Comprehensive Clinical Pharmacology and Therapeutics Notes

Cardiovascular Health and Hypertension

• Hypertension Diagnosis: Elevated blood pressure ($BP$) is an independent risk factor for cardiovascular disease ($CVD$). Diagnosis requires measurements on multiple occasions.

• Measurement Protocol: Patient seated/relaxed, avoid stimulants (nicotine, caffeine) for $2\,hr$. Use correct cuff size at heart level. Calculate average of two measurements; remeasure after $5\,min$ if difference exceeds $10\,mmHg$.

• Criteria and Targets: Treatment recommended for Grade 1 hypertension ($140–159/90–99$), high normal ($130–139/85–90$) with lifestyle changes, or >160/100\,mmHg regardless of risk. Standard target is <140/90\,mmHg; high-risk target <120\,mmHg systolic.

• Drug Classes:

  • ACE Inhibitors ($Perindopril, Ramipril$): Block angiotensin I to II conversion. Risks: Hyperkalaemia, dry cough, angioedema (bradykinin accumulation).

  • ARBs ($Irbesartan, Telmisartan$): Block $AT_1$ receptors. Same monitoring as ACEi; no dry cough.

  • DHP CCBs ($Amlodipine, nifedipine$): Reduce peripheral vascular resistance. Risks: Peripheral oedema, GORD, postural hypotension.

  • Thiazides ($Indapamide$): Inhibit $Na/Cl$ reabsorption. Risks: Hyponatraemia, gout, increased diabetes risk.

• Hypertensive Emergencies: Goal is <25\% reduction in $2\,hr$ using IV therapy ($Nitroprusside$ or $GTN$). Nitroprusside requires monitoring for cyanide toxicity.

• Pregnancy: Chronic ($≤ 20 \, \text{weeks}$) vs. Preeclampsia ( > 20 \, \text{weeks} + organ involvement). Target $≤ 135/85 \, \text{mmHg}$. ACEi/ARBs are Category D (fetal malformation, oligohydramnios). Preferred: $Methyldopa, Labetalol, Hydralazine$.

Dyslipidaemia Management

• Statins ($Atorvastatin, Rosuvastatin$): Inhibit $HMG–CoA$ reductase. Target <2\,mmol/L (primary) and <1.8\,mmol/L (secondary).

• Risks: Myalgia, rhabdomyolysis ($creatine\,kinase$ monitoring), elevated aminotransferases. Rosuvastatin has fewer drug interactions than Atorvastatin ($CYP3A4$ substrate).

• Add-on Therapy: $Ezetimibe$ (inhibits cholesterol absorption); $PCSK9$ inhibitors ($Evolocumab$) for familial hypercholesterolaemia or resistant cases.

• Fibrates ($Fenofibrate, Gemfibrozil$): Targeted for elevated triglycerides ($TGs$). $Gemfibrozil$ interacts with $OATP1B1$, increasing statin toxicity risk.

Thrombosis and Anticoagulation

• Clot Types: Arterial (platelet-rich, use antiplatelets) and Venous (fibrin-rich, use anticoagulants).

• Antiplatelets: $Aspirin$ (nonselective $COX$ inhibitor), $Clopidogrel, Ticagrelor$ ($P2Y_{12}$ antagonists). Ticagrelor is reversible; Clopidogrel is irreversible.

• VTE Prophylaxis: $Enoxaparin$ ($40\,mg$ daily, reduce to $20\,mg$ if CrCl < 30\,mL/min).

• Warfarin: Vitamin K antagonist targeting factors $II, VII, IX, X$. Monitor $INR$ (target $2.0–3.0$). Interactions: $CYP2C9$ inhibitors.

• DOACs ($Rivaroxaban, Apixaban, Dabigatran$): Factor $Xa$ or $IIa$ inhibitors. Preferred for ease of use. Reversal: $Idarucizumab$ (Dabigatran), $Andexanet\,alpha$ (Xa inhibitors).

• $ACS$ Management: STEMI requires immediate reperfusion (PCI or Thrombolysis). Long-term DAPT ($Aspirin + P2Y_{12}$) for $6–12$ months.

Heart Failure ($CHF$) and Arrhythmias

• Heart Failure Core Therapy: ACEi/ARNI ($Valsartan/Sacubitril$), Beta-blockers ($Carvedilol, Bisoprolol$), SGLT2i ($Dapagliflozin$), and MRA ($Spironolactone$).

• ARNI Switching: Requires $36\,hr$ washout from ACEi to prevent angioedema.

