IB CHEMISTRY: OPTION D (MEDICINAL CHEMISTRY)

How to calculate therapeutic index

How to calculate therapeutic index

LD50/ED50

Therapeutic window

The range of doses between the minimum dosage and maximum dosage that produces a therapeutic effect

What can affect a patient's response to a drug?

Gender, age, weight

Tolerance

When the body becomes less responsive to the effects of a drug, so larger doses are needed

Effect of high tolerance

Toxic effects are more likely

Why might tolerance occur?

1. Repeated use of a drug stimulates increased metabolism of that drugs, so the body gets better at breaking it down
2. The body may adapt to offset the effects of the drug by desensitising target receptors

What prescription drugs can people become addicted to?

Valium

Physical dependence

When the body cannot function without the drugs, the user must keep taking it to avoid withdrawal effects

Ways to administer a drug

1. Oral
2. Rectal
3. Pulmonary
4. Injection
5. Topical

Pros to rectal

Good when the patient cannot take oral, e.g. vomiting or unconscious

Suppositories

Solid, cone-shaped, medicated substances inserted into the rectum, vagina, or urethra

Pulmonary

Administered to the lungs in a form of gas

Topical

On the skin, used normally for local, but patches can be used also

Subcutaneous

Administers directly under the skin, absorption is slow giving a sustained effect

What can affect the bioavailability?

The formulation of the tablets, the solubility, how easily absorbed it is, susceptibility to being broken down by enzymes

What do prostaglandins do?

Cause pain, inflammation and fever

What happens when a tissue is injured?

Prostaglandins are synthesised and bind to receptors

What do these prostaglandins receptors do?

Stimulate sensory nerve fibres at the site of injury to send signals to the brain, which interprets it as pain

What makes a good synthesis?

It has very few steps, good yield and little waste, also should be cheap and readily available

Therapeutic effect

The desirable and beneficial effect - alleviates symptoms

Side effect

Unintended secondary effect of the drug on the body

Toxic effect

A side effect that is harmful to the body

What can cause a toxic effect?

Taking the drug in too high a quantity

Therapeutic index

The ratio of the toxic dose to the therapeutic dose

What does a high therapeutic index mean?

That there is a large difference between the toxic dose and the therapeutic dose

Psychological dependence

Needing a drug to feel good

How is oral taken in?

Absorbed by the stomach or small intestine into the blood

Pros to oral

Easy to administer, convenient for patient

Cons to oral

Slow effect

How is rectal taken in?

Into the bus, vagina or urethra

Pros to pulmonary

Very fast onset

Ways of injection

Intravenous, subcutaneous and intramuscular

Intravenous

Straight into the blood stream

Intramuscular

Into skeletal muscle

Bioavailability

The proportion of the administered dose that reaches the blood circulation

Prostaglandins on blood vessels

Causes dilation of blood vessels, causing inflammation and can send a signal to the hypothalamus to increase the body temperature

What is a drug?

A substance that when introduced to an organism, brings about a change in biological function

4 ways drugs can be made

1. Completely from extracting plants
2. Pure compounds isolated from natural resources
3. Semi-synthetic compounds
4. Synthetic compounds

What is a medicine?

A substance that treat, prevents or alleviates the symptoms of disease

What do non active substances in a drug do?

Improve taste, consistency or administration

How does a drug produce an effect on the body?

It interacts with a particular target molecule, such as a specific enzyme or receptor

What is the ultimate goal of drug researching?

To find a drug better than the current ones

First stage in drug development process

To identify lead compounds

How are lead compounds found?

Through biological testing of compounds obtained by:
1. Isolation from natural sources
2. Chemical synthesis
3. Searching through existing banks of compounds

What do lead compounds do?

