Lecture 3 - Drugs and the Treatment of Disease Flashcards
(17 cards)
What three things are needed to understand a disease?
- Epidemiology (who/where in the world the disease affects), needs to affect a large amount of people e.g. cancer, cardiovascular disease
- Cause (factors responsible)
- Pathology (important as if you understand where in the body the disease is occurring, can identify systems and cells involved)
What are 3 things needed to be understood about the system/cell involved in the disease?
- Mechanism
- Signalling pathways - alter body physiology leading to disease
- “Natural” defence i.e. the immune system - improved to target disease
What are 3 things needed to be understood about the molecular target (drug target of the disease i.e. a protein)?
- Cellular role
- Critical role in disease
- Drug binding site
What are the 4 steps involved in “man to molecule, molecule to man”?
- Select disease
- Identify target (protein, DNA, etc)
- Synthesise selective ligand (small molecule)
- Assess function
Name 4 examples of drug binding sites (targets)
- Enzymes
- Receptors
- Ion channels
- DNA
How do molecules interact with targets? (types of bonds involved and what the molecules interact with)
Small molecules interact with specific amino acids in the target protein or bases in DNA
Involves reversible bonds:
- Ionic
- Hydrogen bonding
- Van der Waals
- Hydrophobic (interaction)
Why do we want to develop molecules that interact with targets? 5 examples
- If the target is an enzyme, enzyme inhibition
- If the target is a receptor, agonist will stimulate response/antagonist will block response of ligand
- If target is an ion channel, drugs can open/close it
- If target is human i.e. protein, drug will change function
- If target is cancerous, drug will make target lose function
What are sulfonamides? Adverse properties?
- 1st synthetic antibacterial agents (antibiotics)
- Enzyme inhibitors (inhibit enzyme dihydropteroate synthetase)
- Effective against a wide range of infections (still used today)
- Ineffective against Salmonella - organism responsible for typhoid
- Highly toxic in some patients (can kill)
What is the mechanism of action of sulfonamides?
- Inhibits enzyme dihydropteroate synthetase (enzyme responsible for converting para-aminobenzoic acid –> folic acid (vitamin critical for bacteria growth) –> tetrahydrofolic acid (coenzyme F))
- Blocking production of folic acid blocks bacteria replication, shouldn’t adversely affect humans
- Humans get folic acid via diet so enzyme isn’t required, unlike in bacteria
How do sulfonamides work? (Reference size and charge)
- At physiological pH, sulfonamide is charged (negative charge on the N atom becomes delocalised).
- So sulfonamide now has similar distribution of electrons and a similar size to p-aminobenzoate (PAB)
- Sulfonamide is competitive inhibitor of PABA (mimicks PABA to prevent it binding) - has same binding interactions
- H bond from N atom on terminal amine group, van der Waals bonding from ring and ionic bonding from negatively charged O atom
- Binds with high affinity and blocks interaction of the substrate PABA
What are the adverse effects of sulfonamides? What causes this?
- Can be toxic: can cause allergic reactions and haematoxicity (blood cell toxicity) in some patients, can cause life threatening skin reactions
- Toxic hydroxylamine metabolites are responsible (product of sulfonamide reaction with P450 enzyme)
- Amino group of sulfonamide essential for activity, so it cannot be removed to prevent metabolisation of sulfonamide
What is asthma, what are the statistics and how can it be treated?
- Syndrome in which there is a recurrent obstruction of the airways in reponse to stimuli which do not affect non-asthmatic subjects
- In UK, 3.4 million suffer from asthma
- Kills at least 2000 people a year
- “Bronchospasm”: narrowing of tubes carrying air into lungs as a result of muscle constriction
- To treat disease, require an agent that dilates lungs selectively
Man to molecule, molecule to man (asthma example)
- Select disease - asthma
- Identify target - beta-adrenoreceptor
- Synthesise selective ligand - noradrenaline (interacts with receptor)
- Assess function
What are the steps involved in control of breathing by the brain? (2)
- Electrical impulse - the brain sends electrical signals down nerves from brain to lungs to control how rapidly you breathe
- Chemical transmission - at the nerve terminal, there is a release of chemicals. To dilate the airways, the main transmitter released from nerves is noradrenaline. There are 3 main sites on noradrenaline where it can interact with the target: ring structure, hydroxyl group and terminal amine group.
Which receptor reacts with noradrenaline and what is the effect?
- beta(2)-adrenoceptor reacts with noradrenaline, which increases bronchodilation
Why can’t noradrenaline be used to treat asthma? What type of drug is needed instead?
- It is not selective for the beta(2)-adrenoceptor (in the lungs), it also interacts with the beta(1)-adrenoceptor (in the heart) and alpha receptors in blood vessels
- This increases heart rate
- We require a selective beta(2) drug (i.e. lung specific)
How was noradrenaline altered to be beta-selective?
- Isoprenaline: Bulky substituent added to terminal amine group. Highly active for both beta 1 and 2 receptors equally but not active at alpha receptors
- Salbutamol: Me group added to hydroxyl group on ring. Highly active at beta 2 receptor selectively. Known as “Ventolin” commercially.
