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Steps 1. Synthesis of the transmitter in the presynaptic terminal. 2. Storage in vesicles. 3. Release by calcium-dependent exocytosis after an action potential. 4. Binding to postsynaptic (and presynaptic) receptors: ionotropic (fast, ligand-gated channels) or metabotropic (G-protein coupled, slower). 5. Termination: reuptake by transporters, enzymatic breakdown, or diffusion. Drug actions: precursor supply, synthesis inhibitors, vesicle depleters (reserpine), release enhancers or blockers (botulinum toxin), receptor agonists and antagonists, reuptake inhibitors, and enzyme inhibitors (MAO, cholinesterase). Exam trap: an agonist and an antagonist at the same receptor give opposite effects, and an antagonist has no effect in the absence of the natural agonist.

Glycine: main inhibitory transmitter in the spinal cord and brainstem. Its receptor is a chloride channel blocked by strychnine (convulsions). GABA: main inhibitory transmitter of the brain. - GABA-A receptor: chloride channel. Benzodiazepines increase the frequency of channel opening, barbiturates increase the duration, and both need GABA present. Alcohol, propofol and anaesthetics also potentiate it. - GABA-B receptor: G-protein coupled, target of baclofen. Glutamate: main excitatory transmitter. Receptors: AMPA and kainate (fast sodium entry), NMDA (needs glycine, is blocked by magnesium, admits calcium; blocked by ketamine, memantine and phencyclidine) and metabotropic receptors. Excess glutamate causes excitotoxicity in stroke and neurodegeneration. Clinical tip: benzodiazepine overdose is reversed by flumazenil, a competitive antagonist at the benzodiazepine site.

Histamine: made from histidine; stored in mast cells and basophils and released in allergy. H1 receptors (bronchoconstriction, vasodilation, itch): H1 antagonists treat allergy, and first-generation ones sedate. H2 receptors (gastric acid): blocked by ranitidine-type drugs. Also H3 (presynaptic) and H4. Catecholamines: tyrosine -> DOPA (tyrosine hydroxylase, rate-limiting) -> dopamine -> noradrenaline -> adrenaline. Removed by reuptake (NET, DAT) and by MAO and COMT. Adrenergic receptors: alpha1, alpha2, beta1, beta2, beta3. Dopamine: pathways are nigrostriatal (movement; lost in Parkinson disease), mesolimbic and mesocortical (reward, psychosis), and tuberoinfundibular (inhibits prolactin). D2 blockers (antipsychotics) can cause parkinsonism and raise prolactin. Serotonin (5-HT): made from tryptophan; many receptor families (5-HT1 to 5-HT7); functions in mood, sleep, gut motility, vomiting (5-HT3, blocked by ondansetron) and migraine (5-HT1B/1D, agonised by triptans). SSRIs block reuptake (SERT).

Synthesis by choline acetyltransferase; choline uptake is blocked by hemicholinium. Storage in vesicles (vesamicol blocks). Release is blocked by botulinum toxin. Removal by acetylcholinesterase (choline is recycled). Receptors - Muscarinic M1-M5, G-protein coupled. M1 (CNS, ganglia, gastric acid), M2 (heart, slows rate), M3 (smooth muscle, glands), M4 and M5 (CNS). - Nicotinic: ligand-gated sodium channels at ganglia (Nn) and the neuromuscular junction (Nm). Exam trap: muscarinic effects are the actions of the parasympathetic system (slow heart, salivation, miosis, bronchoconstriction, increased gut motility), and nicotinic effects include muscle contraction and ganglionic transmission.

1. List the five steps of chemical neurotransmission. 2. How do benzodiazepines and barbiturates differ in their action at the GABA-A receptor? 3. Which glutamate receptor is blocked by magnesium and by ketamine? 4. Which enzyme is rate-limiting in catecholamine synthesis? 5. Name the dopaminergic pathway lost in Parkinson disease. 6. Which muscarinic receptor slows the heart?

1. Synthesis, storage, release, receptor binding, termination (reuptake or degradation). 2. Benzodiazepines increase the frequency of chloride channel opening, barbiturates increase the duration, and at high dose barbiturates open the channel directly. 3. The NMDA receptor. 4. Tyrosine hydroxylase. 5. The nigrostriatal pathway. 6. M2.

