IB Chemistry HL - option D (Medicinal Chemistry) - flashcards

The only quasi-enjoyable part of chemistry.

What is the difference between medicines and drugs?

A drug is a chemical that affects how the body works (either positively or negatively). A medicine is a substance that improves health. Medicines contain beneficial drugs.

Define therapeutic effect.

The therapeutic effect is the beneficial effect of a medical treatment.

What are the ways in which drugs can be administered?

* oral - taken by mouth
* inhalation - vapour breathed in, smoking
* skin patches - absorbed directly from the skin into blood
* suppositories - inserted into the rectum
* eye or ear drop - liquids delivered directly to the opening
* parenteral (injections):
* intramuscular - into muscle, like many vaccines
* intravenous - into blood (the fastest way of injection), e.g. local anaesthetics
* subcutaneous - under the skin, like dental injections

What is the bioavailability of the drug?

It is the fraction of the administered dosage that reaches the bloodstream.

What is the first-pass effect?

It is the term describing the relatively low bioavailability of a drug taken orally (as little as 20-40%). This is the result of enzymes digesting the drug by the enzymes in digestive system. Additionally, a significant percentage of the absorbed portion is further metabolised by the liver.

What are side effects?

These are **unintended** physiological effects that the drug has on the body. They vary greatly between drugs and with the same drug in different people. They can be both **benign** (like nausea, constipation or even damage to some organs) and **beneficial** (like aspirine protecting against heart disease).

What is the difference between tolerance and addiction?

==Tolerance== occurs when repeated doses of a drug result in smaller ohysiological effect.

==Addiction== (dependence) occurs when a patient becomes dependent on the drug in order to feel normal, and suffers from ==withdrawal symptoms== when the drug is not taken.

What is a dosing regime?

A specific quantity of drug to be taken at one time, and the frequency of administration.

What is the therapeutic window?

It is the range of a drug’s concentration in the blood between minimum amount that produces that produces the therapeutic effects and a medically unacceptable adverse effect. Therapeutic window can be quantified as the ==therapeutic index== (TI).

What is therapeutic index and how to calculate it?

Therapeutic index (TI) is the ratio of the dose that produces toxicity to the dose that produces a clinically effective response in a population. It is therefore a measure of drug’s safety.

* ==Minimum effective dose (ED50)== - the dose that produces the therapeutic effect in 50% of the population.
* ==Lethal dose (LD50)== - the dose that is lethal to 50% of the population.
* ==Toxic dose (TD50)== - the dose that is toxic to 50% of the population.

In animals, TI = LD50/ED50

In humans, TI = TD50/ED50

What is meant by rational drug design?

It is the approach focused on identifying a suitable molecular target in the body and designing a drug to interact with it based on the knowledge of drug-receptor interactions. Drug-receptor interactions are based on the chemical structure of the drug and the site of its activity.

What are the stages of discovery and development of a new medicine?

1. ==Discovery research== (identification of lead compounds, synthesis of ^^analogues^^ via ^^combinatorial chemistry^^, and biological testing)
2. ==Development research:==
* phase I (50-100 healthy volunteers)
* phase II (200-400 patients)
* phase III (3000+ patients, half are given a drug and the other half are given a placebo, neither the doctor not the patient knows which preparation is being given)
3. ==Regulatory view==
4. ==Post-marketing monitoring== (collection of adverse drug reaction data)

What are analgesics?

Drugs that function as painkillers.

How is pain detected by the body?

Oain is detected by the brain thanks to nerve impulses sent from ==pain receptors== located around the body. The receptors themselves are stimulated by chemicals called ==prostaglandins== released from damaged cells. Once released, prostaglandins also mediate the ==inflammatory response== by causing dilation of blood vessels near the site of injury, which leads to swelling and increased pain. They may also cause increased body temperature - ==fever==.

What are mild analgesics and how do they function?

Mild analgesics (**aspirin**, **non-steroidal ani-inflammatory drugs (NSAIDs)** such as **ibuprofen**) are painkillers that block the sensation of pain at the source. They act by preventing stimulation of the nerve endings at the site of pain and inhibit the release of prostaglandins from the site of injury. Because they don’t interfere with the functioning of the brain, they are also known as ==non-narcotics==.

