P12

Question 1

Azathioprine

Answer 1

Antagonist of purine metabolism

MoA: Incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity

Use: Treatment of autoimmune diseases, and transplant recipients

Question 2

Diclofenac

Answer 2

Non-specific COX inhibitor (NSAID)

MoA: Inhibition of both COX-1 and COX2 enzymes. In addition it has anti-pyretic properties due to effects on the hypothalamus leading to peripheral dilation, increased cutaneous blood flow, and subsequent heat dissipation.

Uses: Pain, dysmenorrhea, and ocular inflammation

Question 3

Celecoxib

Answer 3

COX-2 specific inhibitor, reducing production of prostaglandins.

MoA: As it only targets COX-2 it does not possess anti-platelet effects. Inhibition of prostaglandin synthesis can cause sodium and water retention in the ascending LoH, through increased fluid reabsorption, whilst in the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting antidiuretic hormone.

Use: Treat rheumatoid arthritis, osteoarthritis, and familial adenomatous polyposis (FAP). It is still used but more sparingly due to the possible effects on the cardiovascular system

Question 4

Cyclophosphamide

Answer 4

An alkylating agent (non-cell cycle specific hence inducce cell death for all cells)

Antineoplastic, antimmunosuppressive agent which is activated by the cytochrome P450 isoforms

Question 5

Vitamin D

Answer 5

A coenzyme

Vitamin D, has little biological activity. However, once it is metabolised to 1,25-dihydroxycholecalciferol it is hormonally active. This metabolic change occurs in 2 steps:
♣ In the liver: cholecalciferal is hydroxylated to 25-hydroxycholecalciferol by 25-hydroxylase.
♣ Within the kidney, 25-hydroxycholecalciferol is metabolised to 1,25-dihydroxycholecalciferol, due to the action of 1--hydroxylase

Question 6

Cyclosporine

Answer 6

Immunosupressive agent (cyclophilin binder)

MoA: It binds to cyclophilin, which causes the inhibition of calcineurin, which is responsible for activating the transcription of IL-2.

Use: Prophylaxis of graft rejection in organ and tissue transplantation

Question 7

Aurothiomalate

Answer 7

A gold based anti-inflammatory (cytokine inhibitor)

MoA: Unknown

Use: It’s been superseded by other DMARDs, and biological treatments.

Question 8

Chloroquine (antimalarial)

Answer 8

An anti-inflammatory agent (DNA/RNA synthesis inhibitor).
Chloroquine is more widely known as an anti-malarial drug.

MoA: Inhibition of the parasitic enzyme heme polymerase, causing a build-up of toxic heme within the parasite.

Question 9

Methotrexate

Answer 9

Folate antagonist (antimetabolite)

MoA: They are synthetic versions of purine or pyrimidines.
Prevent purine or pyrimidines becoming incorporated in to DNA during the “S” phase (of the cell cycle), stopping normal development and cell division.

Use: At low dose in the management of severe, active, classical, or definite rheumatoid arthritis.

Question 10

Sulfasalazine

Answer 10

Immunomodulatory agent

MoA: Sulfasalazine is broken down into its active metabolite (5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) within the body. In ulcerative colitis, the major therapeutic action via 5-ASA

Use: Anti-inflammatory agent used to treat ulcerative colitis and rheumatoid arthritis

Note: Sulfasalazine has been replaced with Mesalazine to a certain extent. It has the same active metabolite but no longer contains the sulphur group and so is better tolerated by some patients

Question 11

Calcitonin

Answer 11

GPCR (calcitonin receptor) agonist

MoA: Antagonises action of parathyroid hormone. Binds to calcitonin receptors found primarily in osteoclasts (acts as agonist).

Use: Control of the calcium concentration within the blood. Produced in thyroid gland. Increases bone mass and reduces plasma calcium levels.

Action in kidney: Calcitonin promotes the renal excretion of calcium, phosphate, sodium, magnesium, and potassium ions by decreasing tubular reabsorption, and so increases jejunal secretion of water, sodium, potassium, and chloride ions

Question 12

Salcatonin

Answer 12

Salcatonin is the type of calcitonin hormone found in salmon.

As in humans, salmon calcitonin is a peptide hormone secreted by the parafollicular cells of the thyroid gland in response to hypercalcemia, which lowers blood calcium and phosphate by promoting renal excretion.

