Cardiovascular

Competitive β-adrenergic antagonists that blunt Gs–cAMP signalling in the heart and kidney. β1 selectivity, partial agonism (ISA), α1 or nitric-oxide vasodilation and the route of elimination tell the ten drugs apart.

Each pressor or inotrope is a receptor recipe: α1 and V1 receptors signal through Gq (IP3, calcium) to constrict vessels, β1 through Gs and cAMP to speed and strengthen the heart, β2 through cAMP to relax smooth muscle. Milrinone reaches the same cAMP by blocking PDE3, and oral midodrine is a prodrug of an α1 agonist. Baroreceptor reflexes decide what happens to heart rate.

Competitive inhibitors of the zinc metallopeptidase ACE (kininase II): less angiotensin II, more bradykinin. Prodrug status, the sulfhydryl group, renal versus hepatic handling and the one IV agent tell the four drugs apart.

Selective AT1-receptor antagonists: angiotensin II is still made — renin and angiotensin II even rise — but cannot reach AT1. Prodrug activation, losartan’s active metabolite and uricosuric effect, and olmesartan’s enteropathy tell the drugs apart.

Anions secreted into the tubule that block NKCC2 in the thick ascending limb, the segment that reclaims about a quarter of filtered sodium and builds the medullary gradient. Bioavailability, metabolic route, half-life and the one non-sulfonamide agent tell the four drugs apart.

Competitive blockers of the Na-Cl cotransporter (NCC) in the distal convoluted tubule. The same site explains calcium retention, the dilution defect behind hyponatremia, and the hypokalemia-driven fall in insulin release; thiazide-like agents last longer and keep working at low GFR.

Two routes to the same channel: mineralocorticoid-receptor antagonists (spironolactone, eplerenone) and ENaC blockers (amiloride, triamterene). Both shut down electrogenic sodium entry in the aldosterone-sensitive distal nephron, so K⁺ and H⁺ secretion fall.

Block the L-type calcium channel. Dihydropyridines bind the inactivated channel in depolarized vascular smooth muscle and dilate arterioles; verapamil and diltiazem bind the open channel in the SA and AV nodes and slow rate and conduction.

Four ways around the first-line drugs: alpha-1 blockers relax arterioles and the prostate; clonidine and methyldopa (via a false transmitter) cut sympathetic outflow from the brainstem; hydralazine, minoxidil and nitroprusside relax vascular smooth muscle directly and provoke a reflex response; aliskiren inhibits renin itself.

Pulmonary arterial hypertension drugs correct three endothelial signals: endothelin receptor antagonists block endothelin-1 at ETA (with or without ETB) receptors; PDE-5 inhibitors and the sGC stimulator riociguat raise cGMP; epoprostenol and treprostinil raise cAMP through the IP receptor. The signature hazards follow from those mechanisms — ERA and riociguat teratogenicity, cGMP-stacking hypotension with nitrates, PDE-6 color-vision changes, and rebound when a short-lived prostacyclin stops.

Prodrugs of nitric oxide: bioactivated (ALDH2) to NO, which turns on soluble guanylate cyclase, raises cGMP and dephosphorylates myosin light chains. Veins dilate most and preload falls. The same cGMP pathway explains the PDE5-inhibitor danger, while tolerance demands daily nitrate-free intervals and nitrate ions cause methemoglobinemia in overdose.

Ranolazine inhibits the late sodium current of ischemic myocytes, which lowers intracellular sodium and, through the Na⁺–Ca²⁺ exchanger, calcium overload — reducing wall tension and oxygen use without changing heart rate, blood pressure or the rate-pressure product. It also blocks IKr (QT prolongation) and is a CYP3A and P-gp substrate, so drug interactions set its level.

Digoxin reversibly inhibits the Na⁺/K⁺-ATPase: retained sodium leaves more calcium in the myocyte (inotropy, and at toxic levels afterdepolarizations), while indirect vagal stimulation slows the SA and AV nodes. P-glycoprotein, renal clearance and electrolytes move a narrow window; digoxin Fab reverses toxicity but confounds the serum level.