How was aspirin discovered?

It was known from the ancient times that willow bark releases pain and fever. It was discovered in 1800s that the active ingredient in willow bark is **salicin**, which is converted to **salicylic acid** by the body. It was effective in treating pain, but its unpleasant taste caused vomiting and diarrhoea.

In 1890 an **ester derivative of salicylic acid** was discovered. It was less palatable and irritable to the body and still an effective painkiller. The newly discovered drug - **acetylsalicylic acid** - was named **aspirin**.

How is aspirin produced?

* Salicylic acid is mixed with excess ethanoic anhydride and several drops of a catalyst (concentrated phosphoric acid or concentrated sulphuric acid)
* The mixture is warmed gently
* The obtained product is cooled to cause crystals to form and then suction filtered and washed with chilled water. Aspirin has a very low solubility in water at low temoerature, so this process removes the soluble acids while not leading to the loss of the aspirin product.
* The next step is purification, which involves a technique known as recristallization - dissolving the impure crystals of aspirin in a minimum volume of hot ethanol (which is a better solvent for the impurities than for the aspirin product). A saturated solution of aspirin is formed and as it is cooled slowly, the solubility of the aspirin decreases, causing it to crystallize out of the solution first. Then it can be separated by filtration, as the impurities and unreacted salicylic acid remain in solution.
* The purity of the product can be determined by melting point determination (138-140°C for pure aspirin, 159°C of salicylic acid) - the mixture would have a lower and less well-defined melting point. The identity of the product can also be confirmed by IR spectroscopy (aspirin has esther group which isn’t present in salicylic acid but does not have -OH group present in salicylic acid)

What does anticoagulant mean?

Anticoagulant is a drug that reduces the ability of blood to clot. Aspirin is an anticoagulant (which is a benefit for patients at risk of strokes and heart attacks, but quite dengerous effect for people whose blood does not clot easily.

What are some negative side-effects of aspirin intake?

* irritation or even ulceration of the stomach and duodenum (can lead to bleeding)
* allergies (especially in people prone to asthma)
* Reye’s syndrome (rare and potentially fatal liver and brain disorder), that’s why aspirin shouldn’t be taken by children under 12

What is meant by synergy?

The physiological effects of aspirin becoming more acute when it is taken with ethanol in alcoholic drinks. The synergic effects of ethanol and aspirin can cause bleeding of stomach lining and increased risk of ulcers.

How and why is aspirin modified for absorbtion and distribution?

It is chemically modified by reacting it with ==alkali== (NaOH, NaHCO3) so that it forms ==ionic salt==. In this form it is polar and therefore more soluble in water, so it dissolves better in the plasma of blood, increasing its bioavailability. These compounds are kniwn as ==soluble aspirin== or ==dispersible aspirin==.

What is penincillin?

The chemical produced by ==microorganisms== (fungus *Penicillium notatum*) that have the abilty to act against other microorganisms; an ==antibiotic==.

Why did we stop using sulfonamide drugs (e.g. Protonsil) as antimicrobial?

It was found to cause a large number of deaths of mothers in childbirth.

Describe the structure of penicillin G. How it is related to its function?

Penincillin G is a dipeptide formed from two amino acids: cysteine and valine. It contains a nucleus of a five-membered ring containing a sulfur atom (==thiazolidine==) attached to four-membered ring containing a cyclic amide group (==beta-lactam==).

Beta-lactam (consisting of one nitrogen and three carbon atoms) is the part of the molecule responsible for its antibacterial properities. This ring breakes relatively easily as its bond angles are 90° despite sp2 and 3p3 hybridization.

Beta-lactam ring acts by disrupting the formation of cell walls of bacteria by inhibiting a key bacterial enzyme, ==transpeptidase==. As the drug approaches the enzyme, the high reactivity of the amide group in the ring causes it to bind irreversibly near the active site of the enzyme as the ring breaks. Transpeptidase becomes inactivated and the polypeptide cross-links between mucopeltide chains cannot form. Without these strenghtening links, the cell wall is unabke to support the bacteriumx

What is a disadvantage of penincillin G?

