2011 02 28 Development Classification of Medicine

7/29/2019 2011 02 28 Development Classification of Medicine

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Development and

Classification of Medicine

Brenda McCartney

2nd February 2011


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Development of a Medicine


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What is a drug?

Any biologically active chemical that doesnot occur naturally in the human bodythat can affect living processes

It is used for the treatment, prevention oralleviating the symptoms of disease.


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A little light history

16th century Egypt

Ebers papyrus

poppy juniper berriesbeer leadswine teeth goose greaselizard's blood donkey hoovescrushed precious stonesexcreta from various animals


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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


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The Pharmaceutical Industry

Develops, produces and markets drugslicensed for use as medicine.

Companies can deal in generic and / orbrand medications.

Average cost to develop a successful new

drug 145million - 1.2 billion Subject to variety of laws and regulations.


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Stages in Drug Development

1 Drug discovery

Research & identification of compounds

2 Pre-clinical testing

Lab testing

3 Clinical trials

Testing on humans.


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1. Drug Discovery

From traditional remediesAspirin

Penicillin


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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 (salicylicacid (1838))

(1853) Charles Frederic Gerhardt first synthesisedacetyl-salicylic acid (ASA)

(1898) Felix Hoffman Chemist at Bayer synthesizedpure sample of ASA

(1899) Bayer receives patentfor Aspirin

Sales today exceed 50 billion

pills per year


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Penicillin the first antibiotic Fleming was a researcher working in an untidy lab

After returning from holiday he noticed that bacterialplates had become contaminated with a fungus

Bacteria were not present near the fungus on the plate

He concluded that the fungus was secreting anantimicrobial 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."


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2. Pre-clinical Testing.

In vitrotesting Test active compound against target cell

Provides evidence of beneficial / harmful

effectsVery simplistic, target organs/tissues made up

of multiple cell types

BUT lacks the homeostatic mechanisms andpathways found in animals / humans


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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)


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Pre-clinical Testing

ED50 Effective Dose 50the amount of the drug required toproduce 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


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

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


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Clinical Trials.


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What are clinical trials?

Research studies involving humans Used to determine if drug treatments are

safe and effectiveAre the safest and quickest way to find

treatments that work


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Types of clinical trails.

Treatment trials Prevention trials

Screening trials Diagnostic trials Quality of life studies Genetics studies


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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


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Clinical trials phases

5 compounds

Stage 3

Clinical trials

7 years

Phase II

100-500 volunteers

Phase III

1000-5000 volunteers

Phase I

20-100 volunteers

250 compounds

Stage 1

Drug Discovery

Stage 2

Preclinical

6.5 years 1.5 yrs

1approved

drug

10,000compounds

Adapted from Pharmaceutical Research and Manufacturers of America.


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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?


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Phase II trials

Use target patient group representative ofthose 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


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Phase III trials

Obtains all data for regulatory agencies Often multi-centered, multinational

Long term safety evaluated Is new drug better than standard?


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Randomised controlled trial (RCT)

Volunteers randomly assigned to newtreatment or best existing treatment

Doctors have no say in who goes in whichgroup to reduce bias


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What is a placebo?

An inactive pill, identical in appearance to thetreatment pill which is given to the controlgroup.

Used to control for the placebo effectPatient feels better due to belief in the

treatment

Test pill Placebo


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Participants in Clinical Trials

Protocol sets out who can participate Use inclusion / exclusion criteria

Factors that allow people in are inclusioncriteria(study for males)

Factors used to reject are exclusioncriteria(may have history of illness)


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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 Aand B.


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Drug Licensing

Application submitted to Medicines andHealthcare products Regulatory Agency

(MHRA)

MHRA carry out pre-marketing assessment

of safety, quality and efficacy, examiningall research and results in detail.


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Medicines and Healthcareproducts Regulatory Agency

An executive agency of the Department of

Health Enhance and safeguard the health of thepublic by ensuring that medicines andmedical devices work and are acceptablysafe. No product is risk free.


