Option D: Medicines and Drugs Section D.1: Pharmaceutical Products pp 405-410 (Green and Damji)

Option D: Medicines and Drugs

Section D.1: Pharmaceutical Productspp 405-410 (Green and Damji)

ObjectivesB.1.1: List the effects of drugs and medicines.B.1.2: Outline the stages involved in research,

development and testing of new pharmaceutical products.

B.1.3: Describe the different methods of administering drugs.

B.1.4: Discuss the terms lethal dosage (LD50), tolerance, and side effects.

What exactly is a medicine? a drug ?

Any chemical (natural or synthetic) that does one or more of the following…

… alters mood or emotions… alters incoming sensory sensations… alters a physiological state including consciousness, activity level, or co-ordination

Why do people use medicines / drugs?

… improve health

… assist the body’s natural healing process

…‘placebo affect’

Medicines and drugs can be…

… helpful or harmful

… natural or synthetic

… legal or illegal

…

How are new drugs developed in USA?

(1) Research

• Disease is selected

• Vulnerable targets are identified

• Potential lead molecules are considered

• Lead molecule is selected

How are new drugs developed?

(2) Preclinical trials–in vitro (lab environment)–in vivo (living organisms)• cell cultures / animals • usu 3 species )– rats, mice, guinea pigs

purpose – identify lethal dose, effective dose, potential side effects

How are new drugs developed?

(3) Phase 1 trials – initial clinical trials– small numbers•healthy volunteers• terminally ill patients (with their consent)

purpose: assess toxicity, effective dose, side effects

How are new drugs developed?

(4) Phase II trials – clinical trial– several hundred– ill patients– treated with drug or placebo• ‘blind’ test or ‘double-blind’ test

– statistical study purpose: determine dosage and

administration; eliminate bias

How are new drugs developed?

(5) Phase III trials – extended clinical trials

– thousands– ill patients– treated with drug and closely

monitoredpurpose: adjust dosage and monitor side

effects

How are new drugs developed?

(6) Drug launched

(7) Phase IV trials–Post-launching

purposes: new formulation, new dosage, new application, product extension

Drug Development…

• takes a long time and a lot of money…

Time – as much as 10-15 yearsCost – up to $800 million

Why does drug development require such an exhaustive process?...

• to protect users from harmful side-effects and/or death– drugs that make it through the approval process

have a reasonable risk/benefit ratio– most proposed drugs never make it through the

process

What is thalidomide and why was it such a problem?...

• non addictive sedative available in Europe

1958-1963

• given to pregnant women to treat ‘morning sickness’ – (which it did)

Structure of Thalidomide

Source: http://www.k-faktor.com/contergan/thalidomide.gif

Thalidomide exists as a racemic mixture of TWO stereoisomers – each with their own special impact on the body!

Why was thalidomide such a problem?...

• babies born dead or with birth defects:– no arms &/or legs, – short arms &/or legs– missing bones– Intestinal abnormalities

• 460 cases in UK• 3000 in former West Germany

What about thalidomide now?

As a result of the impact, thalidomide was initially banned, but

• is currently available (under another name)

to treat severe leprosy in Brazil, Mexico, USA– special warnings provided

• and is being considered for other applications (i.e. cancer treatment)

When are medicines/drugs considered hazardous?

When they pose a risk to the – Physical– Mental– Social

well-being of the user.

What are main vs side effects?• Main effect = desired response• Side effect = the unwanted response to the

use of a medicine or drug

Ex: Morphine – prescribed for painMain impact = pain reliefSide effect = constipation

Ex: Morphine – prescribed for diarrheaMain impact = induced constipationSide effect = pain relief

What are side effects?• NO drug is free of side effects… – range from trivial to serious – even death– allergies (over-reaction of immune system)• Mild skin rashes… to fatal shock• penicillin

