Download Nursing 715 Pharmacological Basis of Therapeutics

Introduction to Principles of Clinical
Pharmacology
Definition of Basic Terms

Drug
Simply – a drug is a chemical or substance that
causes changes in the structure or function of
living organisms

Medicine
A 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 name
Standardised 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 name
Name given by the manufacturer e.g. Ferrogradumet
(ferrous sulfate), Viagra® (sildenafil); Ventolin®
(salbutamol)
Definition of Basic Terms cont.

Pharmacology
Simply: the science of drug actions and uses

Pharmacodynamics
Mechanisms of action (“what the drug does to
the body”)

Pharmacokinetics
Literally, movement of the drug within the body
(“what the body does to the drug”)
Definition of Basic Terms cont.

Toxicity
Manifestation of the harmful effects of the drug
after exposure to high levels (“intoxication” or
“poisoning”)

Therapeutics
Use 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 drugs
Specific molecular processes by which drugs work, e.g.
inhibition of an enzyme or stimulation of a receptor subtype

Mode of action of drugs
General description of the type of action: e.g.
supplements, antihypertensives, analgesics

Site of action of drugs
Specific 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 ‘drugreceptor 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 (‘firstpass’)

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
Pharmacodynamics
HOW BODY ACTS ON DRUG
HOW DRUG ACTS ON BODY
Dose of Drug
•Absorption
•Distribution
•Metabolism
•Elimination
Body
concentration over
time
Drug effect
•Receptor Binding
•Biological Effect