Development and Classification of Medicine

Brenda McCartney 2nd February 2011

Development of a Medicine

What is a drug?
Any biologically active chemical that does
not occur naturally in the human body that can affect living processes

It is used for the treatment, prevention or

alleviating the symptoms of disease.

A little light history

16th century Egypt Ebers papyrus poppy juniper berries beer lead swine teeth goose grease lizard's blood donkey hooves crushed precious stones excreta from various animals

Where do drugs come from now?

Plants:
Digoxin (foxglove) Belladonna (deadly nightshade) Diamorphine (opium poppy) Animal tissue: Insulin, growth hormone

Synthetic manufacture:
Most modern medicines

The Pharmaceutical Industry

Develops, produces and markets drugs
licensed for use as medicine. Companies can deal in generic and / or brand medications. Average cost to develop a successful new drug 145million - 1.2 billion Subject to variety of laws and regulations.

Stages in Drug Development

1 Drug discovery Research & identification of compounds 2 Pre-clinical testing Lab testing 3 Clinical trials Testing on humans.

1. Drug Discovery
From traditional remedies
Aspirin Penicillin

Aspirin first synthetic drug

(460-377 BC) Hippocrates Pain relief treatments with
powder made from the bark and leaves of the willow tree

(1829) Johann Bchner Isolated pure salicin (salicylic

acid (1838))

(1853) Charles Frederic Gerhardt first synthesised

acetyl-salicylic acid (ASA)

(1898) Felix Hoffman Chemist at Bayer synthesized

pure sample of ASA

(1899) Bayer receives patent

for Aspirin

Sales today exceed 50 billion

pills per year

Penicillin the first antibiotic

Fleming was a researcher working in an untidy lab After returning from holiday he noticed that bacterial
plates had become contaminated with a fungus

Bacteria were not present near the fungus on the plate He concluded that the fungus was secreting an
antimicrobial agent

He extracted the agent and named it penicillin

Fleming was presented the Nobel Prize for Medicine in 1945. He humbly said, "Nature makes penicillin; I just found it."

2. Pre-clinical Testing.
In vitro testing
Test active compound against target cell Provides evidence of beneficial / harmful effects Very simplistic, target organs/tissues made up of multiple cell types BUT lacks the homeostatic mechanisms and pathways found in animals / humans

Pre-clinical animal testing

Pharmacology Testing
effects of drug on all major systems (absorption, metabolism, distribution, excretion, plasma levels, half life)

Toxicology Testing Acute toxicity (single dose)

Short term toxicity (daily dosing for 2 weeks 3 months)

Pre-clinical Testing
ED50 Effective Dose 50
the amount of the drug required to produce a specified effect in 50% of an animal population LD50 Lethal Dose 50 The amount of the drug required to cause death in 50% of an animal population

But only human studies can tell use how useful and safe a drug is................

.....So clinical trials in human volunteers are needed.

Clinical Trials.

What are clinical trials?

Research studies involving humans Used to determine if drug treatments are
safe and effective Are the safest and quickest way to find treatments that work

Types of clinical trails.

Treatment trials Prevention trials Screening trials Diagnostic trials Quality of life studies Genetics studies

Clinical trial protocol

Strict scientific guidelines
Purpose of study How many participants Who is eligible How study will be carried out What information will be gathered End points

Clinical trials phases

Stage 1 Drug Discovery Stage 2 Preclinical Stage 3 Clinical trials
Phase I 20-100 volunteers Phase III 1000-5000 volunteers

10,000 compounds

250 compounds

5 compounds

100-500 volunteers

Phase II

1 approved drug

6.5 years

7 years

1.5 yrs

Adapted from Pharmaceutical Research and Manufacturers of America

Phases I trials
Use healthy volunteers How does the drug affect the human
body? Drug absorption, metabolism and excretion Preferred method of administration What dosage is safe?

Phase II trials
Use target patient group representative of
those likely to benefit from the drug. No pregnant women Does the drug have a beneficial effect on the disease? Determine therapeutic dose range. Usually placebo controlled Conducted by experts in the disease field

Phase III trials

Obtains all data for regulatory agencies Often multi-centered, multinational Long term safety evaluated Is new drug better than standard?

