mgs6th dose 100mgs + 97mg still present = 197mg

As can be seen, accumulation becomes less ateach dose- “steady state” is achieved after 3 to 5 half lives.

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Loading Doses

Are used when the medical condition demands high concentrations very quickly

This is achieved by an initial dose that is twice the maintenance dose

Some exam style MCQs:

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Which ONE of the following affects absorption?

Drug formulation Time of administration Mode of action of the drug

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A patient with renal impairment, taking a renally excreted drug, will require which ONE of the following?

Dose reduction Dose increase Same dose

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Which ONE of the following describes bioavailabilty?

The proportion of drug reaching the circulation

The extent of first pass metabolism The quantity of drug absorbed in the GI tract

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Tea break…

http://www.youtube.com/watch?v=tnnoPedWO7M

…best to leave now if easily offended!

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Pharmacodynamics

“is the detailed study of the mode of action of drugs in the body” or how drugs exert their effect at a cellular level

Receptors Ion channels Enzymes Carrier molecules Chemotherapy

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Considering

Receptors-agonist, partial agonist and antagonist Ion channels-gating of intracellular ions Enzymes-drugs act to inhibit or potentiate Carrier molecules-allow molecules not lipid soluble

to cross cell membrane Chemotherapeutic agents Drug tolerance/dependence Effects of pathological state and biological variability

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Receptors

Receptors are a target molecule that a drug molecule has to combine with to produce a specific effect

Receptors must be compatible –like 2 pieces of a jigsaw e.g. neurotransmission

Main types of action at receptor: Receptor agonists Receptor antagonists

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Types of receptors

G-protein-couple receptors, seconds

e.g. Muscarinic ACh receptors, adrenoceptors, histamine receptors

http://www.ouhscphysio.org/humanphys/animations/g-protein_coupled_receptors.gif

Kinase linked receptors, hours

e.g. Insulin, Growth factor Nuclear intracellullar receptors, hours

e.g. steroid, thyroid hormone

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Ion Channels Drugs act to affect cellular gating mechanism in

cell wallLigand-gated ion channels, milliseconds e.g GABA benzodiazepines, Nicotinic AChhttp://www.ouhscphysio.org/humanphys/

animations/ligand-gated.swf

Carrier molecules Drugs act on carrier transporters which allow

molecules, not lipid soluble to cross cell membrane

http://www.ouhscphysio.org/humanphys/animations/facilitated_diffusion.swf

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Enzyme inhibitors

An enzyme is a protein that can promote or accelerate a biochemical reaction with a substrate

When the enzyme mistakes the drug for a substrate, a drug-enzyme interaction occurs

This interaction could increase or decrease the rate of the biochemical reaction

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Chemotherapeutic agents

Cytotoxic drugs act by interfering with cell growth and division at different stages of the cycle

Anti-infective drugs

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Cell wall

Cell membraneDNA

Bacterial Cell

Cla

ss 1

reactio

ns

Cla

ss 2 re

actio

ns

Cla

ss 3

reactio

ns

Glucose Precursor molecules

Amino acids

Nucleotides

ProteinsRNADNA

Metabolism of bacterial cell

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Physiological Variability

Liver disease Chronic alcoholism Renal disease Allergy

Exam Style MCQs

A receptor antagonist:

a) binds to a receptor and activates it

b) binds to a receptor without causing activation

c) blocks an enzyme

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The pharmacodynamics of salbutamol can be explained by its:

a) activity on enzymes

b) activity on ion channels

c) activity on receptors

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Warfarin has a:

a)Narrow Therapeutic Index

b)Wide therapeutic range

c)Neither are important

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Write brief notes on any TWO of the following modes of drug action:

Receptor agonists Receptor antagonists Action at enzymes Ion channels Carrier molecules Chemotherapy

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Short answer questions:

What is a narrow therapeutic index? What is bioavailability? What is half life? What is a loading dose? What is pharmacodynamics?

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Further reading

Downie, George (2008) Pharmacology and medicine management for nurses George Downie, Jean Macke 4th Edition , Edinburgh. Churchill Livingstone

ORTrounce, J, Greenstein, B, Gould, D. Trounces Clinical

Pharmacology For Nurses. 18th Edition Churchill Livingstone Edinburgh.

British National Formulary www.bnf.org Rang Dale Ritter and Moore (2003) Pharmacology

Churchill Livingstone Bath Press 5th edition www.emc.medicines.org.uk