Development And Classification Of A Medicine

Niall Byrne

Wednesday 30th January 2012

Lecture plan•Development of a medicine:•How can we categorise drugs?•How do drugs cause their effects?•Specific receptors: lock & key•Non-specific effects•Pharmacokinetics

Introduction

•What is a drug? •Any biologically active chemical that does

not occur naturally in the human body that can affect living processes

A little light history16th century EgyptEbers papyruspoppy juniper berriesbeer leadswine teeth goose greaselizard's blooddonkey hoovescrushed precious stonesexcreta 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

Development of a medicine

•Drug discovery

•Pre-clinical

▫Testing drug in a lab

•Clinical Trials

▫Testing drug on humans

Drug discovery• In 1928 Alexander Fleming returned from holiday

to find his bacterial plates had been contaminated with a fungus.

• Fungus had killed the bacteria on the plate• Realised the potential of the mould to kill bacteria• He called the agent penicillin• it was over a decade before someone else turned

penicillin into the miracle drug for the 20th century.

• Awarded the 1945 Nobel Prize in Physiology or Medicine

Pre clinical testing• Identify a compound which has the desired

effect on a cell (~ 20 - 50 out of several 1000)•Test on panel of cell lines (5 - 10 / 50)

▫Pharmacodynamics (What drug does to body)•Test in animals ( 1 - 3 / 10)

▫Pharmacodynamics▫Pharmacokinetics (What body does to drug)▫Drug metabolism and elimination

mechanisms▫Toxicity

Schematic of possible outcomes

•Lecture plan•Development of a medicine:

▫Clinical trials•How can we categorise drugs?•How do drugs cause their effects?•Specific receptors: lock & key•Non-specific effects•Pharmacokinetics

Clinical trials: What are they?

•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

▫Three stages: I II and III

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

•5 compounds5 compounds

•Stage 3Stage 3•Clinical trialsClinical trials

•7 years7 years

•Phase IIPhase II•100-500 volunteers100-500 volunteers

•Phase IIIPhase III•1000-5000 volunteers1000-5000 volunteers

•Phase IPhase I•20-100 volunteers20-100 volunteers

•250 compounds250 compounds

•Stage 1Stage 1•Drug DiscoveryDrug Discovery

•Stage 2Stage 2•PreclinicalPreclinical

•6.5 years6.5 years •1.5 yrs1.5 yrs

•1 1 approved approved

drugdrug

•10,000 10,000 •compoundcompoundss

Adapted from Pharmaceutical Research and Manufacturers of AmericaAdapted 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 effectPatient feels better due to belief in the

treatment

Test pill Test pill PlaceboPlacebo

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.

Lecture plan

•Development of a medicine:

•How can we categorise drugs?

•How do drugs cause their effects?

•Specific receptors: lock & key

•Non-specific effects

•Pharmacokinetics

Names of drugs

•Chemical name: describes the chemical structure: acetyl-p-amino-phenol

•Generic name: a name that can be used by anyone: paracetamol

•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

•To prevent disease (prophylactic) e.g., immunisation

How does the drug act?

•Replace a deficiency, e.g., vitamins, minerals, hormones

•Interfere with cell function, e.g., block enzyme action

•Kill / prevent growth of viruses, bacteria, fungi, protozoa, cancer

Categories of drug

•Anti-inflammatory•Analgesic•Antipyretic•Vaccine•Antihypertensive•Vitamin

supplement•Antitussive

•Antiviral

•Antifungal

•Antibiotic

• Anaesthetic

• Surfactant

• Laxative

Content of today’s lecture•How can we categorise drugs?•How do drugs cause their effects?•Specific receptors: lock & key•Non-specific effects•Pharmacokinetics

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

receptorreceptor

signalsignal

Receptors•Receptors are proteins on the cell surface or

inside the cell.

•They bind the body’s own chemical messenger

•Convert the binding event to a signal that the cell can recognize and respond to

“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

fitting into the same receptor molecules.

•The drug picks the lock and triggers a response by the cell.

receptorreceptor

drugdrug

Agonists and Antagonists•Agonist: a drug that fits into a receptor

and activates a response e.g., morphine, nicotine

•Antagonist: a drug that fits into a receptor but blocks the receptor and does not activate a response.

Content of today’s lecture•How can we categorise drugs?•How do drugs cause their effects?•Specific receptors: lock & key•Non-specific effects•Pharmacokinetics

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

Content of today’s lecture•How can we categorise drugs?•How do drugs cause their effects?•Specific receptors: lock & key•Non-specific effects•Pharmacokinetics

Pharmacokinetics

How the body deals with the drugWe need to consider•Dose•Route of Administration•Absorption and distribution•Metabolism and excretion

Doseamount 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

AdministrationRoute of administration depends on how easy it is to use for patient how quickly a drug needs to reach site

of action where it has to work in the body

Routes of Administration

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 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

• Used predominately in the treatment of asthma

• Drugs delivered directly to their site of action ie lungs

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 the skin

rectal injected into skin or muscle

Intra-venous

local action

Vick’s Vaporub

antacid cold sore cream

foam enema

Novocaine (the dentist’s choice!)

Local thrombo-lytic therapy

systemic action

cigarette

Nurofen tablets

Nicotene patch

Panadol suppos-itory

contra-ceptive

adrenalin

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 distribution1.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 can’t 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

TimeTimeDru

g C

once

ntr

ati

on

Dru

g C

once

ntr

ati

on

TherapeuticTherapeutic

RangeRange

Sub-Sub-TherapeutTherapeut

icic

LethalLethalDoseDose

Injected DoseInjected Dose

Oral DoseOral Dose

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?

And finally…

•Pharmacodynamics is…

•Pharmacokinetics is…

•Receptor is like…

•Ligand or drug is like a…

•First pass occurs in…

•Many drugs are excreted

by…

• What the drug does to the body

• What the body does to the drug

• Lock

• Key

• Liver

• Kidney