Direct agonists: choline esters (acetylcholine, methacholine, carbachol, bethanechol) and alkaloids (pilocarpine, muscarine). Bethanechol is resistant to cholinesterase and stimulates bladder and gut in urinary retention and ileus. Pilocarpine treats glaucoma and dry mouth. Indirect agonists: anticholinesterases. - Reversible: physostigmine, neostigmine, pyridostigmine, edrophonium; donepezil and rivastigmine (Alzheimer disease). Neostigmine and pyridostigmine are used in myasthenia gravis and to reverse neuromuscular block. - Irreversible organophosphates (sarin, parathion): poisoning gives the SLUDGE picture (salivation, lacrimation, urination, defecation, GI upset, emesis), miosis, bradycardia, bronchospasm and paralysis. Treatment: atropine plus pralidoxime, which reactivates the enzyme if given early.

Atropine and hyoscine (scopolamine) are natural alkaloids. Effects by organ: eye (mydriasis, cycloplegia), heart (tachycardia; low doses may cause paradoxical bradycardia by presynaptic block), bronchi (dilation and less secretion), gut (less motility), bladder (retention), glands (dry mouth, dry skin), CNS (hyoscine causes sedation and is used against motion sickness). Uses: bradycardia, premedication to reduce secretions, organophosphate poisoning, mydriasis for eye examination (tropicamide), asthma and COPD (ipratropium, tiotropium), overactive bladder (oxybutynin), Parkinson disease (benztropine). Adverse effects: dry mouth, blurred vision, urinary retention, constipation, and in overdose hyperthermia and delirium (hot as a hare, dry as a bone, blind as a bat, mad as a hatter). Contraindications: closed-angle glaucoma and prostatic hypertrophy.

Non-depolarising blockers (competitive antagonists at the nicotinic receptor): tubocurarine, atracurium, cisatracurium (isoquinolines) and rocuronium, vecuronium (steroidal). Reversed by neostigmine with an antimuscarinic, or by sugammadex for rocuronium and vecuronium. Atracurium and cisatracurium undergo Hofmann elimination, useful in renal and hepatic failure. Depolarising blocker: suxamethonium (succinylcholine). Persistent depolarisation gives fasciculations then paralysis (phase I, not reversed by neostigmine). Rapid onset and short action, hydrolysed by plasma cholinesterase. Risks: hyperkalaemia, malignant hyperthermia, and prolonged block in pseudocholinesterase deficiency. Botulinum toxin: cleaves SNARE proteins and blocks acetylcholine release, causing flaccid paralysis lasting about three months. Uses: dystonia, spasticity, strabismus, migraine, hyperhidrosis and cosmetic.

Receptor effects - Alpha1: vasoconstriction, mydriasis. - Alpha2: reduces noradrenaline release (presynaptic), lowers central sympathetic outflow. - Beta1: heart rate and force, renin release. - Beta2: bronchodilation, vasodilation in muscle, uterine relaxation. Drugs: adrenaline (anaphylaxis, cardiac arrest), noradrenaline (vasopressor in shock), dopamine (dose-dependent: renal, beta1, alpha), dobutamine (beta1, acute heart failure), phenylephrine (alpha1, nasal decongestant), salbutamol and salmeterol (beta2, asthma), midodrine (orthostatic hypotension), ritodrine (tocolytic). Indirect agents: amphetamine and ephedrine release stored noradrenaline, cocaine blocks its reuptake.

Alpha-blockers: prazosin, doxazosin and tamsulosin (selective alpha1) reduce blood pressure and relax the prostate, so they are used for hypertension and benign prostatic hyperplasia. Adverse: first-dose hypotension, and floppy iris syndrome with tamsulosin. Phentolamine and phenoxybenzamine (non-selective) are used in phaeochromocytoma. Beta-blockers: propranolol (non-selective), atenolol, metoprolol, bisoprolol (beta1-selective), carvedilol and labetalol (also alpha-blocking), nebivolol. Uses: hypertension, angina, arrhythmias, heart failure, post-infarction, migraine prophylaxis, thyrotoxic symptoms, tremor, glaucoma (timolol). Adverse: bradycardia, heart block, fatigue, bronchospasm (avoid non-selective in asthma), cold extremities, masked hypoglycaemia in diabetics. Do not stop abruptly (rebound).

1. Give two uses of bethanechol or pilocarpine. 2. Describe the treatment of organophosphate poisoning. 3. List the effects of atropine. 4. How is a non-depolarising block reversed, and why is this not effective in phase I depolarising block? 5. Why is botulinum toxin effective in dystonia? 6. When must non-selective beta-blockers be avoided?