Randomised controlled trial (RCT)

Volunteers randomly assigned to new
treatment or best existing treatment Doctors have no say in who goes in which group to reduce bias

What is a placebo?
An inactive pill, identical in appearance to the treatment pill which is given to the control group. Used to control for the placebo effect Patient feels better due to belief in the treatment
Test pill Placebo

Participants in Clinical Trials

Protocol sets out who can participate Use inclusion / exclusion criteria Factors that allow people in are inclusion
criteria (study for males)

Factors used to reject are exclusion

criteria (may have history of illness)

Clinical trials the results

Endpoint used to test trials success Ideally use a hard endpoint cure from

disease Statisticians analyse results is A better than B? Only after analysis do you tell which is A and B.

Drug Licensing
Application submitted to Medicines and
Healthcare products Regulatory Agency (MHRA)

MHRA carry out pre-marketing assessment

of safety, quality and efficacy, examining all research and results in detail.

Medicines and Healthcare products Regulatory Agency

An executive agency of the Department of
Health Enhance and safeguard the health of the public by ensuring that medicines and medical devices work and are acceptably safe. No product is risk free.

European Medicines Evaluation Agency (EMEA)

The EMEA co-ordinate drug licence
applications within the European Union (EU). Committee for Proprietary Medicinal Products (CPMP)

Product Launch
When a drug has marketing authorisation,
it is not available straight away. The company first have to apply to market their product. In the UK, they will apply to the MHRA. When this is done, the product is launched, and doctors can prescribe it. The time it takes from marketing authorisation to launch in the UK is one of the fastest in the world.

Black Triangle Drugs.

If the drug is an active substance which
has been newly licensed for use in the UK. If it contains a new combination of active substances. If administration is via a new route or delivery system. If the medicine is to be used in a new patient population. If the drug is to be used for a new indication.

MHRA monitoring of Black Triangle Drugs

confirm risk/benefit profiles established
during the pre-marketing phase increase understanding of the safety profiles of new medicines ensure identification of previously unrecognised side effects as quickly as possible.

Uses Yellow Card Scheme.

Classification of a Medicine

Names of drugs
Chemical name: describes the chemical
structure: by anyone: acetyl-p-amino-phenol paracetamol

Generic name: a name that can be used Trade name: owned by the
manufacturer: Calpol

Other ways to categorise drugs

What kind of molecule is it?
What organ system (or what disease) is it
for? e.g., cardiac, psychotropic

What parts of cells are affected?

What is the drug used for?

To cure e.g., infections, cancer
To suppress diseases or symptoms
without attaining a cure e.g., hypertension, diabetes, pain control
e.g., immunisation

To prevent disease (prophylactic)

How does the drug act?

Replace a deficiency, e.g., vitamins,
minerals, hormones enzyme action

Interfere with cell function, e.g., block Kill / prevent growth of viruses, bacteria,
fungi, protozoa, cancer

Categories of drug

Anti-inflammatory Analgesic Antipyretic Vaccine Antihypertensive Vitamin supplement Antitussive

Anaesthetic Antiviral Surfactant Antifungal Laxative Antibiotic

How do drugs work?

Pharmacodynamics: study of how
chemicals exert their effects The practical importance of this is enabling the design of new and better drugs

Receptors
Receptors are proteins on the cell surface or inside
the cell.

They bind the bodys own chemical messenger

Convert the binding event to a signal that the cell

can recognize and respond to
signal

receptor

Lock & Key

Interaction between a receptor and its signal

molecule (ligand) is like lock & key. Perfect fit depends on exact 3D shape and size of both molecules.

Receptors
Drugs also bring information to cells by The drug picks the lock and triggers a
response by the cell.
drug

fitting into the same receptor molecules.

receptor

Agonists and Antagonists

Agonist: a drug that fits into a receptor
and activates a response e.g., morphine, nicotine but blocks the receptor and does not activate a response e.g., beta-blockers

Antagonist: a drug that fits into a receptor

Non-specific effects
Acidic or alkaline properties
Surfactant properties (amphotericin)

Osmotic properties (laxatives, diuretics)

Interactions with membrane lipids
(anaesthetics)

Side-effects and other effects

Not the wanted effect e.g. aspirin causes
gastric ulcer Diphenhydramine has a useful side-effect

Side-effects and other effects

Hypersensitivity / allergy: exaggerated
adverse reaction to drug

Toxic effects e.g., Thalidomide: teratogenic Tolerance: increasing amounts are needed
to produce the same effect

Pharmacokinetics
How the body deals with the drug We need to consider Dose Route of Administration Absorption and distribution Metabolism and excretion

Dose

amount of drug taken at any one time

Aim is to give the patient a dose of drug

that achieves the desired effect without causing harmful side effects Therapeutic Index(TI) is the ratio of the therapeutic dose to the toxic dose Egs of drugs with low TI include digoxin lithium and methotrexate

Administration
Route of administration depends on

how easy it is to use for patient how quickly a drug needs toreach site of action where it has to work in the body

Routes of Administration
Intravenous

Inhaled
Oral Transdermal

Subcutaneous or intramuscular injection

Rectal

Topical

Oral Route
Medications taken by mouth Formulated in either a solid or liquid

form Absorbed from the GI tract mainly in the small intestine which is specialised for absorption (large surface area due to villi and microvilli).