– damage to liver &/or kidney• often long term• alcohol damages liver• users of one drug over a long time… or of multiple

drugs often have periodic liver / kidney function test

What is toxicity?• TOXICITY: – LD50 value

– Lethal dose of a substance that kills off 50% of a population• Not humans – numbers extrapolated from animal

studies

– Molecules with small LD50 numbers are the most toxic

Some interesting LD50

Substance Animal, Route LD50

Vitamin C (ascorbic acid) rat, oral 11,900 mg/kg

Paracetamol (acetaminophen) rat, oral 1,944 mg/kg

Aspirin (acetylsalicylic acid) rat, oral 200 mg/kg

Some interesting LD50

Substance Animal, Route LD50

Grain alcohol (ethanol) rat, oral 7,060 mg/kg

THC (main psychoactive substance in Cannabis) rat, oral

730 mg/kg females; 1,270 mg/kg males

Caffeine rat, oral 192 mg/kg

Nicotine rat, oral 50 mg/kg

Some interesting LD50

Substance Animal, Route LD50

Metallic Arsenic rat, oral 763 mg/kg

Arsenic trisulfide rat, oral 185 mg/kg - 6400 mg/kg

Strychnine rat, oral 16 mg/kg

Arsenic trioxide rat, oral 14 mg/kg

Some interesting LD50Substance Animal, Route LD50

Aflatoxin B1 (from Aspergillus flavus) rat, oral 0.048 mg/kg

Venom of the Inland taipan (Australian snake)

rat, subcutaneous 0.025 mg/kg

Dioxin (TCDD) rat, oral 0.020 mg/kg

VX (nerve agent) human, oral 0.0023 mg/kg (est)

Batrachotoxin (from poison dart frog)human, sub-cutaneous injection

0.002-0.007 mg/kg (est)

Botulinum toxin (Botox) human, oral, injection 0.000001 mg/kg (est)

What is tolerance?• User needs increasing amounts of a drug to

get the same physiological effect. – Due to use over time and with regular use

• Maximum daily tolerance– amount that can be taken into the body without

undesirable symptoms occurring

Why is tolerance a problem?• Body may become tolerant to the positive

effect, not NOT to the harmful effect(s)– User needs more of the drug… and this intensifies

the harmful effect(s). – Barbituates – users develop a tolerance to

sedative but not to its effect on breathing (slows it down) – so they take so much of the drug their breathing stops.

Why is tolerance a problem?• Tolerance changes after the user stops using…– Body’s tolerance decreases with time and non-use– User begins using again… but at former dose (which was increasingly higher with time…)• User experiences more intense side effect(s)• Overdose may occur

What is dependence?• A person is ‘drug-dependent’ when an

individual continues to use a drug because s/he does not feel ‘right’ without it

• Dependence can be – Physical

• Without the drug, user experiences physical symptoms – Mild discomfort…. Convulsions– ‘withdrawal’

– Psychological• Intense craving for the drug and its effects

– difficult to stop using

–Drug Addiction

What is a therapeutic window?

• Measure of the relative margin of safety of the drug for a particular treament.

• Ratio of LD50 to ED50 – ED50 is the therapeutic dose – the effective dose

for 50% of the population.• If the window is WIDE, the effective dose is below

toxicity – so there is a safe margin• If the window is NARROW, small doses need to be

administered for successful treatment.

How are medicines/ drugs administered?

(1) Oral– Through the mouth• Tablet / capsule• Syrup

– adv: self-administer, easy– disadv: must be able to survive the digestive

system

How are medicines/ drugs administered?

(2) Rectal– suppository– adv: self-administer, efficiency– disadv: yuck factor

How are medicines/ drugs administered?

(3) Inhalation– by breathing (i.e. via an inhaler)– adv: rapid– disadv: drug must be for the lungs – or able to be

absorbed through the lungs

How are medicines/ drugs administered?

(4) Injections– intravenous – into blood stream (quick, but spreads

out dose)– subcutaneous – into body fat (good for fat-soluble

molecules)– intramuscular – into muscle tissue– adv: put directly where it is needed, requires

reduced dose, reduces chance of altercation by body– disadv: requires trained person, people don’t like

shots

How are medicines/ drugs administered?

(4) Injections– intravenous – into blood stream (quick, but spreads

out dose)– subcutaneous – into body fat (good for fat-soluble

molecules)– intramuscular – into muscle tissue– adv: put directly where it is needed, requires

reduced dose, reduces chance of altercation by body– disadv: requires trained person, people don’t like

shots

How are medicines/ drugs administered?

• Patches– Molecules absorbed through the skin barrier –

gradually – Adv: continuous and controlled rate; people like

them; can receive a strong medication without IV– Disadv: patch may come off; takes up to 72 hours

for drug to saturate the body; heat (from fever or use of heating pad) may increase side effects