Clinical Pharmacology: Concept Checklist

Concepts covered across the module lectures, grouped by lecture. Tick each once you can explain it from memory.

L1 Neurotransmitters (20 Feb) L1 Clinical Pharmacology Neurotransmitters

• Sequence of events in chemical synaptic transmission and mechanisms of neurotransmitter removal
• Three criteria a chemical must meet to be a neurotransmitter
• Relative prevalence and roles of glutamate, GABA, acetylcholine and the monoamine neuromodulators
• AMPA vs NMDA receptors: ion flow, speed, and voltage-dependent Mg2+ block
• Synthesis of GABA, and GABA-A vs GABA-B receptor mechanism and timescale
• Mechanism of long-term potentiation: NMDA Ca2+ influx, CaMKII, AMPA insertion, input specificity
• Neurotransmitter imbalances linked to epilepsy, anxiety, Parkinson’s, depression, schizophrenia and ADHD
• Ionotropic vs metabotropic receptors: mechanism and timescale
• Drug classes acting on neurotransmission: agonists, antagonists, enzyme inhibitors, reuptake inhibitors, releasing agents, PAMs, ion channel blockers
• Dose-dependent effects of ketamine as an NMDA antagonist
• Reuptake inhibitor classes (SSRI, SNRI, NDRI) with examples and indications
• Mechanism of amphetamine-type releasing agents
• MAO inhibitors, and CYP3A4 inhibition as an off-target effect of fluoxetine and bupropion
• Positive allosteric modulation: propofol at GABA-A; Na+ channel block by lidocaine

L2 Anti-Epileptic Drugs (27 Feb) L2 Clinical Pharmacology Anti-Epileptic Drugs

• Epilepsy as an excitation/inhibition imbalance, and ILAE diagnostic criteria
• Seizure classification by onset (focal aware, focal impaired awareness, focal to bilateral, generalised, unknown) and by clinical presentation
• Localising symptoms of focal seizures by lobe
• Glutamate-glutamine cycle: glutaminase, VGLUT, EAATs, glutamine synthetase; glutamate excitotoxicity
• Causes of neuronal hyperactivity and the three mechanistic classes of anti-epileptic drugs
• Epidemiology, comorbid associations (Alzheimer’s, TBI, stroke, tumour) and prognosis of epilepsy, including role of non-adherence
• Principles of treatment: low-dose monotherapy, titration, add-on therapy
• Drug choice by seizure type: focal/generalised, absence, status epilepticus
• Levetiracetam: SV2A mechanism, first-line status, cautions and adverse effects
• Valproate: mechanism, breadth of indications, adverse effects including teratogenicity and hepatotoxicity, interactions with carbapenems and lamotrigine
• Gabapentin: Ca2+ channel mechanism, second-line role, neuropathic pain use
• Phenytoin: Na+ channel block, adverse effects, CYP3A4 induction and polypharmacy risk
• Benzodiazepines in acute seizures: GABA-A binding site and mechanism of positive allosteric modulation
• Ethosuximide and T-type Ca2+ channels in absence seizures; vigabatrin and tiagabine as GABA-enhancing drugs

L3 Parkinson’s Disease (9 Mar) L3 Clinical Pharmacology Parkinson’s Disease

• Dopaminergic nuclei and the nigrostriatal, mesolimbic and mesocortical pathways
• Reward prediction error firing of VTA dopamine neurons
• Direct basal ganglia pathway as a disinhibition circuit, and dopamine’s role in it
• Clinical features, epidemiology and causes of idiopathic Parkinson’s disease, including MPTP and rotenone
• Pathophysiology: nigral neuron loss, striatal dopamine depletion, dopamine/ACh imbalance; PET imaging correlates
• D1-family vs D2-family receptors: G protein coupling, cAMP effect, distribution
• Dopamine synthesis, reuptake by DAT and breakdown by MAO-B and COMT
• Dopamine excess vs deficiency: why Parkinson’s and schizophrenia treatments produce each other’s side effects
• Five drug strategies for raising striatal dopamine or restoring DA/ACh balance
• L-DOPA with carbidopa: rationale, peripheral decarboxylase inhibition and brain-available fraction
• Acute adverse effects of L-DOPA and their mechanisms
• Long-term L-DOPA problems: narrowing therapeutic window, on-off phenomenon, wearing off, dyskinesia
• Selegiline: MAO-B inhibition, uses and interactions with reuptake inhibitors
• Ropinirole and other dopamine agonists: receptor selectivity, role, adverse effects including impulse control disorders

