Introduction to Principles of Clinical Pharmacology

Definition of Basic Terms

DrugSimply – a drug is a chemical or substance that causes changes in the structure or function of living organisms

MedicineA medicine is the vehicle for administration of the drug (active ingredient) to the human or animal e.g. tablet, capsule, injection, ointment, inhaler, suppository etc.

Does This Apply to Foods/Minerals etc?

Obviously, they are not ‘drugs’ in the conventional use of the term

However, from a prescribing perspective, many are regarded as ‘medicines’

In addition, all prescribers should have a general understanding of pharmacology and pharmacokinetics as their patients will be on a range of medications

Does This Apply to Foods/Minerals etc?

In this course ‘Drug’ is used as a generic term, to include vitamins/minerals/supplements etc. when they are used for therapeutic purposes

From a pharmacological perspective, ‘drugs’ are not ‘good’ or ‘bad’; they are simply molecules that cause some physiological event to occur

Sources of Drugs

Plant sources eg morphine, atropine, some vitamins

Animal sources eg thyroxine, insulin

Mineral sources eg lithium, magnesium

Microorganisms eg penicillins, cephalosporins

Synthetic eg benzodiazepines, phenothiazines, some vitamins

Bioengineered (recombinant DNA technology) eg human insulin, human growth hormone

Definition of Basic Terms cont.

Generic nameStandardised internationally recognised name for a drug e.g. ferrous sulfate, metoprolol, omeprazole, ibuprofen etc. (some exceptions in US e.g. paracetamol = acetominophen)

Trade or Brand nameName given by the manufacturer e.g. Ferrogradumet (ferrous sulfate), Viagra® (sildenafil); Ventolin® (salbutamol)

Definition of Basic Terms cont.

PharmacologySimply: the science of drug actions and uses

PharmacodynamicsMechanisms of action (“what the drug does to the body”)

PharmacokineticsLiterally, movement of the drug within the body (“what the body does to the drug”)

Definition of Basic Terms cont.

ToxicityManifestation of the harmful effects of the drug after exposure to high levels (“intoxication” or “poisoning”)

TherapeuticsUse of drugs for intended clinical benefits – cure of a disease, relief of symptoms etc.

Therapeutic Prescribing

Prime goal of drug therapy is to achieve the desired beneficial effects with minimal adverse effects

Choice of drug will be governed by mechanism of action (pharmacodynamics)

Dose of drug, route, formulation etc. will be determined by how the body handles the drug (pharmacokinetics)

Pharmacodynamics:Basic Principles

Mechanism of action of drugsSpecific molecular processes by which drugs work, e.g. inhibition of an enzyme or stimulation of a receptor sub-type

Mode of action of drugsGeneral description of the type of action: e.g. supplements, antihypertensives, analgesics

Site of action of drugsSpecific organs, tissues or cells affected by the drug: e.g. sensory neurones; myocardium, bronchii, etc.

How Do Drugs Work (Mechanism of Action)?

Fundamental premise of pharmacodynamics is ‘drug-receptor interactions’

Within the organs of the body are specific receptors with which specific drugs can interact

The analogy often used is ‘lock and key’: only drugs (chemicals) with the ‘correct’ molecular shape can interact with a particular receptor

Example: Morphine

Naturally-occurring substance found in the Opium Poppy (Papaver somniferum)

One of a family of natural substances known as opiates or opioids (includes codeine)

Some synthetic derivatives also available e.g. heroin, methadone, pethidine

Been used for both therapeutic (medicinal) and recreational purposes throughout history

Opium Poppy (Papaver somniferum)

Opioid receptors

In the 1970s pharmacologists identified a number of ‘endogenous’ (within the body) opioids known as enkephalins and endorphins

Found to have a role in pain perception, mood and a number of other physiological functions

Also discovered opioid receptors in key areas of the body e.g. brain, spinal cord, gut, eye etc.

