Transcript Different categories of medicines and their actions

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 Büchner 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
•10,000
•compounds
•250 compounds
•Phase III
•1000-5000 volunteers
•5 compounds
•Phase II
•100-500 volunteers
•6.5 years
•7 years
•1
approved
drug
•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:
acetyl-p-amino-phenol
• Generic name: a name that can be used
by anyone:
• Trade name: owned by the
manufacturer:
paracetamol
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
• 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 body’s 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
fitting into the same receptor molecules.
• The drug picks the lock and triggers a
response by the cell.
drug
receptor
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 e.g., beta-blockers
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
Topical
Rectal
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
local
action
inhaled
oral
across
rectal
the skin
injected
into skin
or
muscle
Intravenous
Vick’s
Vaporub
antacid
cold sore foam
cream
enema
Novocaine
(the
dentist’s
choice!)
Local
thrombolytic
therapy
systemic cigarette Nurofen
action
tablets
Nicotene Panadol contrapatch
suppos- ceptive
itory
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 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
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
Drug Concentration
Metabolism: what happens to a drug
Lethal
Dose
Injected Dose
Therapeutic
Range

Oral Dose
SubTherapeutic
Time
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