L4 Drug treatment of stroke (23 Mar) L4 Clinical Pharmacology Drug treatment of stroke

• Definition of stroke, the four vascular causes and their relative frequency
• Modifiable, comorbid and drug-induced risk factors for stroke (HRT, OCP, antipsychotics, COX-2 inhibitors, procoagulants)
• Infarct core vs penumbra, and the ischaemic cascade that threatens the penumbra
• Thrombotic vs embolic occlusion, and why each maps to antiplatelet vs anticoagulant therapy
• AF as a stroke risk factor, and the rate control, rhythm control and stroke prevention arms of AF management
• Warfarin: mechanism, INR target and its rationale, emergency reversal options (PCC, FFP, vitamin K)
• Dabigatran: mechanism, pharmacokinetics, renal clearance, P-gp interactions, reversal with idarucizumab
• RE-LY trial findings: dabigatran doses vs warfarin
• Sites of action of anticoagulants, antiplatelets and rt-PA on the coagulation and fibrinolytic pathways
• TIA: definition, immediate treatment, and ABCD3-I risk stratification
• Secondary prevention: dual antiplatelet therapy, anticoagulation in AF, and clopidogrel CYP2C19 bioactivation and non-response
• Acute ischaemic stroke workup and management: NIHSS, CT to exclude haemorrhage, glucose and temperature, reperfusion options
• Alteplase: mechanism, dosing, pharmacokinetics, time windows (4.5 h, extended 9 h with perfusion mismatch), eligibility criteria
• Acute treatments not recommended: aspirin within 24 h of thrombolysis, neuroprotectants, tight glycaemic control, corticosteroids for oedema
• Haemorrhagic stroke management: supportive care, BP target, nimodipine, limits of factor VIIa

L5 Antidepressants (26 Mar) L5 Clinical Pharmacology Antidepressants

• Measures of antidepressant efficacy: odds ratio, SMD, remission, and statistical vs clinical significance
• Diagnostic criteria (5 of 9 symptoms over 2 weeks), prevalence and burden of major depressive disorder
• Genetic, environmental, psychological and biological contributors to depression
• Monoamine hypothesis: evidence for and against
• Synthesis, central projections and peripheral roles of serotonin; central roles and projections of noradrenaline
• MAO-A vs MAO-B substrates, and SERT and NET as reuptake transporters
• SSRIs: first-line rationale, delayed onset explained by 5-HT1A autoreceptor downregulation, role of BDNF
• SSRI adverse effects and interactions with MAOIs, NSAIDs/aspirin and codeine
• SNRIs: mechanism, position in therapy, overdose risk and blood pressure effect
• TCAs: mechanism, overdose toxicity via Na+ channel block, and adverse effects from alpha-1, H1 and muscarinic antagonism
• MAOIs: MAO-A vs MAO-B inhibitor uses and serotonin syndrome risk
• Serotonin syndrome: cause, drug combinations and clinical features
• STAR-D findings and the definition of treatment-resistant depression
• Ketamine and esketamine: glutamatergic mechanism, onset and duration, administration requirements, adverse effects

L6 Drug Tolerance and dependence (20 Apr) L6 Clinical Pharmacology Drug Tolerance and dependence