Question 13

Prednisolone

Answer 13

Glucocorticoid receptor agonist

Heavily prescribed corticosteroid

MoA:

• Prednisolone crosses the cell membrane and bind to the corticosteroid receptor.
• This leads to changes in DNA transcription reducing the production of inflammatory proteins.

Question 14

Raloxifene

Answer 14

Selective oestrogen receptor modulator (SERM)

MoA: Raloxifene, produces oestrogen-like effects on bone and lipid metabolism, while antagonising the effects of oestrogen on breast and uterine tissue.

Use: Raloxifene can inhibit the proliferation of pre-osteoclastic cells so used to slow bone loss in postmenopausal women.

Question 15

Alendronic acid (aka Alendronate)

Answer 15

Nitrogen-containing, second generation bisphosphonate

MoA: Nitrogen containing bisphosphonates inhibit farnesyl pyrophosphate (FPP) synthase by acting as analogues of isoprenoid diphosphate lipids. Inhibition of this enzyme in osteoclasts prevents the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins, such as Rac and Rho. This causes a reduction in osteoclast activity reducing bone resorption and turnover. Furthermore osteoclast survival is also affected, further increasing the ability of the bone to be rebuilt

Use: Alendronate, strengthens bone and as such is used to treat corticosteroid-induced osteoporosis and Paget’s disease, and to prevent osteoporosis in postmenopausal women

Question 16

Betaxolol

Answer 16

Competitive beta (1) -selective (cardioselective) adrenergic antagonist which has no partial agonist activity.

MoA: Activation of the receptor leads to G(s) activation and cAMP signalling. The resulting effect is a reduction in heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension.

Question 17

What is more commonly used than betaxolol

Answer 17

Bisoprolol

Question 18

Diazepam

Answer 18

Benzodiazepine (GABA receptor agonist)

MoA: Benzodiazepines generates the same active metabolite as chlordiazepoxide and clorazepate and binds nonspecifically to benzodiazepine receptors (BR). These receptors mediate sleep, affects muscle relaxation, anticonvulsant activity, motor coordination, and memory.

Use: Selectively used for anxiety and as a muscle relaxant

Question 19

Propofol

Answer 19

Anaesthetic agent (GABA receptor modulator)

Propofol is an intravenous anaesthetic agent used for induction and maintenance of general anaesthesia.

MoA: Induces increased binding of GABA through the GABA-A receptors. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation).

Question 20

Describe the recovery from propofol-induced anaesthesia compared to: thiopental, methohexital, etomidate

Answer 20

Recovery from propofol-induced anaesthesia is generally rapid and associated with less frequent side effects (e.g. drowsiness, nausea, vomiting) than with thiopental, methohexital, and etomidate

Question 21

Lamotrigine

Answer 21

Anticonvulsant (sodium channel inhibitor)

Possible MoA: Inhibition of voltage sensitive sodium and or calcium channels, which stabilises neuronal membranes, and modulates presynaptic transmitter release of glutamate and aspartate

Use: Lamotrigine is an anticonvulsant drug used to treat epilepsy and bipolar disorder

Question 22

Carbamazepine

Answer 22

Anticonvulsant (sodium channel inhibitor)

MoA: Believed to inhibit sustained repetitive firing by blocking use-dependent sodium channels. Pain relief is believed to be associated with blockade of synaptic transmission in the trigeminal nucleus whilst seizure control with reduction of post-tetanic potentiation of synaptic transmission in the spinal cord.

Use: Control grand mal and psychomotor or focal seizures

Question 23

Phenytoin

Answer 23

Anticonvulsant (sodium channel inhibitor)

Possible MoA: Primary site of action is the motor cortex, where it prevents the spread of seizure activity. This spread of seizure activity is achieved by promoting sodium efflux from neurons, leading to reduced electrical conductance between brain cells and therefore reducing the unwanted brain activity in a seizure

Question 24

Difference between phenytoin and phenobarbital?

Answer 24

Phenytoin is an anticonvulsant that lacks the sedation effects associated with Phenobarbital

Question 25

Sodium valproate

Answer 25

Anti-convulsant (sodium channel inhibitor/GABA receptor agonist)

Possible MoA:
o Increasing gamma-aminobutyric acid (GABA) levels in the brain through inhibition of enzymes that catabolise GABA
o Altering the properties of voltage dependent sodium channels.
o Act as a histone deacetylase inhibitor

Question 26

Donepezil

Answer 26

Reversible acetyl cholinesterase inhibitor

MoA: Reversible inhibition of acetylcholinesterase, leading to an increase in acetylcholine at cholinergic synapses, enhancing cholinergic function

Note: Donepezil is structurally unrelated to other anticholinesterase agents. It is relatively specific for brain acetylcholinesterase.