It is broken down by the stomach acid, so it has to be injected directly into the blood or undergo a modification of side chains (which enable it to retain its activity when digested). Also, a number of people suffers from allergic response to penicillin, which limits its use.

What is antibiotic resistance?

Penincillin loses its activity when the beta-lactam ring is broken. This happens if bacteria show antibacterial resistance, meaning that they are able to produce an enzyme (==penincillinase== or ==beta-lactamase==) which opens the ring and renders it inactive.

Anibiotic resistance genes spread in bacteral population and the more antibiotics are present in the environment, the higher the chance of development of resistance.

That is why new forms of penincillin have to be synthesized, such as ==methicillin== and (when methicillin-resistant bacteria developed) - ==oxacillin==. These derivatives still have the beta-lactam ring, but modified side chains prevent penincillinase binding.

What are opiates?

Opiates or opioids are strong analgesics derived from opium found in poppy seeds.

What is the difference between mild and strong analgesics?

Mild analgesics stop the pain at its source by stopping the nerve impulses from pain receptors from being sent. Strong analgesisc act directly on the brain by temporarily binding to the ==opioid receptors== in the brain. This blocks the transmission of impulses between brain cells that would signal pain. Therefore, strong analgesics interfere with the perception of pain without depressing the central nervous system. They can also cause changes in mood and behaviour, so they are known as narcotics.

What is blood-brain barrier?

It is a membrane-bound structure that protects the brain by restricting the chemicals that can enter from blood. It is made largely of lipids, therefore it is a hydrophobic, non-polar environment that is not easily crossed by polar molecules.

It is therefore easier for the drug to enter the brain if it is non-polar, but in order to travel in blood it is better for it to be polar and water-soluble.

Outline the relative structure and function of morphine, codeine and diamorphine (heroin).

Morphine is the principle drug derived from opium. It has ==two -OH groups==, making it ==polar== (so it is well-soluble in blood, but does not cross the blood-brain barrier easily).

Codeine is a ==semi-synthetic== drug - it is found in opium at low levels and is usually chemically prepared from morphin by ==methylation== (one -OH group is substituted with ==methyl ether==). This makes codeine less polar than morphine, so it crosses the blood-brain barrier more easily, but does not bind that well to the opioid receptor, which makes it a weaker analgesic.

Diamorphine (heroin) is produced from morphine by en ==esterification== reaction in which both -OH groups are converted into ==ethanoate (ester) groups== by reacting with ==ethanoic acid== CH3COOH or ==ethanoic anhydride== (CH3CO)2O. This significantly reduces the polarity, makinf it the fastest acting and mist active opioid (however, with a lot of side effects).

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How does diamorphine act on the brain?

After crossing the blood-brain barrier, diamorphin must undergo metabolic change before it can act at the opioid receptors. The ester links are broken by enzymes called ==esterases==. That is why diamorphine is described as ==pro-drug==, meaning that its metabolic products (mostly morphine) actually bring about its effect.

What is 6-acetylmorphine?

It is a derivative of morphine that contains the ester link at only one of the positions. It is even more potent than heroin as it does not need to undergo hydrolysis before interacting with the brain cells. It is produced as a metabolite from heroin in the body, but due to its high activity it is an extremely dangerous drug when taken in pure form.

Describe analgesic ladder.

1. Use mild analgesic (like aspirin)
2. Use a weak opioid (like codeine)
3. Use a strong opioid (like morphine)

What are some side effects of strong analgesics?

* constipation
* supression of the cough reflex
* constriction of the pupil in the eye
* narcotic effects:
* in the short term: well-being, contentment, dulling of pain, lessening of fear and tension, euphoria
* addiction
* withdrawal effects: cold sweat, anxiety

What is methadone?

It is an alternate analgesic to heroin used to help the addicts break their dependence. It is taken orally and has a longer duration of action, reducing drug craving and preventing the symptoms of withdrawal.