• Epidemiology and relative harms of drug use in New Zealand and the US
• DSM-5 substance use disorder criteria and severity grading, and why tolerance and withdrawal are excluded for supervised prescribed drugs
• Define and distinguish physical dependence, psychological dependence and tolerance
• Risk factors for substance use disorder
• Dopamine theory of addiction: phasic vs tonic dopamine release
• Mechanism of amphetamine and methamphetamine as releasing agents via monoamine transporters and VMAT
• Mechanism of cocaine as an NDRI, and D1 vs D2 receptor affinity in the drug high
• How route and speed of delivery affect dependence risk
• Opioid reward via disinhibition of VTA dopamine neurons at mu receptors
• Molecular mechanism of opioid tolerance: GRK phosphorylation, beta-arrestin, internalisation, degradation
• Rationale for opioid substitution therapy with methadone and partial agonists; dependence risk of prescribed opioids
• Alcohol: GABA-A and NMDA mechanisms, acute tolerance, and dopaminergic reward effect
• Long-term effects of alcohol: thiamine deficiency and Wernicke’s encephalopathy, grey matter loss, genetic and stress risk factors for AUD
• Subjective effects of psychedelics vs cocaine on sense of self; prescribing considerations for drugs with abuse potential

L7 Hypnotics and anxiolytics (25 Mar) L7 Clinical Pharmacology Hypnotics and anxiolytics

• Modest effect sizes of drugs and psychotherapy for mental health disorders, and societal burden of anxiety
• Types and prevalence of anxiety disorders, and sympathetic overactivity as the physiological basis of anxiety
• Non-pharmacological treatments for anxiety and their relative effect sizes
• First-line vs second-line drug treatment of anxiety
• Proposed mechanism of venlafaxine in anxiety via alpha-2 receptors in the locus coeruleus
• Propranolol: non-selective beta blockade, use in performance anxiety, contraindication in asthma
• GABA-A receptor structure and the location of GABA, benzodiazepine and other binding sites
• Mechanism of benzodiazepines and Z-drugs as positive allosteric modulators of GABA-A
• GABA-A vs GABA-B receptors: mechanism, kinetics and agonists
• Benzodiazepine adverse effects, therapeutic index relative to barbiturates, and CNS depressant interactions
• Mechanisms of benzodiazepine tolerance; dependence, withdrawal features and the need for gradual withdrawal
• Insomnia: definition of chronic insomnia, psychological, physical, drug and environmental causes
• Sleep hygiene measures
• Zopiclone: mechanism, duration of use, adverse effects and interactions
• Other uses of GABAergic drugs: general anaesthesia and baclofen for muscle spasm

L8 Antipsychotics (20 Apr) L8 Clinical Pharmacology Antipsychotics

• Dopaminergic nuclei and the three dopamine pathways, and tonic vs phasic dopamine firing
• Reward prediction error signalling by VTA dopamine neurons
• Schizophrenia: aetiological associations, epidemiology, age of onset by sex, course and prognosis
• First class symptoms, positive vs negative symptoms, and reduced cognition
• Dopamine hypothesis: mesolimbic hyperactivity, mesocortical hypoactivity, nigrostriatal site of extrapyramidal side effects
• Salience network in schizophrenia and the hollow mask illusion
• Historical evidence implicating muscarinic, NMDA, 5-HT2A and dopamine systems (hyoscine, PCP, LSD, amphetamine)
• Correlation of antipsychotic clinical potency with D2 receptor affinity
• D1-family vs D2-family receptor signalling, including D2 Gi, GIRK and Ca2+ channel effects
• Typical antipsychotics: haloperidol mechanism, indications and adverse effects (extrapyramidal, negative symptoms, anticholinergic, weight gain)
• Atypical antipsychotics: receptor targets, clozapine efficacy for negative symptoms, neutropenia/agranulocytosis and other adverse effects
• Comparative efficacy of antipsychotics, and the hypoglutamate hypothesis
• Xanomeline-trospium: M1/M4 partial agonism, proposed mechanism in the VTA, rationale for peripheral trospium
• Which drug classes treat positive vs negative symptoms