Disadvantages
Onset of action is relatively slow Absorption may be irregular Some drugs destroyed by enzymes or
other secretions found in GI tract Because blood from GItract passes through live it is subject to hepatic metabolism before reaching systemic circulation

Buccal Route
Drug is formulated as a tablet or a spray and is absorbed from the buccal cavity Sublingual absorption very fast onset of action but duration is short Buccal absorption quick onset of action that is of longer duration than sublingual route

Rectal Route
Drugs formulated as liquids ,solid dosages and semi solids. The chosen preparation is inserted into the rectum where it is released to give local effect or absorbed to give a systemic effect

Rectal & Vaginal Route

Advantages Can be used when oral route unsuitable Useful when drug causes GI irritation Can be used for local action

Disadvantages Absorption irregular and unpredictable Less convenient than oral route Low patient acceptability

Inhalation Route
Advantages Drugs inhaled through

Used predominately in
the treatment of asthma Drugs delivered directly to their site of action ie lungs

the nose or mouth to produce local or systemic effects Drug dose required to produce desired effect is much smaller than oral route therefore reduction in side effects

Topical Route
Skin used as site of administration Lotions creams ointments powders Skin has natural barrier function but

specialised dosage forms have been developed that when applied they allow the drug to pass through and produce systemic effect

Parenteral Route (drugs that are given by injection)

IV route -drugs injected directly into the
systemic circulation (fast onset of action) Subcutaneous route -drugs injected into the s/c layer of the skin (easiest and least painful) Intramuscular route drugs injected into muscle layers

Examples in each category

inhaled oral across rectal the skin injected into skin or muscle Novocaine (the dentists choice!) Intravenous

local action

Vicks Vaporub

antacid

cold sore foam cream enema

Local thrombolytic therapy adrenalin

systemic cigarette Nurofen action tablets

Nicotene Panadol contrapatch suppos- ceptive itory

ADME
Absorption: the mechanism by which a
drug enters the body Distribution: the drug is transported throughout the body Metabolism: the drug interacts with, and is processed by, the body Elimination: the drug is removed from the body

Absorption
Disintegration Dissolution Direct absorption at site of action,
e.g., in the gut

Steps in distribution
Drug must spread throughout blood

volume Drug must get out of the bloodstream between or through endothelial cells Drug must cross the cell membrane into cells

Factors affecting distribution

1.Binding to plasma proteins: if a
drug is bound to large plasma proteins, it will be unable to get out as the proteins are too large.

Arggh! I cant fit through!

Factors affecting distribution

2. Extent of blood supply. If a tissue is well
perfused with blood, drugs will get there faster. Adipose tissue has low blood perfusion so drugs reach it slowly.

Factors affecting distribution

3. pH. A drug will pass through membranes
better if it is not ionised 4. Binding of drugs to other tissue components

Metabolism: what happens to a drug

Drug Concentration
Lethal Dose

Injected Dose

Oral Dose

Time

Therapeutic Range
SubTherapeutic

First pass effect

All nutrients and drugs absorbed from the
gut travel in the blood directly to the liver. The liver breaks down many drugs so they are inactivated before they ever enter the systemic circulation! This can decrease drug delivery to target tissues But some drugs are activated by the first pass effect

Elimination
Mainly in the kidney. Also bile, gut, lung,
breast milk. Elimination of a drug is usually linked to renal function.

Individual variation
Each person is unique how they respond
to a drug Age and sex (hormonal differences) Weight: some drugs are stored in fat so less effective and longer lasting in obese people Allergy Kidney & liver function: how will they affect elimination?

Memory work

Pharmacodynamics is Pharmacokinetics is Receptor is like Ligand or drug is like First pass occurs in Many drugs are excreted by

Liver Lock What the body does

to the drug Kidney What the drug does to the body Key

Memory work

Pharmacodynamics is Pharmacokinetics is Receptor is like Ligand or drug is like First pass occurs in Many drugs are excreted by

Liver Lock What the body does

to the drug Kidney What the drug does to the body Key