• Symptom Control: Loop diuretics ($Furosemide$). Avoid the "Triple Whammy" ($ACEi/ARB + Diuretic + NSAID$).

• Atrial Fibrillation ($AF$): Rate control (BB, non-DHP CCB) vs. Rhythm control ($Flecainide, Sotalol, Amiodarone$). Stroke prevention based on $CHA_2DS_2-VA$ score using anticoagulants.

• $Amiodarone$ Risks: Thyroid dysfunction, pulmonary toxicity, corneal microdeposits, photosensitivity.

• $Digoxin$: Narrow TI; target $0.5–1\,nmol/L$ ($CHF$) or $0.5–2\,μg/L$ ($AF$). Signs of toxicity: yellow vision, anorexia.

Gout and Arthritis

• Acute Gout: NSAIDs, Colchicine ($1\,mg$ then $0.5\,mg\,1\,hr$ later), or Corticosteroids.

• Urate Lowering Therapy ($ULT$): $Allopurinol$ (start $50–100\,mg$, titrate to target <0.30–0.36\,mmol/L). Risks: SJS/TEN ($HLA–B*5801$ allele).

• Rheumatoid Arthritis: csDMARDs ($Methotrexate$ weekly + $Folic\,acid$, $Sulfasalazine, Hydroxychloroquine$). bDMARDs ($TNF\,inhibitors$ like $Adalimumab$) for non-responders.

• Osteoporosis: T-score $≤ -2.5$. First line: Bisphosphonates ($Alendronate$, take on empty stomach, stay upright) or $Denosumab$ ($SC$ every $6\,months$).

Endocrinology and Diabetes

• Thyroid: Hypothyroidism (Levothyroxine replacement, target $TSH$). Hyperthyroidism (Carbimazole; PTU in 1st trimester; risk of agranulocytosis).

• Adrenal: Addison’s (Hydrocortisone/Fludrocortisone; stress dosing required). Cushing’s (excess glucocorticoids).

• Diabetes Mellitus ($T2D$):

  • First line: $Metformin$ (renal dosing: stop if CrCl < 15\,mL/min).

  • Add-ons: SGLT2i ($Empagliflozin$ - CV/Renal benefits), GLP-1 RA ($Semaglutide$ - weight loss), DPP-4i ($Sitagliptin$ - weight neutral).

  • Hypoglycaemia: BGL < 4.0\,mmol/L. Management: Fast-acting glucose, then slow-acting carb. $Glucagon$ for severe cases.

• T1DM: Physiological insulin profile using MDI ($Basal + Bolus$) or Continuous Pump ($CSII$).

Respiratory Health

• Asthma: SABA relievers and ICS preventers. Attack management: 4  4  4 (4 puffs, 4 breaths, wait 4 mins). SMART/MART therapy uses $Budesonide/Formoterol$.

• COPD: Confirmed by FEV_1/FVC < 0.7. Management via LAMA ($Tiotropium$) and LABA. Triple therapy ($LAMA + LABA + ICS$) reduces exacerbation frequency but increases pneumonia risk.

Infectious Diseases and Antibiotics

• Principles: Use narrowest spectrum based on culture/sensitivity (MIND ME).

• UTI: Uncomplicated cystitis (Trimethoprim $300\,mg$ for $3\,days$ or Nitrofurantoin $100\,mg$ for $5\,days$). Pyelonephritis/Urosepsis (IV Gentamicin or Ceftriaxone).

• Respiratory Infections: CAP (Amoxicillin + Doxycycline); HAP (target $MDR$ organisms like $MRSA/Pseudomonas$).

• Endocarditis: Long-term IV antibiotics ($Benzylpenicillin + Gentamicin$ for synergy). Prophylaxis for high-risk dental procedures using $Amoxicillin\,2g$.

Dermatology

• Therapy: Emollients (repair barrier); TCS (lowest effective potency). Fingertip unit ($FTU$) for dosing.

• Retinoids: Oral ($Isotretinoin$) is highly teratogenic; requires contraception during and after treatment ($3\,years$ for $Acitretin$).

• Acne: Topical BPO/Retinoids (mild); add oral antibiotics ($Doxycycline$) for moderate/severe.

Oncology

• Diagnosis and Staging: TNM system ($Tumour, Node, Metastasis$). Grading ($1–4$) reflects cell abnormality.

• Treatment Modalities: Surgery/Radiation (local); Chemotherapy/Targeted/Immunotherapy (systemic).

• Toxicity: proactive management of N/V (antiemetics), neutropenia (G-CSF), and immune-related adverse events ($irAEs$ - corticosteroids).