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European Medicines EvaluationAgency (EMEA) The EMEA co-ordinate drug licence

applications within the European Union (EU).

Committee for Proprietary MedicinalProducts (CPMP)


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Product Launch

When a drug has marketing authorisation,it is not available straight away. Thecompany first have to apply to market

their product. In the UK, they will apply tothe MHRA. When this is done, the productis launched, and doctors can prescribe it.

The time it takes from marketingauthorisation to launch in the UK is one ofthe fastest in the world.


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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 activesubstances.

If administration is via a new route ordelivery system.

If the medicine is to be used in a newpatient population. If the drug is to be used for a new

indication.


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MHRA monitoring of BlackTriangle Drugs

confirm risk/benefit profiles establishedduring the pre-marketing phase

increase understanding of the safetyprofiles of new medicines

ensure identification of previously

unrecognised side effects as quickly aspossible.

Uses Yellow Card Scheme.


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Classification of a Medicine


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Names of drugs

Chemical name: describes the chemicalstructure: acetyl-p-amino-phenol

Generic name: a name that can be usedby anyone: paracetamol

Trade name: owned by themanufacturer: Calpol


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Other ways to categorise drugs

What kind of molecule is it?

What organ system (or what disease) is itfor? e.g., cardiac, psychotropic

What parts of cells are affected?


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What is the drug used for?

To cure e.g., infections, cancer

To suppress diseases or symptomswithout attaining a cure e.g.,hypertension, diabetes, pain control

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


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How does the drug act?

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

Interfere with cell function, e.g., blockenzyme action

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


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Categories of drug

Anti-inflammatory Analgesic

Antipyretic Vaccine Antihypertensive

Vitamin supplement Antitussive

AntiviralAntifungal

Antibiotic

Anaesthetic Surfactant

Laxative


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How do drugs work?

Pharmacodynamics: study of howchemicals exert their effects

The practical importance of this is enablingthe design of new and better drugs


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receptor

signal

Receptors

Receptors are proteins on the cell surface or insidethe cell.

They bind the bodys own chemical messenger

Convert the binding event to a signal that the cellcan recognize and respond to


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Lock & Key

Interaction between a receptor and its signalmolecule (ligand) is like lock & key.

Perfect fit depends on exact 3D shape andsize of both molecules.


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Receptors

Drugs also bring information to cells byfitting into the same receptor molecules.

The drug picks the lockand triggers aresponse by the cell.

receptor

drug


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Agonists and Antagonists

Agonist: a drug that fits into a receptorand activates a response e.g., morphine,nicotine

Antagonist: a drug that fits into a receptorbut blocks the receptor and does not

activate a response e.g., beta-blockers


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Non-specific effects

Acidic or alkaline properties

Surfactant properties (amphotericin)

Osmotic properties (laxatives, diuretics)

Interactions with membrane lipids(anaesthetics)


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Side-effects and other effects

Not the wanted effect e.g. aspirin causesgastric ulcer

Diphenhydramine has a useful side-effect


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Side-effects and other effects

Hypersensitivity / allergy: exaggeratedadverse reaction to drug

Toxic effects e.g., Thalidomide: teratogenic

Tolerance: increasing amounts are needed

to produce the same effect


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Pharmacokinetics

How the body deals with the drug

We need to consider

Dose Route of AdministrationAbsorption and distribution Metabolism and excretion


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Doseamount of drug taken at any one time

Aim is to give the patient a dose of drugthat 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 digoxinlithium and methotrexate


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Administration

Route of administration depends on

how easy it is to use for patient

how quickly a drug needs toreach site ofaction

where it has to work in the body


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Intravenous Inhaled

Oral

Transdermal

Rectal

Topical

Subcutaneousor intramuscular

injection

Routes of Administration


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Oral Route

Medications taken by mouth Formulated in either a solid or liquid

formAbsorbed from the GI tract mainly in

the small intestine which is specialised

for absorption (large surface area dueto villi and microvilli).