1. Bethanechol: urinary retention, ileus. Pilocarpine: glaucoma, dry mouth. 2. Atropine to block muscarinic effects plus pralidoxime to reactivate cholinesterase, with supportive care and airway management. 3. Mydriasis, cycloplegia, tachycardia, bronchodilation, reduced secretions, slower gut, urinary retention, CNS effects at high dose. 4. With an anticholinesterase such as neostigmine (or sugammadex). Depolarising block is already caused by excess acetylcholine-like action, so more acetylcholine worsens it. 5. It blocks acetylcholine release and so reduces muscle overactivity for about three months. 6. In asthma and COPD (bronchospasm), and in heart block.

Definitions: chemotherapy is treatment of infection or cancer with selective toxic drugs. Bactericidal drugs kill (beta-lactams, aminoglycosides, quinolones) and bacteriostatic drugs inhibit growth (tetracyclines, macrolides, sulfonamides). Gram-positive bacteria have a thick peptidoglycan wall, gram-negative have a thin wall plus an outer membrane that limits drug entry. Pharmacodynamics - Time-dependent killing (beta-lactams): efficacy depends on how long the concentration stays above the MIC. - Concentration-dependent killing (aminoglycosides, quinolones): efficacy depends on peak concentration relative to MIC. Resistance mechanisms: enzymatic inactivation (beta-lactamases), altered target (PBP2a in MRSA), reduced permeability (porin loss), efflux pumps, and alternative pathways. Antimicrobial resistance is a global health threat driven by misuse. Not covered: general pharmacokinetics (absorption, distribution, metabolism, excretion) is not in the slides.

Mechanism: beta-lactams mimic D-Ala-D-Ala and acylate penicillin-binding proteins, so the wall is weak and the cell lyses. They act only on growing bacteria. Penicillins: penicillin G and V (gram-positive, streptococci, syphilis), anti-staphylococcal penicillins (flucloxacillin, resistant to staphylococcal beta-lactamase), aminopenicillins (ampicillin, amoxicillin), and antipseudomonal penicillins (piperacillin). Combination with beta-lactamase inhibitors (clavulanate, tazobactam) extends the spectrum. Cephalosporins by generation: first (cefazolin, gram-positive), second (cefuroxime), third (ceftriaxone, cefotaxime; meningitis and gonorrhoea; ceftazidime for Pseudomonas), fourth (cefepime), fifth (ceftaroline, active against MRSA). Adverse effects: hypersensitivity (rash to anaphylaxis, some cross-reactivity), diarrhoea, and seizures at high dose. Others: carbapenems (meropenem), monobactams (aztreonam), vancomycin (binds D-Ala-D-Ala, for MRSA), and newer combinations for multidrug-resistant gram-negatives (ceftazidime-avibactam, ceftolozane-tazobactam, cefiderocol).

Aminoglycosides (gentamicin, amikacin, streptomycin): bind the 30S subunit and cause misreading. Bactericidal, concentration dependent, given once daily. Not absorbed orally. Toxicity: nephrotoxicity (proximal tubule), ototoxicity, neuromuscular block. Monitor levels. Tetracyclines (doxycycline, tigecycline): 30S subunit, bacteriostatic; chelate calcium. Avoid in pregnancy and children under 8 (teeth and bone). Uses: rickettsiae, chlamydia, acne, Lyme disease. Macrolides (azithromycin, clarithromycin): 50S subunit; QT prolongation and CYP3A4 inhibition (erythromycin, clarithromycin). Fluoroquinolones (ciprofloxacin, levofloxacin): inhibit DNA gyrase and topoisomerase IV. Bactericidal. Adverse: tendinopathy, QT prolongation, CNS effects, cartilage damage in children. Sulfonamides and trimethoprim: sequentially block folate synthesis (dihydropteroate synthase and dihydrofolate reductase). Combined as co-trimoxazole. Adverse: rash, crystalluria, haemolysis in G6PD deficiency, folate deficiency.

Standard regimen: an initial intensive phase of about 2 months with isoniazid, rifampicin, pyrazinamide and ethambutol, then a continuation phase of about 4 months with isoniazid and rifampicin. - Isoniazid: inhibits mycolic acid synthesis. Adverse: hepatitis, peripheral neuropathy (give pyridoxine). - Rifampicin: inhibits bacterial RNA polymerase. Strong CYP450 inducer, so it reduces levels of many drugs including oral contraceptives. Orange discolouration of body fluids, hepatitis. - Pyrazinamide: hepatotoxicity, hyperuricaemia. - Ethambutol: optic neuritis (colour vision). Multidrug-resistant tuberculosis (resistant to at least isoniazid and rifampicin) needs second-line drugs such as bedaquiline, linezolid and fluoroquinolones.