L9 Local anaesthetics (22 Apr) L9 Clinical Pharmacology Local anaesthetics

• Distinguish analgesia, local anaesthesia and general anaesthesia
• Indications, contraindications, precautions and ideal properties of local anaesthetics
• Routes of administration, and local infiltration vs nerve block
• Connective tissue barriers of a peripheral nerve
• Chemical structure of local anaesthetics: lipophilic ring, ester vs amide link, amine group; examples of each class
• Ester vs amide metabolism, elimination, PABA and allergy, pseudocholinesterase deficiency
• Mechanism of use-dependent voltage-gated Na+ channel block, and the three channel states
• Role of ionisation and pKa in nerve entry; why infected or inflamed tissue reduces efficacy; bicarbonate buffering
• Relationship of pKa, lipid solubility and protein binding to onset, potency and duration
• Differential nerve block: order of fibre blockade and its basis in fibre size and internodal distance
• Adjunct vasoconstrictors: benefits, cautions and end-artery sites
• Local anaesthetic systemic toxicity: cardiac and vascular mechanisms, concentration-dependent CNS and cardiovascular features, lipid emulsion treatment

L10 General anaesthetics (30 Apr) L10 Clinical Pharmacology General anaesthetics

• Goals and desirable components of general anaesthesia, and desirable vs adverse effects
• Four stages of anaesthesia, and which drug route manages induction vs maintenance
• Conscious sedation vs general anaesthesia: definition, agents and indications for GA
• Balanced anaesthesia: premedication, induction, maintenance and recovery agents, and adjuncts (analgesics, antiemetics, neuromuscular blockers)
• Propofol: formulation, mechanism, pharmacokinetics, adverse effects, and management of injection pain and hypotension
• Noradrenaline vs phenylephrine for correcting anaesthetic hypotension
• Blood:gas partition coefficient and speed of induction and recovery
• Oil:gas partition coefficient, MAC and the Meyer-Overton correlation with potency
• Properties of nitrous oxide, sevoflurane, isoflurane and halothane
• Sevoflurane as the volatile agent of choice, including in raised intracranial pressure
• Theories of general anaesthetic action: lipid solubility correlation and protein theory; synaptic rather than axonal effects
• Receptor targets of volatile agents vs nitrous oxide and xenon (GABA-A, glycine, NMDA)
• Dose-dependent order of behavioural endpoints with increasing MAC fraction
• Systemic effects of general anaesthetics: cardiovascular and respiratory depression, arrhythmias
• Malignant hyperthermia: triggers and nature of the syndrome

L11 Hypoglycaemics 1 (1 May) L11 Clinical Pharmacology Hypoglycaemics 1

• Pancreatic hormonal control of blood glucose, and the beta-cell glucose-stimulated insulin secretion pathway
• Autonomic and incretin modulation of insulin release
• Insulin receptor action, and hepatic and renal clearance of insulin
• Classification of diabetes, cellular basis of type 1 vs type 2, and insulin resistance
• Micro- and macrovascular consequences of inadequate glycaemic control
• HbA1c and fasting glucose thresholds for diagnosis and screening of type 2 diabetes; aims of management
• Overview of antidiabetic drug classes and their principal mechanisms
• Insulin analogue engineering: hexamer dissociation as rate-limiting step, lispro, aspart, glargine, detemir
• Onset and peak of rapid, short, intermediate and long-acting insulins; basal-bolus regimen
• Insulin pharmacokinetics in renal impairment, injection sites, and adverse effects of insulin
• Stepwise treatment algorithm for type 2 diabetes, including HbA1c triggers for escalation and insulin
• Metformin: AMPK and complex I mechanisms, hepatic, muscle and gut effects, pharmacokinetics and OCT transport
• Metformin adverse effects and contraindications: GI effects, B12 malabsorption, lactic acidosis, renal, hepatic and cardiac failure
• Sulphonylureas: K-ATP channel mechanism, requirement for beta-cell function, hypoglycaemia, avoidance in obesity