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Disadvantages

Onset of action is relatively slowAbsorption may be irregular

Some drugs destroyed by enzymes orother secretions found in GI tract Because blood from GItract passes

through live it is subject to hepaticmetabolism before reaching systemiccirculation


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Buccal Route

Drug is formulated as a tablet or a sprayand is absorbed from the buccal cavity

Sublingual absorption very fast onset ofaction but duration is short

Buccal absorption quick onset of action

that is of longer duration than sublingualroute


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Rectal Route

Drugs formulated as liquids ,solid dosagesand semi solids.

The chosen preparation is inserted into therectum where it is released to give localeffect or absorbed to give a systemic

effect


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Rectal & Vaginal Route

Advantages

Can be used when

oral route unsuitable Useful when drugcauses GI irritation

Can be used for localaction

Disadvantages

Absorption irregularand unpredictable

Less convenient thanoral route

Low patientacceptability


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Inhalation Route

Used predominately inthe treatment ofasthma

Drugs delivereddirectly to their site ofaction ie lungs

Advantages Drugs inhaled through

the nose or mouth to

produce local or systemiceffects

Drug dose required toproduce desired effect is

much smaller than oralroute therefore reductionin side effects


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Topical Route

Skin used as site of administration Lotions creams ointments powders

Skin has natural barrier function butspecialised dosage forms have beendeveloped that when applied they allow

the drug to pass through and producesystemic effect


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Parenteral Route(drugs that are given by injection)

IV route -drugs injected directly into thesystemic circulation (fast onset of action)

Subcutaneous route -drugs injected intothe s/c layer of the skin (easiest and leastpainful)

Intramuscular routedrugs injected intomuscle layers


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Examples in each category

inhaled oral acrossthe skin

rectal injectedinto skinormuscle

Intra-venous

localaction

VicksVaporub

antacid cold sorecream

foamenema

Novocaine(thedentistschoice!)

Localthrombo-lytictherapy

systemicaction

cigarette Nurofentablets

Nicotenepatch

Panadolsuppos-itory

contra-ceptive

adrenalin


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ADME

Absorption: the mechanism by which adrug enters the body

Distribution: the drug is transportedthroughout the body Metabolism: the drug interacts with, and is

processed by, the body

Elimination: the drug is removed from thebody


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Absorption

Disintegration

Dissolution Direct absorption at site of action,

e.g., in the gut


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Steps in distribution

Drug must spread throughout bloodvolume

Drug must get out of the bloodstreambetween or through endothelial cells

Drug must cross the cell membraneinto cells


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Factors affecting distribution

1.Binding to plasma proteins: if adrug is bound to large plasma

proteins, it will be unable to getout as the proteins are too large.

Arggh! Icant fitthrough!


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2. Extent of blood supply. If a tissue is wellperfused with blood, drugs will get there

faster. Adipose tissue has low bloodperfusion so drugs reach it slowly.


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3. pH. A drug will pass through membranesbetter if it is not ionised

4. Binding of drugs to other tissuecomponents


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Metabolism: what happens to a drug

TimeDrug

Concentr

ation

Therapeutic

RangeSub-

Therapeutic

LethalDose

Injected Dose

Oral Dose


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First pass effect

All nutrients and drugs absorbed from thegut travel in the blood directly to the liver.The liver breaks down many drugs so theyare inactivated before they ever enter thesystemic circulation!

This can decrease drug delivery to targettissues

But some drugs are activated by the firstpass effect


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Elimination

Mainly in the kidney. Also bile, gut, lung,breast milk.

Elimination of a drug is usually linked torenal function.


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Individual variation

Each person is unique how they respondto a drug

Age and sex (hormonal differences) Weight: some drugs are stored in fat so

less effective and longer lasting in obesepeople

Allergy Kidney & liver function: how will theyaffect elimination?


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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 doesto the drug Kidney What the drug does

to the body

Key


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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 doesto the drug Kidney What the drug does

to the body

Key

Documents

2011 02 28 Development Classification of Medicine