They can be developed further

Stage one of trials

Animal testing

Stage two of trials

Human testing - for side effects

Stage three of trials

Human testing - for therapeutic effect

Stage four of trials

Human testing on a large group (placebo done here)

Stage five of trials

Human testing to the public

Placebo effect

When someone feels better but without taking the real drug

LD50

The dose that causes a lethal effect in 50% of the population - using in animal testing

TD50

The dose that causes a toxic effect in 50% of the population - using in human testing

Why does the solubility of the drug affect its bioavailability so much?

Only soluble molecules can pass through the intestinal wall, and only soluble can be transported n the blood

Why are fat soluble drugs good?

Because they will be able to pass through the cell membranes quicker

What do receptor agonists do?

Bind to a cell membrane protein receptor, mimicking the effect of the normal molecule that binds, triggering the reaction

What do receptor antagonists do?

Bind to the receptor so the normal molecule cannot, preventing a response from the cell

What do analgesics do?

Reduce pain

Mild analgesics

Prevent the production of prostaglandins

How is the production of prostaglandins prevented?

The enzyme cyclooxygenase is inhibited

What does cyclooxygenase do?

Helps synthesise prostaglandins

How do mild analgesics work?

Inhibit the production of chemical messengers that cause pain swelling and fever - at the site of the pain

Why is salicylic acid not good?

It causes severe irritation of the stomach lining and vomiting and gastric bleeding

Salicylic acid

What is the difference between salicylic acid and acetyl salicylic

The OH group is replace with an ester

Why is acetyl salicylic acid better than salicylic acid?

Because it doesn't cause stomach bleeding

What is acetylsalicylic acid also know as?

Aspirin

What is aspirin used as?

An analgesic and anti inflammatory agent

How has aspirin be used to prevent heart attacks?

If taken in low doses daily, it has an anti blood clotting effect, acting as an anticoagulant

Prophylactic

Something that prevents a disease

Synergism

Combination of two drugs causes an effect that is greater than the sum of the individual effects of each drug alone

Example of synergism

Ethanol and aspirin

How can you make aspirin?

Warming excess ethanoic anhydride with 2-hydroxybenzoic acid

Reactants in aspirin synthesis

2-hydroxybenzoic acid and excess ethanoic anhydride

What type of reaction is the synthesis of aspirin?

Addition elimination

What happens when you added water to the reaction mixture?

A white precipitate forms

What can you do with this white precipitate?

Filter it out, wash with pure water and leave to dry

Percentage yield

Actual yield/theoretical yield x 100

Anhydride

How can we purify aspirin?

Recrystallisation

Main impurities in aspirin

Unreacted salicylic acid

Recrystallisation

1. Dissolve the aspirin in hot solvent to form an almost saturated solution
2. Filtered while hot to remove any insoluble impurities
3. The solution cools and the aspirin forms solid crystals
4. Filter out the crystals

Determination of purity of an aspirin sample

Chromatography or melting point

How can we tell if a particular compound has been made?

IR

How can you increase the solubility of a drug?

Make the ionic salt of the drug

Making the ionic salt of aspirin

Reacting the carboxyl group with a strong alkali to for a COO-

Most common salt of acidic drugs

Sodium salts

How to convert aspirin to aspirin sodium?

React it with NaOH

How can you convert an anime to its salt?

Reacting the amine with a strong acid

Most common salt of basic drugs

Chloride salt

Beta lactam ring

A four carbon rim that helps penicillin to work

What happens to penicillin if the ring is broken?

The penicillin is no longer active

Bacteria cell wall formation?

Contains a polymer made up of sugar chains cross linked with peptides

How does penicillin work?

Irreversibly inhibiting transpeptidase

What does transpeptidase do?

Cause the cross links in the cell wall

How does the beta lactam ring react with the transpeptidase?

The OH on the side chain of transpeptidase reacts with the ring, breaking it open and reacting with the penicillin instead of its normal substrate

What was the first penicillin to be found?

Penicillin G

Cons to penicillin G

Easily broken down by stomach acid, must be given by injections

How was penicillin modified?

The side chains were modified so it can resist stomach acid

How are some bacteria now resistant to penicillin?

They produce an enzyme called penicillinase