L12 Hypoglycaemics 2 (4 May) L12 Clinical Pharmacology Hypoglycaemics 2

• The incretin effect: GIP and GLP-1 sources, DPP-IV degradation, and impairment in type 2 diabetes
• Systemic effects of GLP-1 on brain, pancreas, liver and stomach
• Dulaglutide: exendin-4 origin, structure, weekly dosing, mechanism, pharmacokinetics
• Cardiovascular benefits of GLP-1 receptor agonists and their guideline position
• Dulaglutide adverse effects, contraindications and interactions (pancreatitis, hypoglycaemia with sulphonylureas, delayed gastric emptying)
• Vildagliptin: mechanism, uses, efficacy, renal clearance and adverse effects
• SGLT isoforms: distribution and function of SGLT1 vs SGLT2, and why intestinal SGLT1 inhibition is undesirable
• Renal glucose handling: filtered load, SGLT2 in S1 vs SGLT1 in S3, GLUT2, and the renal threshold for glucose in health vs T2DM
• Gliflozins: mechanism, effect on renal threshold, glycaemic and non-glycaemic effects
• Renal protection by SGLT2 inhibitors via tubuloglomerular feedback, and why the initial eGFR dip is protective
• Empagliflozin dosing, pharmacokinetics and renal function requirements
• SGLT2 inhibitor adverse effects: UTI, genital infections including Fournier’s gangrene, and mechanism and risk factors of euglycaemic DKA
• Benefits of SGLT2 inhibitors in heart failure, and comparative myocardial effects of diabetic drug classes

L13 Diuretics (3 Jun) L13 Clinical Pharmacology Diuretics

• General principles: dependence on Na+ delivery, luminal site of action (except spironolactone), synergism between segments
• Nephron sites and transporter targets of each diuretic class
• Choice of diuretic by CKD stage and why thiazides fail at low GFR
• Loop diuretics: NKCC2 mechanism, potency, and mechanism of Ca2+ and Mg2+ loss
• Frusemide pharmacokinetics: bioavailability, protein binding, OAT secretion, and why dose must rise in renal impairment
• OAT-mediated interactions of frusemide (cephalosporins, valproate) and with NSAIDs
• Uses, adverse effects and electrolyte/acid-base disturbances of loop diuretics, including ototoxicity
• Loop diuretic effects on venous capacitance, renin release and TGF, and why they do not lower GFR
• Diuretic resistance: pharmacokinetic and pharmacodynamic mechanisms, and stepwise treatment
• Benefits vs harms of loop diuretics in chronic heart failure
• SGLT2 inhibitors combined with diuretics in heart failure
• Thiazides: NCC mechanism, GFR limits, vascular effects, pharmacokinetics and uses including hypercalciuria and nephrogenic diabetes insipidus
• Thiazide adverse effects: hypokalaemia, hyponatraemia, hypercalcaemia, hyperuricaemia, hyperglycaemia
• Aldosterone renal and cardiac actions; spironolactone mechanism, pharmacokinetics, indications and toxicity
• Amiloride: ENaC block, luminal access, combination with thiazides
• Prescribing loop diuretics in oedema: all-or-none response, equivalent doses, myths, dry-weight dosing

L14 ACE inhibitors and angiotensin receptor blockers (12 Jun) L14 Clinical Pharmacology ACE inhibitors and angiotensin receptor blockers