Empagliflozin and dapagliflozin block SGLT2, the proximal-tubule transporter that reclaims most filtered glucose, so glucose and sodium leave in the urine. The glucosuria lowers blood glucose; the natriuresis lowers cardiac preload and intraglomerular pressure — the basis of the heart-failure and kidney indications — while the same glucose-rich urine and ketone shift explain genital infections, Fournier’s gangrene and euglycemic ketoacidosis.

Three targets in heart failure: neprilysin inhibition keeps natriuretic peptides active while valsartan blocks the extra angiotensin II; ivabradine blocks the sinoatrial If current to slow the rate without weakening contraction; vericiguat stimulates soluble guanylate cyclase to restore cGMP.

Antiarrhythmics are sorted by the current they change: class I blocks the sodium upstroke (phase 0), class II blunts sympathetic cAMP, class III blocks potassium repolarization (phase 3, the QT), and class IV blocks the calcium current that drives the nodes.

Statins competitively inhibit HMG-CoA reductase, the committed step to mevalonate; the hepatocyte senses less cholesterol, activates SREBP and makes more LDL receptors, which clear LDL from the blood. Lipophilicity, CYP3A4 versus non-CYP3A4 clearance and the OATP1B1 transporter (gene SLCO1B1) decide exposure — and exposure drives myopathy.

Evolocumab and alirocumab bind circulating PCSK9, so LDL receptors recycle to the hepatocyte surface instead of being degraded; more receptors clear more LDL. Statins raise PCSK9 activity, which is why the antibodies add to them — and why patients with two LDL-receptor-negative alleles do not respond.

Fibrates are PPAR-α agonists: the activated nuclear receptor raises lipoprotein lipase, lowers apolipoprotein C-III and boosts fatty-acid oxidation, so triglyceride-rich VLDL is cleared and triglycerides fall. Gemfibrozil also blocks OATP1B1, a transporter many statins are substrates of — the reason it is the dangerous statin partner — and is a strong CYP2C8 inhibitor.

Positively charged, non-absorbed resins bind bile acids in the gut and break the enterohepatic cycle. The liver disinhibits cholesterol 7-α-hydroxylase to rebuild the pool, upregulates LDL receptors and pulls LDL from plasma while making more cholesterol; serum triglycerides may rise. Everything else (constipation, vitamin and drug binding, chloride acidosis) follows from a resin that never leaves the gut.

Six drugs, six steps: ezetimibe blocks intestinal cholesterol uptake (NPC1L1); bempedoic acid blocks ATP-citrate lyase upstream of HMG-CoA reductase, but only in liver; inclisiran silences PCSK9 mRNA; niacin and icosapent ethyl cut VLDL-triglyceride output; lomitapide blocks MTP, the protein missing in abetalipoproteinemia.

Anticoagulants hit the cascade at three kinds of point: warfarin stops vitamin K recycling so II, VII, IX and X are made inactive; heparin, LMWH and fondaparinux make antithrombin work harder; and the direct inhibitors block factor Xa or thrombin themselves.

Platelets amplify their own activation through thromboxane A₂ (made by COX-1) and ADP (acting on P2Y12), then link together through GP IIb/IIIa and fibrinogen. Aspirin and the thienopyridines inhibit irreversibly, for the platelet’s 7–10-day life; ticagrelor, cangrelor and the GP IIb/IIIa blockers are reversible; clopidogrel needs CYP2C19 to become active.

Recombinant tissue plasminogen activators convert fibrin-bound plasminogen to plasmin, which digests the fibrin mesh of a formed clot. Fibrin specificity keeps most of the action at the clot, but systemic plasmin still lowers fibrinogen — so bleeding is the price, cryoprecipitate and lysine-analog antifibrinolytics are the counter-moves, and tenecteplase’s engineered PAI-1 resistance and longer half-life allow a single bolus.