Antifungals - Amphotericin B: binds ergosterol and forms pores. Broad spectrum for severe systemic mycoses. Toxicity: infusion reactions and nephrotoxicity (liposomal forms are safer). - Azoles (fluconazole, itraconazole, voriconazole): inhibit ergosterol synthesis (CYP51). Many drug interactions through CYP inhibition. - Echinocandins (caspofungin): inhibit beta-glucan synthesis in the wall. - Terbinafine and nystatin for superficial infection. Anthelmintics: albendazole and mebendazole (microtubules, nematodes), ivermectin (glutamate-gated chloride channels, strongyloides, onchocerciasis), praziquantel (calcium influx, schistosomes and tapeworms). Antiprotozoals: metronidazole and tinidazole (anaerobes, amoebiasis, giardia, trichomonas; disulfiram-like reaction with alcohol). Malaria: artemisinin combination therapy for uncomplicated falciparum malaria, artesunate for severe disease, primaquine for radical cure of vivax and ovale (check G6PD), chloroquine for sensitive species, prophylaxis with atovaquone-proguanil or doxycycline.

1. Compare time-dependent and concentration-dependent antibiotic killing with an example of each. 2. What is the target of beta-lactams? 3. Name the toxicities of aminoglycosides. 4. Why must tuberculosis be treated with several drugs? 5. Which adverse effect must be monitored with ethambutol? With isoniazid? 6. Why does rifampicin cause drug interactions?

1. Time-dependent: beta-lactams (time above MIC). Concentration-dependent: aminoglycosides or quinolones (peak/MIC). 2. Penicillin-binding proteins (transpeptidases) needed for peptidoglycan cross-linking. 3. Nephrotoxicity, ototoxicity and neuromuscular blockade. 4. To prevent selection of resistant mutants and to kill bacilli in different metabolic states. 5. Ethambutol: optic neuritis. Isoniazid: hepatitis and peripheral neuropathy. 6. It strongly induces CYP450 enzymes, increasing metabolism of other drugs.

Replication steps (all targets): attachment and entry, uncoating, nucleic acid synthesis, protein synthesis and processing, assembly and release. Aciclovir: a guanosine analogue. Viral thymidine kinase phosphorylates it first, so it is selectively activated in infected cells, then it terminates the DNA chain by viral polymerase. Used for herpes simplex and varicella zoster (valaciclovir is an oral prodrug with better bioavailability). Adverse: crystal nephropathy (hydrate the patient) and neurotoxicity. Ganciclovir (valganciclovir): for cytomegalovirus; bone marrow suppression. Foscarnet: pyrophosphate analogue, does not need activation, nephrotoxic. Brivudine: used for zoster; must not be given with fluoropyrimidines such as 5-fluorouracil (fatal toxicity).

Hepatitis C: an RNA virus with six genotypes. Direct-acting antivirals (DAAs) target viral proteins: NS3/4A protease inhibitors (glecaprevir, -previr), NS5A inhibitors (velpatasvir, ledipasvir, -asvir) and the NS5B polymerase inhibitor sofosbuvir. Combinations for 8-12 weeks give a sustained virological response (cure) in over 95 percent. Caution: hepatitis B reactivation and interactions with amiodarone. Hepatitis B: DNA virus with a reverse transcription step. Nucleos(t)ide analogues (entecavir, tenofovir) suppress replication with a high barrier to resistance. Pegylated interferon-alpha is an alternative with a finite course. The goal is viral suppression and preventing cirrhosis and hepatocellular carcinoma.

HIV life cycle targets - Entry: fusion inhibitors (enfuvirtide), CCR5 antagonists (maraviroc). - Reverse transcription: nucleoside reverse transcriptase inhibitors (NRTIs: tenofovir, emtricitabine, abacavir, zidovudine) and non-nucleoside inhibitors (NNRTIs: efavirenz, rilpivirine). - Integration: integrase strand transfer inhibitors (dolutegravir, raltegravir). - Maturation: protease inhibitors (darunavir, atazanavir), usually boosted with ritonavir or cobicistat, which inhibit CYP3A4. Standard first-line regimen: two NRTIs plus an integrase inhibitor. Adverse effects: abacavir hypersensitivity (HLA-B*5701 testing), tenofovir renal and bone toxicity, zidovudine anaemia, protease inhibitor lipid and glucose disturbances, efavirenz CNS effects. Pre-exposure prophylaxis uses tenofovir with emtricitabine.

1. Why is aciclovir selective for infected cells? 2. Which combination of DAAs cures hepatitis C and for how long? 3. Name the classes of antiretroviral drugs with one example each. 4. Why is ritonavir added to protease inhibitors? 5. What test is needed before abacavir?