Question 27

Suxamethonium

Answer 27

Depolarising nicotinic cholinergic receptor antagonist

MoA: Mimic acetylcholine at the neuromuscular junction. Suxamethonium is hydrolysed much slower than acetylcholine, causing prolonged depolarisation and therefore desensitisation, and muscle relaxation.

Use: Suxamethonium is given after a general anaesthetic as muscle relaxation can be preceded by painful muscle fasciculations. Anticholinesterases such as neostigmine given alongside Suxamethonium can potentiate the neuromuscular block

Note: Unlike the non-depolarising neuromuscular blocking drugs, suxamethonium cannot be reversed and recovery is spontaneous

Question 28

Levodopa

Answer 28

Levodopa is a natural form of dihydroxyphenylalanine

MoA: Is an immediate precursor of dopamine. It can be taken orally (alongside a dopamine decarboxylase to reduce metabolism at the gut wall) and can readily cross the blood brain barrier. Within the brain it is taken up by dopaminergic neurons and converted to dopamine

Use: Dopamine replacement therapy in Parkinson’s disease.

Question 29

Bromocriptine

Answer 29

Dopamine agonist

It’s a ergot alkaloid derivative that stimulates dopamine activity through the D2 receptor

MoA: The D2 receptor once activated stimulates the Gi signalling cascade. In lactotrophs this leads to inhibition of adenyl cyclase, and a reduction in cAMP, and blockage of calcium release. Alternatively the stimulation of D2 receptors in the nigrostriatal pathway improves muscle activity and co-ordination.

Use: Parkinsonian Syndrome, dysfunctions associated with hyperprolactinemia, acromegaly, and pulmonary fibrosis

Question 30

Gabapentin

Answer 30

Anticonvulsant (GABA analogue)

MoA: It increases the synaptic concentration of GABA, and therefore can enhance GABA responses at non-synaptic sites in neuronal tissues, and reduce the release of mono-amine neurotransmitters.

Use: Used less for epilepsy and more for neuropathic pain or as an adjunct in chronic pain syndromes

Question 31

Selegiline

Answer 31

Dopamine therapy (monoamine oxidase B inhibitor)

MoA: Ireversibly inhibit monoamine oxidase type B (MAO-B), which is involved in the oxidative deamination of dopamine in the brain. Therefore, by blocking this enzyme, it blocks the microsomal metabolism of dopamine within the nigrostriatal pathways in the CNS, enhancing the dopaminergic activity in the substantial nigra

Use: Treat Parkinson’s Disease

Note: At higher doses, it can also inhibit monoamine oxidase type A (MAO-A), allowing it to be used for the treatment of depression

Question 32

Isoflurane

Answer 32

Anaesthetic agent (neuronal ion channel modulator)

MoA:
o Induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times
o Activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane

Use: General anaesthetic as it induces muscle relaxation, and reduces pain sensitivity

Question 33

Atracurium

Answer 33

Competitive cholinergic receptor antagonist

MoA: Antagonises the neurotransmitter action of ACh by binding competitively with cholinergic receptor sites on the motor end-plate. This leads to muscle relaxation. The duration of neuromuscular block is between 1/3 to ½ of d-tubocurarine, metocurine, and pancuronium at initially equipotent doses. Repeated administration of maintenance doses of Atracurium has no cumulative effect on the duration of neuromuscular block if recovery is allowed to begin prior to repeat dosing

Use: It’s a non-depolarising skeletal muscle relaxant

Note: Atracurium can be reversed by Acetylcholinesterase inhibitors. E.g. neostigmine, edrophonium, pyridostigmine

Question 34

Memantine

Answer 34

NMDA receptor antagonist

Use:

• Treat moderate to severe Alzheimer’s disease.
• It acts on the glutamatergic system by blocking NMDA receptors.

Question 35

Fentanyl

Answer 35

Opioid analgesic (opioid receptor agonist)

MoA:
Eventually leads to hypopolarisation and reduced neuronal excitability.

Use:
Fentanyl is commonly in anaesthesia as an IV analgesic, in epidurals and spinals for regional anaesthesia/analgesia and as transdermal patches for chronic pain