• Stimuli for renin release, the RAS cascade, and its negative feedback termination
• Sites of action of renin inhibitors, ACE inhibitors, ARBs and MR antagonists on the cascade
• ACE Janus effect: bradykinin accumulation, its beneficial effects and adverse effects (cough, angioedema)
• Actions of angiotensin II on vasculature, kidney, adrenal, sympathetic system, ADH and cardiovascular structure
• Ang II in multi-organ injury, endothelial dysfunction and profibrotic TGF-beta signalling
• Role of Ang II and hyperglycaemia in diabetic nephropathy, and how ACE inhibitors slow progression
• Profibrotic and cardiovascular effects of aldosterone excess
• Ang II regulation of GFR via efferent arteriole; progression from microalbuminuria to ESRD; albumin:creatinine thresholds
• ACE inhibitors: mechanism, effect on GFR, and danger in bilateral renal artery stenosis
• Enalapril pharmacokinetics as a prodrug
• ACE inhibitor class adverse effects
• Candesartan: mechanism, pharmacokinetics, and theoretical advantages of ARBs over ACE inhibitors (non-ACE pathways, AT2 activation)
• Trial evidence and K/DOQI guidance for ACE inhibitors and ARBs in diabetes and CKD
• Prescribing precautions for RAS modulators, and mechanism of the triple whammy
• Neprilysin substrates, why neprilysin inhibitors are paired with an ARB, and ARNi effects in heart failure
• Quadruple therapy for HFrEF and its initiation sequence

L15 Endocrine Pharmacology (27 Jul) L15 Clinical Pharmacology Endocrine Pharmacology

• Key properties of hormones, hypothalamic releasing hormones and pituitary hormone targets
• Logic of endocrine drug treatment: deficiency vs hypersecretion, feedback propagation, diagnostic use of drugs
• Thyroid axis and the metabolic, cardiovascular, neurological and developmental actions of thyroid hormones
• Graves’ disease: epidemiology, biochemistry, TSH receptor stimulating antibodies; other causes of hyperthyroidism (nodules, thyroiditis)
• Clinical features of thyroid hormone excess vs deficiency
• Carbimazole: mechanism, dosing, bone marrow suppression and other adverse effects, clozapine interaction
• Definitive treatment of hyperthyroidism and symptomatic role of beta blockers
• Hashimoto’s thyroiditis: biochemistry and TSH receptor blocking antibodies; iodine deficiency goitre
• Levothyroxine: mechanism, dosing, low therapeutic index, cautions and contraindications
• Adrenal glucocorticoid axis and actions of glucocorticoids
• Cushing’s syndrome: causes including iatrogenic, dexamethasone suppression biochemistry, features, treatment
• Ketoconazole and metyrapone: steroidogenic CYP targets and safety
• Addison’s disease: causes, biochemistry, features and adrenal crisis
• Glucocorticoid replacement: receptor mechanism (transactivation and transrepression), hydrocortisone and fludrocortisone regimen, dose increase in stress, infection or vomiting
• Relative glucocorticoid and mineralocorticoid potencies and durations of common corticosteroids
• Corticosteroid adverse effects, contraindications, CYP3A4 and hypokalaemia interactions, and risks of prolonged use and abrupt withdrawal

L16 Sex hormones (21 Aug) L16 Clinical Pharmacology Sex hormones

• Steroidogenesis pathway to sex steroids and glucocorticoids, and sites of steroidogenesis inhibitors
• Relative potency of natural oestrogens and progestagens
• Genomic mechanism of steroid hormone action via nuclear receptors
• Hypothalamic-pituitary-ovarian axis: FSH and LH actions, and the switch from negative to positive feedback before ovulation
• Oestrogen and progesterone effects on endometrium and cervical mucus across the cycle
• Mechanism of combined oral contraceptives
• COC composition: ethinyloestradiol, mestranol, progestogen generations, cyproterone
• COC vs progestogen-only pill: advantages of each
• Relative effectiveness of contraceptive methods, and fixed vs variable dose regimens
• Ethinyloestradiol pharmacokinetics and enterohepatic recycling
• Drugs that reduce contraceptive efficacy, and when backup contraception is needed
• Emergency contraception: levonorgestrel, ulipristal, copper IUD, time windows
• Minor and serious adverse effects of COCs; VTE risk by progestogen generation; cardiovascular risk with smoking and age
• Effects of COCs on hypertension, cancer risk and non-contraceptive benefits