Receptor Interactions

Only substances with a similar chemical structure to morphine can attach to opioid receptors (‘key-lock’ analogy)

These substances are called opioid agonists – when they attach to the opioid receptors they trigger certain responses

Effects of Opioids (Morphine etc.)

Relief of pain (analgesia) – main therapeutic use Mood elevation (euphoria) Sedation Constriction of pupil (miosis) Reduction in gut motility (constipation) Suppress cough (anti-tussive) Tolerance to effects, and dependence in some

individuals with repeated doses Respiratory depression leading to death in overdose

A Mix of Desirable and Unwanted Effects

Because there is a variety of opioid receptors in different parts of the body, it is very difficult to separate desirable and unwanted effects of morphine and other opioid drugs

Example – all patients receiving morphine or codeine for ongoing treatment of cancer pain become very constipated

But, these drugs can also be used as anti-diarrhoeals!

Opioid Antagonists

Some chemical substances can attach to the opioid receptors and just ‘occupy’ them without triggering an effect

These ‘antagonists’ prevent access of the receptor to endogenous chemicals and drugs

Naloxone (Narcan®) is an opioid antagonist. It is used to ‘block’ the effects of morphine etc. and will reverse respiratory depression caused by high doses of morphine

Receptor sites

Where are receptors (drug targets) found?

- Cell membranes – usually associated with ion channels, transducer proteins or enzymes

- Cell nucleus

- Enzymes (many vitamins are co-factors)

- Carrier molecules

Agonists and Antagonists

Most conventional drugs are ‘agonists’ i.e. stimulate receptors or ‘antagonists’ i.e. block receptors

For example, salbutamol (Ventolin®) is a beta-receptor stimulant; stimulation of beta-receptors in the lungs causes bronchodilation

Metoprolol (Betaloc®) is a beta-receptor antagonist (‘blocker’); blockade of beta-receptors in the heart will slow rate and be ‘cardiprotective’. Note that by blocking the beta-receptors in the lungs ‘beta-blockers’ can cause bronchoconstriction in asthmatics etc.

Mechanism of Action of Minerals/Vitamins/Supplements

Not classic agonists/antagonists at specific receptors

Generally, they are replacing or supplementing body stores, or enhancing effects in certain diseases and disorders

Generally, they are co-factors or essential elements in normal metabolic and physiological processes

You will already have much more knowledge than us of specific actions and effects

Pharmacokinetics

“What the body does to the drug”

Usually described by the acronym ADME:- Absorption- Distribution- Metabolism- Excretion

NB we do not expect dietitians to be experts in pharmacokinetics but to understand some of the basic principles that are commonly used in prescribing

Absorption

Refers to the processes whereby the drug reaches the bloodstream (systemic circulation)

Other than by the intravenous route, or for agents designed to have a direct local effect, drugs must first be absorbed into the circulation before they can be distributed to the site of action

Absorption cont.

Requires the drug to pass through cells and cell membranes to reach the bloodstream (e.g. in g.i. tract, across the skin, across mucous membranes etc.)

Cell membranes are comprised of phospholipids and are essentially lipid (fatty) sheets

In general, drugs must be in a lipid-soluble form in order to be absorbed (there are exceptions including minerals and some vitamins)

Factors Influencing Oral Absorption

We concentrate on oral absorption because it is the main route of drug delivery, but the same basic principles apply to other routes

Mechanisms of Drug Absorption(Gastrointestinal Tract)

Passive diffusion (major mechanism): lipid-soluble drugs will passively diffuse across membranes on a concentration gradient e.g. fat soluble vitamins A, D, E, K

Active transport: for a small number of drugs using carrier molecules in the membrane – can work against a concentration gradient (for example Vitamin B12, iron)

Filtration through pores (especially for small water soluble molecules such as glucose, ions such as sodium, magnesium etc.)