1. Only viral thymidine kinase efficiently phosphorylates it, so activation happens in infected cells. 2. A regimen combining, for example, NS5A and NS5B (or protease) inhibitors, usually for 8-12 weeks. 3. NRTI (tenofovir), NNRTI (efavirenz), integrase inhibitor (dolutegravir), protease inhibitor (darunavir), entry inhibitor (maraviroc). 4. It inhibits CYP3A4 and increases the levels of the protease inhibitor. 5. HLA-B*5701 typing.

Tumour cells acquire genetic changes that allow uncontrolled growth, evasion of apoptosis and invasion. A clinically detectable tumour (about 1 g) already holds around 10^9 cells. First-order kinetics: each cycle kills a fixed fraction of cells, not a fixed number, so many cycles are needed. Strategies: combination chemotherapy with drugs of different mechanisms and non-overlapping toxicity, adjuvant treatment after surgery, neoadjuvant treatment before surgery, and intermittent dosing to allow normal tissue recovery. Common toxicities: bone marrow suppression, nausea and vomiting, mucositis, alopecia, and specific organ toxicities.

- Antimetabolites: methotrexate (dihydrofolate reductase, rescued with folinic acid), 5-fluorouracil (thymidylate synthase), 6-mercaptopurine, cytarabine, gemcitabine. S-phase specific. - Alkylating agents: cyclophosphamide (haemorrhagic cystitis, prevented with mesna), cisplatin (nephrotoxicity, ototoxicity, emesis), temozolomide. - Topoisomerase inhibitors: irinotecan, etoposide, doxorubicin (also intercalates DNA; cumulative cardiotoxicity). - Antimitotics: vincristine (neuropathy), vinblastine, paclitaxel (stabilises microtubules). - Antibiotic cytotoxics: bleomycin (pulmonary fibrosis), dactinomycin. Exam trap: the cell-cycle-specific drugs act in one phase (antimetabolites in S, vinca alkaloids in M), while alkylating agents act in any phase.

Breast cancer (oestrogen-receptor positive) - Tamoxifen: selective oestrogen receptor modulator, antagonist in breast but agonist in endometrium and bone. Adverse: hot flushes, thromboembolism, endometrial cancer. - Fulvestrant: receptor antagonist and degrader. - Aromatase inhibitors (anastrozole, letrozole) in postmenopausal women; osteoporosis is a risk. Prostate cancer: androgen deprivation with GnRH agonists (leuprorelin), androgen receptor antagonists (bicalutamide, enzalutamide) and abiraterone (blocks androgen synthesis). Glucocorticoids are used in lymphoid malignancies and to control the side effects of chemotherapy.

Tyrosine kinase inhibitors: imatinib blocks BCR-ABL in chronic myeloid leukaemia (Philadelphia chromosome) and KIT in gastrointestinal stromal tumours. Others: erlotinib and gefitinib (EGFR), sunitinib (VEGFR). Resistance arises from kinase mutations (T315I). PARP inhibitors (olaparib): cells with BRCA1/2 mutations cannot repair double-strand breaks by homologous recombination. Blocking PARP-mediated repair of single-strand breaks kills them, a concept called synthetic lethality. Proteasome inhibitors (bortezomib): block degradation of ubiquitinated proteins, used in multiple myeloma; neuropathy is a common adverse effect. Monoclonal antibodies: trastuzumab (HER2, cardiotoxicity), rituximab (CD20), bevacizumab (VEGF), cetuximab (EGFR). Immune checkpoint inhibitors (pembrolizumab, nivolumab against PD-1; ipilimumab against CTLA-4) release the brake on T cells, and cause immune-related adverse effects (colitis, hepatitis, pneumonitis, endocrinopathies).

1. Why are several chemotherapy cycles required? 2. What is the rescue for methotrexate toxicity? 3. Which cytotoxics are known for cardiotoxicity, pulmonary fibrosis and neuropathy? 4. What is synthetic lethality with PARP inhibitors? 5. Name the target of imatinib. 6. What class of adverse effects is typical of checkpoint inhibitors?

1. Each cycle kills a fixed fraction of cells, so repeated cycles are needed to eradicate the tumour. 2. Folinic acid (leucovorin). 3. Doxorubicin (cardiac), bleomycin (lung), vincristine (neuropathy). 4. BRCA-deficient cells rely on PARP for DNA repair, so inhibiting PARP causes lethal DNA damage only in tumour cells. 5. BCR-ABL tyrosine kinase (also KIT). 6. Immune-related adverse events such as colitis, hepatitis, pneumonitis and endocrine disorders.

