Transcript Different categories of medicines and their actions

Development And
Classification Of A Medicine
Niall Byrne
Wednesday 30th January 2012
Lecture plan
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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 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
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
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Purpose of study
How many participants
Who is eligible
How study will be carried out
What information will be gathered
End points
Clinical•Stage
trials
–
phases
2
•Stage 1
•Drug Discovery
•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
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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
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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
Clinical trials – the results
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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
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Anti-inflammatory
Analgesic
Antipyretic
Vaccine
Antihypertensive
Vitamin supplement
Antitussive
• Anaesthetic • Antiviral
• Surfactant • Antifungal
• Laxative
• Antibiotic
Content of today’s lecture
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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
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.
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 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 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
Disadvantages
• Can be used when oral route
• Absorption irregular and
unsuitable
• Useful when drug causes GI
irritation
• Can be used for local action
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
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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?
And finally…
• Pharmacodynamics is…
• What the drug does to the body
• Pharmacokinetics is…
• What the body does to the drug
• Receptor is like…
• Lock
• Ligand or drug is like a…
• Key
• First pass occurs in…
• Liver
• Many drugs are excreted by… • Kidney