First Pass Metabolism

Extent of metabolism that occurs before drug enters the systemic circulation. Includes metabolism in the gut lumen, gut wall, and lungs; main site, however, is the liver

All blood from g.i. tract drains through the portal vein to liver before it reaches systemic circulation (‘first-pass’)

First-pass and other pre-systemic metabolism is a very important determinant of oral bioavailibility especially for lipid soluble drugs (see later)

Distribution

Distribution describes the reversible transfer of drug from the bloodstream to the various other tissues and organs of the body

Water-soluble vitamins and minerals will rapidly distribute to the extracellular fluid and be taken up by cells. Lipid-soluble vitamins will follow passive diffusion (as for absorption)

Distribution cont.

Like absorption, most drugs follow passive diffusion along a concentration gradient

Diffusion as reversible: when tissue levels of the drug exceed those in ECF and circulation, then the drug will passively diffuse back to the bloodstream

Distribution cont.

Extent of distribution also depends on:

- the perfusion of the tissue (circulation) – well perfused tissues generally no problems with distribution

- the existence of any ‘special’ physiological barriers (e.g. blood-brain barrier)

Distribution: Special Barriers

‘Blood-brain barrier’ excludes a number of drugs, esp. more water soluble e.g. dopamine, atenolol, some water soluble-vitamins

BBB not a discrete anatomical structure but specialised collection of cells in CNS with ‘tight junctions’ that exclude certain substances

Highly Lipid-soluble drugs penetrate BBB readily

Distribution: Special Barriers contd.

Cerebrospinal fluid (CSF) normally impenetrable to antibiotics (e.g. penicillins) – except when inflamed

Some tissues have poor perfusion e.g. bone and nails – for example very difficult to treat infections

Metabolism (Biotransformation)

Alteration of a drug by the body to one or more chemically different molecules termed metabolites

Regulated by enzymes in many tissues e.g. gut, skin, lungs, but predominant organ of metabolism is the liver

Metabolism

Main purpose of metabolism is to prepare the molecule for excretion (i.e. make it more water-soluble)

For minerals and water-soluble vitamins metabolism may not be required, they are excreted unchanged

Phase 1 Metabolism

Chemical conversion to a metabolite by hydrolysis, reduction, oxidation etc.

Most metabolites are inactive pharmacologically,

however some drugs may produce active metabolites

Some inactive drugs may produce an active metabolite (known as ‘pro-drugs’)

Phase 2 Metabolism

Phase 2 is addition of another chemical structure by conjugation (joining together) e.g. glucuronic acid, sulphate (example morphine glucuronide)

These conjugates are very water-soluble

Conjugation increases the water solubility of the

drug and prepares it for excretion

Metabolism contd.

Most drugs undergo both Phase 1 and Phase 2 metabolism to produce a range of metabolites

However, some may undergo only Phase 1 or Phase 2

Some drugs may be excreted unchanged (i.e. without biotransformation) – especially if they are already water-soluble e.g. atenolol and of course many vitamins (e.g. Vitamin C) and minerals

Excretion (Kidney)

Some drugs excreted via lungs, skin etc., but main organ of excretion is the kidney

Three phases of drug removal from the blood via the kidney:- filtration at the glomerulus- active secretion into the proximal tubule- passive diffusion (reabsorption) from urine back to blood along the length of the renal tubule

Excretion contd.

Most drugs and metabolites are filtered at the glomerulus and enter the filtrate in the nephron

Some drugs are not filtered but may meet the requirements for active secretion from the arterioles into the nephron at the proximal tubule

If filtered drug or metabolite is lipid soluble, it is reabsorbed back into the bloodstream by passive diffusion; if it is water soluble it is excreted in urine

PHARMACOLOGY

Pharmacokinetics HOW BODY ACTS ON DRUG

Pharmacodynamics HOW DRUG ACTS ON BODY

Dose of Drug Body concentration over

time

Drug effect

•Absorption

•Distribution

•Metabolism

•Elimination

•Receptor Binding

•Biological Effect