Insulin is made in beta cells from preproinsulin, released in response to glucose (glucose enters via GLUT2, ATP closes the K-ATP channel, depolarisation opens calcium channels), and acts through a receptor tyrosine kinase to increase glucose uptake (GLUT4), glycogen and fat synthesis and to inhibit gluconeogenesis and lipolysis. Type 1 diabetes: autoimmune loss of beta cells. Type 2: insulin resistance plus beta-cell failure. Some drugs (glucocorticoids, thiazides) can raise glucose. Preparations (recombinant human insulin or analogues) - Rapid-acting: lispro, aspart, glulisine. - Short-acting: regular insulin. - Intermediate: NPH. - Long-acting: glargine, detemir, degludec. Basal-bolus regimens mimic physiology. Adverse effects: hypoglycaemia (the main risk), weight gain and lipodystrophy at injection sites.

- Metformin (biguanide): first-line. Reduces hepatic gluconeogenesis and improves insulin sensitivity (AMP kinase). No hypoglycaemia or weight gain. Adverse: gastrointestinal upset, B12 deficiency, rare lactic acidosis; avoid in severe renal impairment. - Sulfonylureas (gliclazide, glimepiride): close K-ATP channels and stimulate insulin release. Risk of hypoglycaemia and weight gain. - Thiazolidinediones (pioglitazone): PPAR-gamma agonists, improve sensitivity; fluid retention and heart failure. - DPP-4 inhibitors (sitagliptin) and GLP-1 receptor agonists (liraglutide, semaglutide): incretin-based, glucose-dependent insulin release; GLP-1 agonists cause weight loss and nausea, with pancreatitis risk. - SGLT2 inhibitors (empagliflozin, dapagliflozin): block renal glucose reabsorption. Benefits in heart failure and kidney disease. Adverse: genital infections, ketoacidosis.

Energy balance depends on intake and expenditure, controlled by hypothalamic circuits (orexigenic NPY and AgRP neurons, anorexigenic POMC neurons) and by hormones such as leptin, ghrelin and GLP-1. History: fenfluramine and sibutramine were withdrawn (cardiac valve damage, cardiovascular events). Current options: orlistat (inhibits pancreatic lipase, so fat is not absorbed; steatorrhoea and fat-soluble vitamin deficiency), GLP-1 receptor agonists (liraglutide, semaglutide) and tirzepatide, and central agents such as naltrexone-bupropion. Therapy is added to diet, exercise and behavioural change.

1. Explain how glucose triggers insulin release. 2. List the insulin preparations by duration of action. 3. Why does metformin not cause hypoglycaemia? 4. What is the mechanism and main risk of sulfonylureas? 5. Give two benefits of SGLT2 inhibitors beyond glycaemic control. 6. How does orlistat work?

1. Glucose enters via GLUT2, its metabolism raises ATP, closing K-ATP channels, so the cell depolarises, calcium enters and insulin is released. 2. Rapid (lispro, aspart), short (regular), intermediate (NPH), long (glargine, degludec). 3. It reduces hepatic glucose output and improves sensitivity without stimulating insulin secretion. 4. They close K-ATP channels, increasing insulin secretion; hypoglycaemia. 5. Reduce heart failure hospitalisation and slow kidney disease progression. 6. It inhibits pancreatic lipase, reducing fat absorption.

Renin (from the kidney) converts angiotensinogen to angiotensin I, ACE converts it to angiotensin II, which vasoconstricts, releases aldosterone and stimulates thirst and sympathetic activity. - ACE inhibitors (captopril, enalapril, ramipril): reduce angiotensin II and increase bradykinin. Adverse: dry cough, angioedema, hyperkalaemia, first-dose hypotension, fetal toxicity. Benefit in heart failure, diabetic nephropathy and after infarction. - Angiotensin receptor blockers (losartan, valsartan): similar benefits without cough. - Aliskiren: direct renin inhibitor. - Mineralocorticoid antagonists (spironolactone). Avoid ACE inhibitors and ARBs in pregnancy and bilateral renal artery stenosis. Other classes: diuretics, calcium channel blockers, beta-blockers, alpha-blockers, and centrally acting drugs (methyldopa, safe in pregnancy).

- Loop diuretics (furosemide): block the Na-K-2Cl cotransporter in the thick ascending limb. Most potent. Adverse: hypokalaemia, hypocalcaemia, ototoxicity, hyperuricaemia. Used in oedema and acute heart failure. - Thiazides (hydrochlorothiazide, indapamide): block the Na-Cl cotransporter in the distal tubule. Hypertension. Adverse: hypokalaemia, hyponatraemia, hypercalcaemia, hyperglycaemia, hyperuricaemia. - Potassium-sparing: spironolactone and eplerenone (aldosterone antagonists), amiloride (ENaC blocker). Adverse: hyperkalaemia, gynaecomastia with spironolactone. - Osmotic (mannitol) and carbonic anhydrase inhibitors (acetazolamide). Clinical tip: the triple whammy of an NSAID, an ACE inhibitor or ARB, and a diuretic can precipitate acute kidney injury.

- Dihydropyridines (amlodipine, nifedipine): act mainly on vascular smooth muscle, cause vasodilation. Adverse: ankle oedema, flushing, headache, reflex tachycardia (short-acting). - Phenylalkylamines (verapamil) and benzothiazepines (diltiazem): act on the heart, reduce rate and conduction. Used for supraventricular tachycardia, rate control in atrial fibrillation and angina. Adverse: bradycardia, AV block, constipation (verapamil). Exam trap: do not combine verapamil or diltiazem with a beta-blocker because of the risk of severe bradycardia and heart block.

Cardiovascular risk depends on LDL cholesterol (atherogenic), HDL and triglycerides, plus hypertension, diabetes, smoking. - Statins (simvastatin, atorvastatin, rosuvastatin): inhibit HMG-CoA reductase, so hepatocytes upregulate LDL receptors and clear LDL. Lower LDL by 30-55 percent. Adverse: myopathy and rare rhabdomyolysis, raised transaminases. Interactions with CYP3A4 inhibitors and fibrates. Avoid in pregnancy. - Ezetimibe: blocks intestinal cholesterol absorption (NPC1L1). - Bempedoic acid: inhibits ATP citrate lyase in the liver. - Bile acid resins (colestyramine): bind bile acids and increase LDL uptake; bloating and drug binding. - Fibrates (fenofibrate): PPAR-alpha agonists, lower triglycerides. Myopathy risk with statins. - Nicotinic acid: lowers LDL and triglycerides, raises HDL; flushing and hyperglycaemia. - PCSK9 inhibitors: monoclonal antibodies that increase LDL receptor recycling.

- Aspirin: irreversibly acetylates COX-1 and so blocks thromboxane A2 for the life of the platelet (7-10 days). Adverse: gastric irritation and bleeding. - P2Y12 antagonists: clopidogrel (prodrug activated by CYP2C19), prasugrel, ticagrelor. Used after coronary stenting and in acute coronary syndrome, often with aspirin. - Glycoprotein IIb/IIIa inhibitors (abciximab, tirofiban): block fibrinogen binding. - Dipyridamole: raises platelet cAMP. Main adverse effect of all: bleeding.

- Unfractionated heparin: binds antithrombin III and inhibits thrombin and factor Xa. Given by injection, monitored with aPTT. Adverse: bleeding, heparin-induced thrombocytopenia. Reversed by protamine. - Low molecular weight heparins (enoxaparin): mainly anti-Xa, predictable, no routine monitoring. - Vitamin K antagonists (warfarin): block synthesis of factors II, VII, IX, X and proteins C and S. Slow onset, monitored with INR, many interactions, teratogenic. Reversed by vitamin K, prothrombin complex concentrate. - Direct oral anticoagulants: factor Xa inhibitors (rivaroxaban, apixaban) and the thrombin inhibitor dabigatran (reversed by idarucizumab; andexanet for Xa inhibitors).

1. Explain the RAAS and where ACE inhibitors act. 2. Compare loop and thiazide diuretics. 3. Why can verapamil not be combined with a beta-blocker? 4. What is the mechanism of statins and their main adverse effect? 5. Why does aspirin's effect last 7-10 days? 6. How is warfarin monitored and reversed?

1. Renin -> angiotensin I -> (ACE) angiotensin II -> vasoconstriction and aldosterone. ACE inhibitors block the conversion to angiotensin II. 2. Loop diuretics act in the thick ascending limb, are more potent, and cause hypocalcaemia. Thiazides act in the distal tubule, cause hypercalcaemia and are used for hypertension. 3. Risk of severe bradycardia and AV block. 4. Inhibit HMG-CoA reductase; myopathy. 5. It irreversibly inhibits COX-1, and platelets cannot make new enzyme. 6. INR monitoring; vitamin K or prothrombin complex concentrate.

- 5-Aminosalicylates: sulfasalazine (sulfapyridine plus 5-ASA, cleaved by colonic bacteria; adverse effects from the sulfapyridine: rash, agranulocytosis, oligospermia) and mesalazine (no sulfa component). Mainly for ulcerative colitis. - Glucocorticoids (prednisolone, budesonide): induce remission, not suitable for maintenance because of adverse effects. - Thiopurines (azathioprine, 6-mercaptopurine): purine antimetabolites. Check TPMT before starting; myelosuppression, hepatotoxicity, pancreatitis. Allopurinol interaction. - Methotrexate: for Crohn disease; teratogenic, needs folic acid.

- Anti-TNF-alpha antibodies: infliximab, adalimumab, golimumab. Risks: serious infections including reactivation of tuberculosis and hepatitis B (screen before treatment), lymphoma, demyelination, heart failure, anti-drug antibodies with loss of response. - Vedolizumab: blocks alpha4beta7 integrin, gut-selective. - Ustekinumab: blocks the p40 subunit of IL-12 and IL-23. - Small molecules: tofacitinib and upadacitinib (JAK inhibitors, oral). Risks: infections, herpes zoster, venous thromboembolism, and raised lipids. Biosimilars are highly similar copies of biologic drugs and are used to reduce costs.

1. Why is TPMT tested before azathioprine? 2. What are the adverse effects of sulfasalazine linked to? 3. What must be screened before starting anti-TNF therapy? 4. What is the target of vedolizumab?

1. Low TPMT activity increases thiopurine toxicity (severe myelosuppression). 2. The sulfapyridine moiety. 3. Latent tuberculosis and hepatitis B (and other infections). 4. The alpha4beta7 integrin.

Pain pathway: nociceptors (A-delta and C fibres) send signals to the spinal cord and cortex. Nociceptive and neuropathic pain need different drugs. NSAIDs (ibuprofen, diclofenac, naproxen, celecoxib): inhibit COX enzymes, reducing prostaglandins. Analgesic, antipyretic, anti-inflammatory. Adverse: gastric ulcer and bleeding (COX-1), kidney injury, hypertension, cardiovascular events, asthma exacerbation. COX-2 selective drugs spare the stomach but raise cardiovascular risk. Paracetamol is analgesic and antipyretic with little anti-inflammatory action; overdose causes hepatic necrosis (antidote: N-acetylcysteine). Opioids (morphine, fentanyl, codeine, tramadol): agonists at mu, delta, kappa receptors. Analgesia, euphoria, respiratory depression, miosis, constipation, nausea. Tolerance and dependence develop. Overdose is reversed by naloxone. Neuropathic pain adjuvants: gabapentin, pregabalin, amitriptyline, duloxetine.

Reward pathway: dopamine neurons of the ventral tegmental area project to the nucleus accumbens. Mechanisms - Stimulants: cocaine blocks dopamine reuptake, amphetamine releases dopamine. - Opioids: activate mu receptors, which inhibit GABA interneurons and so disinhibit dopamine neurons. - Alcohol: enhances GABA-A and inhibits NMDA receptors. - Nicotine: activates nicotinic receptors on dopamine neurons. - Cannabis: activates CB1 receptors. Phases: intoxication, withdrawal and craving, and relapse. Withdrawal from alcohol and benzodiazepines can cause seizures; opioid withdrawal is unpleasant but rarely dangerous. Treatments: methadone or buprenorphine (opioid substitution), naltrexone, disulfiram, varenicline and nicotine replacement.

Parkinson disease: loss of dopaminergic neurons in the substantia nigra. Levodopa (with carbidopa, a peripheral decarboxylase inhibitor) is the most effective drug. Others: dopamine agonists (pramipexole), MAO-B inhibitors (selegiline), COMT inhibitors (entacapone), amantadine. Adverse: dyskinesia, on-off fluctuations, nausea, hypotension, hallucinations. Alzheimer disease: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine (NMDA antagonist) give modest symptomatic benefit. Pharmacovigilance: the detection, assessment and prevention of adverse drug reactions after marketing, including spontaneous reporting. Vaccines are monitored for adverse events following immunisation.

1. Why do NSAIDs cause gastric ulcers? 2. Which antidote treats paracetamol overdose and opioid overdose? 3. Which pathway is common to all drugs of abuse? 4. Why is carbidopa given with levodopa? 5. Name two drug classes used in Alzheimer disease.

1. They inhibit COX-1, reducing protective gastric prostaglandins. 2. N-acetylcysteine for paracetamol, naloxone for opioids. 3. Dopamine release in the mesolimbic pathway (ventral tegmental area to nucleus accumbens). 4. It blocks peripheral dopa decarboxylase, so more levodopa reaches the brain and there is less nausea. 5. Cholinesterase inhibitors and memantine.