Allopurinol

UNDER REVIEW (April 2017)

Mechanism of Action:

Allopurinol inhibits xanthine oxidase, an enzyme involved in the production of uric acid from xanthine and hypoxanthine (purine degradation products). Uric acid is sparingly soluble and, in high concentration can precipitate into crystals. This can cause the extremely painful joint condition known as gout. Allopurinol is an analog of the natural purines in the body, and is quickly metabolised to oxipurinol which is also a xanthine oxidase inhibitor.

 

Tubocurarine

UNDER REVIEW (September 2016)

Mechanism of Action:

Tubocurarine is a plant alkaloid that, although not used clinically in the modern era is a prototype for other drugs that block the neuromuscular junction. It is a slow onset, long-acting, non-depolarizing blocker. It is a competitive antagonist of acetylcholine (ACh) acting at nicotinic acetylcholine receptors (nAChR). It blocks postsynaptic nAChRs, preventing action potential transmission and thus causing skeletal muscle relaxation. This sort of block can be overcome by increasing the relative concentration of ACh (e.g. by administration of an anti-cholinesterase such as neostigmine). Atracurium is another neuromuscular blocking drug that binds to the same site as ACh preventing the activation of the receptor-channel complex.

Lecture and CAL materials:

Methotrexate

Mechanism of Action:

Methotrexate is classified as an antimetabolite drug. It blocks DNA synthesis in proliferating cells by binding with and blocking the action of dihydrofolate reductase which enables regeneration of folate, a cofactor in the production of substrates for DNA and RNA synthesis. By this mechanism it prevents cell proliferation making it both immunosuppressant and cytotoxic.

Lecture and CAL materials:

Infliximab

UNDER REVIEW (September 2016)

Mechanism of Action:

Infliximab is an injectable antibody that blocks the effects of tumor necrosis factor alpha (TNF alpha). TNF alpha is a pro-inflammatory cytokine, a substance made by cells of the body which has an important role in promoting inflammation.

Lecture and CAL materials:

Azathioprine

Mechanism of Action:

Cytotoxic immunosuppressant- azathioprine is a prodrug. It is metabolized to its active form mercaptopurine, a purine analogue which inhibits DNA synthesis. Clonal proliferation of the immune response is thus inhibited&#059; may also inhibit cytokines and growth factors. Mercaptopurine is released slower from azathioprine and is more effective as an immunosuppressant. (mercaptopurine is more useful as an antineoplastic drug). Drug action is potentiated by allopurinol (gout medication-gout is caused by excessive purine degradation to uric acid) which inhibits xanthine oxidase. This enzyme acts to degrade azathioprine. The dosage of azathioprine should be reduced by 25% with concurrent use of allopurinol. Thiopurine methyltransferase (TMPT) is another enzyme that degrades azathioprine. Individuals homozygous for low TMPT are susceptible to myelosuppression (bone marrow suppression). See comments.

Lecture and CAL materials:

Sulfasalazine

UNDER REVIEW (September 2016)

Mechanism of Action:

An aminosalicylate drug that is a combination of a sulphonamide (an antibiotic) and 5-aminosalicylic acid (5-ASA, an aspirin derivative). Mode of action unknown: sulfasalazine is a prodrug, that is, it is not active in its ingested form but is broken down by bacteria in the colon into its two constituents: 5-aminosalicylic acid (5ASA), and sulfapyridine. There is some controversy as to which of these two products are responsible for the activity of sulfasalasine. It reduces cytokine production and inflammatory activity. The anti-inflammatory action of 5-ASA is at least in part mediated through modulation of the endocannabinoid system via elevation of anandamide levels – anandamide being an endogenous cannabinoid.

Lecture and CAL materials:

Neostigmine

UNDER REVIEW (September 2016)

Mechanism of Action:

Neostigmine is a reversible, medium-acting anticholinesterase drug (therapeutic effect up to 4 hours). Anticholinesterases competitively inhibit the action of acetylcholinesterase (AChE), which destroys the neurotransmitter acetylcholine following its release from cholinergic nerve endings. By interfering with the breakdown of acetylcholine, neostigmine indirectly (via action of ACh) stimulates both nicotinic and muscarinic receptors. Because neostigmine increases the effective concentration of acetylcholine, it causes such body changes as contraction of the pupils, increased activity of intestinal muscles, and increased secretion by the salivary and sweat glands. Neostigmine is a parasympathomimetic, ie it mimics the effects of stimulation of the parasympathetic nervous system.

Lecture and CAL materials:

Atracurium

UNDER REVIEW (September 2016)

Mechanism of Action:

Atracurium is a non-depolarizing competitive antagonist acting at the nicotinic ACh receptor (nAChR) on skeletal muscle to cause muscle relaxation. Atracurium binds to the same receptor site as ACh on the muscle end plate, preventing the activation of the receptor-channel complex. It belongs to the non-depolarising class of neuromuscular-blocking drugs (the other class being depolarizing drugs such as suxamethonium – see separate eDrug entry). ACh is released in response to the arrival of an action potential at the nerve ending. The amount of ACh released by the nerve ending and the amount needed to initiate an action potential at the muscle fibre is redundant by several folds. Hence, blocking just a few receptor sites at the muscle end plate will be compensated by the copious amount of ACh activating the remaining receptors. For atracurium to be effective, it needs to block 70-80% of nACHRs at any one muscle fibre. A small muscle end plate potential may still be recorded at the muscle fibre from the remaining nAChRs but this does not exceed the threshold potential required to initiate an action potential at the muscle fibre (all-or-nothing principle of transmission). The degree of muscle relaxation represents the proportion of muscle fibres failing to respond to a nerve action potential. This sort of block can be overcome by increasing the relative concentration of ACh by administration of an anti-cholinesterase drug such as neostigmine (see separate eDrug entry). High levels of ACh will effectively compete with atracurium to occupy nAChR sites on the muscle end plate. Atracurium is designed to spontaneously degrade at physiological plasma pH. It subsequently has a short duration of action and is independent of renal and hepatic function.

Lecture and CAL materials: