Learn — Cardiovascular, diuretic & anticoagulant drugs

12 notes · 35 questions on the topic

Antiplatelet drugs

Antiplatelet drugs prevent the platelet aggregation that builds the white thrombus of arterial disease, and they are the backbone of treatment in acute coronary syndrome, after stenting, and in ischaemic stroke and peripheral arterial disease. They act at four separate points, cyclo-oxygenase, the P2Y12 ADP receptor, phosphodiesterase and the glycoprotein IIb/IIIa receptor, and because the effect of most of them lasts for the life of the platelet, the nursing problem is bleeding that no routine laboratory test will predict.

Aspirin irreversibly acetylates cyclo-oxygenase-1 and abolishes thromboxane A2 production for the platelet's whole 7 to 10 day lifespan: 150 to 325 mg chewed, not enteric-coated, as the loading dose in suspected myocardial infarction, then 75 to 150 mg once daily after food.
Clopidogrel is a prodrug that irreversibly blocks the P2Y12 ADP receptor, loaded at 300 to 600 mg and continued at 75 mg daily; it needs CYP2C19 for activation, so poor metabolisers respond less and omeprazole or esomeprazole should be replaced by pantoprazole.
Ticagrelor, 180 mg loading then 90 mg twice daily, is reversible and faster acting but causes dyspnoea and bradyarrhythmia and must be paired with aspirin no higher than 100 mg daily; prasugrel, 60 mg then 10 mg, is contraindicated after stroke or transient ischaemic attack, above 75 years and below 60 kg.
Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) are intravenous, block the final common pathway of aggregation, are used during percutaneous coronary intervention, and can cause acute profound thrombocytopenia, so the platelet count is checked within hours of starting.
Dipyridamole inhibits phosphodiesterase and adenosine reuptake and is used with aspirin for secondary stroke prevention, causing headache and occasionally angina through coronary steal; cilostazol is used for intermittent claudication and is contraindicated in heart failure.
Dual antiplatelet therapy of aspirin with a P2Y12 inhibitor runs for 12 months after acute coronary syndrome and about 6 months after elective stenting in stable disease, shortened when the bleeding risk is high, after which aspirin alone is continued lifelong.
Monitoring is clinical rather than laboratory: haemoglobin, platelet count, bruising, gum bleeding, haematuria and black stools. There is no INR or aPTT to follow, which is precisely why the nurse's observation is the monitoring parameter.
Contraindications and cautions: active bleeding, peptic ulcer disease, intracranial haemorrhage, severe thrombocytopenia, and aspirin in children under 16 with a viral illness because of Reye syndrome; add a proton pump inhibitor when the gastrointestinal risk is high and avoid combining with NSAIDs.
Aspirin and clopidogrel are stopped about 5 to 7 days before elective surgery, but they are never stopped in the first months after a drug-eluting stent without cardiology advice, because stent thrombosis is frequently fatal.

Thrombolytic therapy — side effects

Thrombolytics are plasminogen activators: they convert plasminogen to plasmin, which digests the fibrin mesh of a formed clot, and they are used for ST-elevation myocardial infarction when primary angioplasty cannot be reached in time, for acute ischaemic stroke within the time window, and for massive pulmonary embolism. Because plasmin cannot tell a coronary thrombus from a haemostatic plug, every serious adverse effect of this class is bleeding, and the one that decides everything is intracranial haemorrhage.

Agents: streptokinase 1.5 million units in 100 mL over 60 minutes, which is cheap, antigenic and not fibrin-specific; alteplase; reteplase as two 10-unit boluses 30 minutes apart; and tenecteplase, 0.5 mg/kg to a maximum of 50 mg as a single bolus over 5 seconds, which is the most practical in a district hospital.
Doses to know: alteplase for stroke is 0.9 mg/kg to a maximum of 90 mg, with 10 per cent as a bolus and the rest over 60 minutes, within 4.5 hours of onset; the accelerated regimen for myocardial infarction is a 15 mg bolus, then 0.75 mg/kg over 30 minutes and 0.5 mg/kg over 60 minutes, to a maximum of 100 mg.
Timing: for ST-elevation myocardial infarction the door-to-needle target is 30 minutes when primary angioplasty cannot be delivered within 120 minutes; for stroke the door-to-needle target is under 60 minutes, and tenecteplase 0.25 mg/kg as a single bolus is now an accepted alternative to alteplase in eligible stroke patients.
The major adverse effect is haemorrhage: intracranial bleeding occurs in under 1 per cent of thrombolysed myocardial infarction patients and in a few per cent of thrombolysed stroke patients, presenting as sudden headache, vomiting, a rise in blood pressure, fresh neurological deterioration or a falling level of consciousness.
Other adverse effects: hypotension and allergic reactions with streptokinase, which is antigenic and must not be repeated between 5 days and about a year after a first dose; reperfusion arrhythmias, most often accelerated idioventricular rhythm, which usually needs no treatment and suggests the artery has opened; bleeding from puncture sites; and systemic embolisation.
Absolute contraindications: any previous intracranial haemorrhage, a known cerebral vascular malformation or intracranial tumour, ischaemic stroke within the last 3 months other than the acute stroke being treated, suspected aortic dissection, active bleeding or a bleeding diathesis, significant closed head or facial trauma within 3 months, and intracranial or intraspinal surgery within 2 months.
Blood pressure is the monitoring parameter with a number: it must be below 185/110 mmHg before thrombolysis for stroke and kept below 180/105 mmHg for the next 24 hours, and severe uncontrolled hypertension is a contraindication in myocardial infarction too.
There is no antidote: when major bleeding occurs the infusion is stopped and the patient is given cryoprecipitate or fibrinogen concentrate, fresh frozen plasma, platelets and tranexamic acid, with an urgent CT head and neurosurgical review.
Nursing during and after the infusion: neurological observations and vital signs every 15 minutes during the infusion and for 2 hours after it, then half-hourly; avoid intramuscular injections, arterial punctures, urinary catheterisation and nasogastric tubes for 24 hours; and give no antiplatelet or anticoagulant for 24 hours after thrombolysis for stroke.
Signs that reperfusion has succeeded in myocardial infarction: the chest pain settles, the ST elevation falls by more than half at 60 to 90 minutes, reperfusion arrhythmias appear and the cardiac markers peak early. Failure means rescue angioplasty, not a second dose.

Vasoconstrictor vs vasodilator

Vasoconstrictors raise systemic vascular resistance by stimulating alpha-1 adrenergic or vasopressin V1 receptors on vascular smooth muscle, and they are used to restore perfusion pressure in shock; vasodilators relax that same muscle through nitric oxide, calcium channel blockade or alpha blockade, and they are used to unload a failing or hypertensive circulation. The distinction that matters at the bedside is preload against afterload: venodilators such as nitroglycerin lower the filling pressure and clear pulmonary oedema, while arterial dilators lower the resistance the ventricle must eject against.

Vasoconstrictors: noradrenaline (alpha-1 with some beta-1, the first choice in septic shock), adrenaline, phenylephrine (pure alpha-1, causing reflex bradycardia and useful in hypotension under spinal anaesthesia), vasopressin and terlipressin acting on V1 receptors, dopamine, and methylergometrine for the uterus.
Vasodilators: nitroglycerin, mainly a venodilator at low dose and an arterial dilator at high dose; sodium nitroprusside, a balanced and almost instantaneous dilator; hydralazine, an arterial dilator used in hypertension of pregnancy; calcium channel blockers such as amlodipine and nifedipine; ACE inhibitors and angiotensin receptor blockers; alpha blockers such as prazosin and phentolamine; and milrinone, an inodilator.
Nitroglycerin is the agent for acute pulmonary oedema and ischaemic chest pain because it drops preload within minutes, but it is absolutely contraindicated within 24 hours of sildenafil or 48 hours of tadalafil, and in right ventricular infarction, where the ventricle depends on preload and the pressure will collapse.
Sodium nitroprusside acts within seconds and stops within seconds, so it runs on a pump with continuous blood pressure monitoring and must be protected from light; prolonged or high-dose use causes cyanide and thiocyanate toxicity with confusion and lactic acidosis, treated with sodium thiosulphate or hydroxocobalamin.
Vasopressors are given ideally through a central line on an infusion pump; that line is never used for a bolus or a flush, the site is inspected hourly, and the drug is weaned rather than stopped abruptly.
Monitoring: continuous or 5-minutely blood pressure with a mean arterial pressure target of at least 65 mmHg for vasopressors, and for vasodilators the blood pressure, heart rate and symptoms, with the infusion slowed or stopped if the systolic falls below the limit written in the prescription.

Digoxin

Digoxin is a cardiac glycoside from Digitalis lanata that inhibits the sodium-potassium ATPase of the myocyte; the resulting rise in intracellular sodium reduces calcium extrusion through the sodium-calcium exchanger, and the extra intracellular calcium gives a positive inotropic effect. It also increases vagal tone and so slows conduction through the atrioventricular node, which means one drug both strengthens the beat and slows the rate, with a therapeutic window so narrow that the nurse's apical pulse count before every dose is part of the prescription.

Indications: rate control in atrial fibrillation, particularly with heart failure or hypotension where beta-blockers are poorly tolerated, and symptomatic heart failure with reduced ejection fraction despite standard therapy, where it reduces hospital admission but not mortality.
Dose: digitalisation, when it is needed, is about 0.75 to 1.5 mg in divided doses over 24 hours, for example 0.5 mg followed by 0.25 mg every 6 hours; maintenance is 0.0625 to 0.25 mg once daily by mouth, reduced in the elderly and in renal impairment. Intramuscular injection is painful and erratic and is not used.
Pharmacokinetics: oral bioavailability about 60 to 80 per cent, onset 1 to 2 hours by mouth and 15 to 30 minutes intravenously, peak effect at 2 to 6 hours, half-life about 36 to 48 hours with normal kidneys and far longer in renal failure, and excretion largely unchanged in the urine.
The therapeutic serum concentration is 0.5 to 2 ng/mL, with 0.5 to 0.9 ng/mL the target in heart failure; the sample is drawn at least 6 hours after a dose and is always read alongside the potassium.
The monitoring parameter before every dose is the apical pulse counted for one full minute: withhold the dose and inform the doctor if it is below 60 per minute in an adult, below 70 in a child or below 90 to 110 in an infant, and record both the rate and the rhythm.
Hypokalaemia is the commonest precipitant of toxicity, because potassium and digoxin compete for the same site on the pump, so digoxin with furosemide, or any vomiting or diarrhoea, must trigger a potassium check.
Interactions: amiodarone, verapamil, quinidine, propafenone, macrolides, itraconazole and spironolactone raise the digoxin level, while antacids, cholestyramine and metoclopramide reduce its absorption.
Early toxicity is anorexia, nausea and vomiting; later come confusion, yellow-green vision with haloes, bradycardia and arrhythmia, and the antidote is digoxin-specific antibody fragments.
Contraindications: ventricular tachycardia or fibrillation, second- or third-degree heart block without a pacemaker, hypertrophic obstructive cardiomyopathy, and atrial fibrillation with Wolff-Parkinson-White syndrome, where slowing the atrioventricular node drives conduction down the accessory pathway.

Diuretics — classes

Diuretics increase urine output by blocking sodium reabsorption at a named point along the nephron, and each class is defined by that point — loop diuretics at the thick ascending limb, thiazides at the distal convoluted tubule, potassium-sparing agents at the collecting duct, carbonic anhydrase inhibitors at the proximal tubule and osmotic agents wherever water can follow. They matter at the bedside because every class moves fluid and electrolytes at the same time, so the daily weight, the intake-output chart and the potassium result are the real monitoring of the drug.

Loop diuretics (furosemide, torsemide, bumetanide) block the Na-K-2Cl carrier in the thick ascending limb, excrete up to a fifth of filtered sodium, still work when the glomerular filtration rate is low, and are the drugs for acute pulmonary oedema, heart failure and the volume overload of renal disease.
Thiazides and thiazide-like drugs (hydrochlorothiazide, chlorthalidone, indapamide, metolazone) block the Na-Cl symporter in the distal convoluted tubule, are moderately potent, lose their effect once the glomerular filtration rate falls below about 30 mL/min, and are first-line antihypertensives that reduce urinary calcium and so protect against calcium stones.
Potassium-sparing drugs act in the collecting duct — spironolactone and eplerenone as aldosterone antagonists, amiloride and triamterene as epithelial sodium channel blockers; they are weak diuretics used to conserve potassium, in resistant hypertension and in the ascites of cirrhosis, and spironolactone and eplerenone improve survival in heart failure.
Acetazolamide inhibits carbonic anhydrase in the proximal tubule, produces an alkaline bicarbonate-rich urine and a self-limiting diuresis as metabolic acidosis develops, and is used in glaucoma, acute mountain sickness and to alkalinise the urine.
Mannitol is filtered and not reabsorbed, holding water osmotically within the tubule; it is given intravenously through a filter set (it crystallises in the cold) to lower raised intracranial and intraocular pressure, and is contraindicated in established anuria, pulmonary oedema and active intracranial bleeding.
The adverse effects that decide nursing action are hypokalaemia with loop and thiazide diuretics (arrhythmia and digoxin toxicity follow), hyperkalaemia with the potassium-sparing group especially alongside an ACE inhibitor, hyponatraemia which is commonest with thiazides in the elderly, and postural hypotension with falls in everyone.
There is no antidote for over-diuresis: the drug is withheld and volume and the missing electrolyte replaced, while dangerous hyperkalaemia from a potassium-sparing agent is treated in the usual sequence of calcium gluconate to protect the myocardium, then insulin with dextrose, then a potassium binder.
Monitoring: daily weight taken the same way each morning (a 1 kg change is about 1 litre of fluid), strict intake and output, postural blood pressure, and serum sodium, potassium, urea and creatinine — the working targets are potassium 3.5 to 5.0 mEq/L and sodium 135 to 145 mEq/L, with about 0.5 to 1 kg of weight loss a day in decompensated heart failure.
Timing and teaching: give the morning dose early and any second dose before late afternoon so the patient is not woken repeatedly, warn about standing up slowly, and keep spironolactone away from potassium supplements and from salt substitutes, which are potassium chloride.

Furosemide (Lasix)

Furosemide is the standard loop diuretic: it blocks the Na-K-2Cl co-transporter in the thick ascending limb of the loop of Henle so that sodium, potassium, chloride, calcium and magnesium are lost in a large, rapid diuresis, and it also produces an early venodilatation that unloads the pulmonary circulation before any urine appears. It matters at the bedside because it is the drug given in acute pulmonary oedema, because its speed makes hypovolaemia and hypokalaemia easy to produce, and because a fast intravenous push can deafen the patient.

Mechanism: furosemide inhibits the Na-K-2Cl carrier in the thick ascending limb so up to a fifth of filtered sodium is excreted, and it increases prostaglandin-mediated venodilatation, which is why breathlessness eases within minutes and before the diuresis begins — an effect that NSAIDs blunt.
Dose and route: the usual adult dose is 20 to 40 mg intravenously or 20 to 80 mg orally, titrated to response and repeated; oral bioavailability is only about 50%, so a patient converted from tablets to injection usually needs roughly half the oral dose intravenously, and a patient already on furosemide needs a higher dose than a diuretic-naive one.
Onset and duration: intravenously it acts within about 5 minutes, peaks near 30 minutes and lasts about 2 hours; orally it acts in 30 to 60 minutes and lasts 6 to 8 hours, so doses are timed to a patient who can reach a toilet and are not given at bedtime.
Rate of injection is a nursing decision that prevents harm: give a bolus slowly, not faster than about 4 mg per minute, which means over at least 1 to 2 minutes for a 40 mg dose, because rapid injection is what causes tinnitus and hearing loss.
The adverse effects that decide nursing action are hypokalaemia with arrhythmia and digoxin sensitivity, hyponatraemia, hypomagnesaemia and hypocalcaemia, hypovolaemia with postural hypotension and prerenal acute kidney injury, metabolic alkalosis, hyperuricaemia that precipitates gout, and hyperglycaemia.
There is no antidote: over-diuresis is reversed by withholding the drug and replacing volume with normal saline together with potassium and magnesium, while ototoxicity is managed by stopping the drug, and an allergic reaction is treated as any drug reaction with intramuscular adrenaline if it is anaphylaxis.
Monitoring: daily weight, strict intake and output, postural blood pressure, serum electrolytes and renal function — the working targets are potassium 3.5 to 5.0 mEq/L, sodium 135 to 145 mEq/L and urine output above 0.5 mL/kg/hour, with a weight loss of about 0.5 to 1 kg a day in decompensated heart failure.
Contraindications are anuria, severe uncorrected hypovolaemia or dehydration, hepatic coma with electrolyte depletion and known hypersensitivity to furosemide; great care is needed alongside an aminoglycoside or cisplatin because the ototoxicity and nephrotoxicity are additive.
The interactions that matter on a ward round are digoxin (hypokalaemia precipitates toxicity), lithium (furosemide raises the lithium level), aminoglycosides (additive ototoxicity), NSAIDs (blunt the diuretic response) and any other antihypertensive (additive postural drop).

Malignant hypertension — pharmacologic management

Malignant hypertension is severe hypertension with acute retinal damage — flame haemorrhages, cotton-wool exudates and papilloedema — and it is one presentation of a hypertensive emergency, which is defined by acute target-organ damage rather than by any particular reading on the cuff. It matters at the bedside because the treatment is a titrated intravenous infusion in a monitored bed and because the commonest harm now comes from lowering the pressure too quickly, not too slowly.

The distinction that governs everything is emergency versus urgency: a hypertensive emergency has acute organ damage — encephalopathy, intracerebral haemorrhage, acute coronary syndrome, pulmonary oedema, aortic dissection, acute kidney injury, eclampsia or malignant retinopathy — and needs intravenous drugs, while a hypertensive urgency is a high pressure without acute damage and is brought down over days with oral drugs.
The general target is a controlled fall: reduce the systolic or mean arterial pressure by no more than about 25% in the first hour, then to roughly 160/100 mmHg over the next 2 to 6 hours, and to normal over 24 to 48 hours, because a faster fall causes cerebral, coronary and renal hypoperfusion and can itself cause a stroke.
The exceptions to that gentle target matter as much as the rule: in aortic dissection the systolic pressure is taken below 120 mmHg within about 20 minutes with an intravenous beta-blocker given before any vasodilator; in eclampsia and severe pre-eclampsia the pressure is lowered promptly with labetalol, nifedipine or hydralazine alongside magnesium sulfate; and in acute ischaemic stroke the pressure is left alone unless it is extremely high or thrombolysis is planned.
Drug choice follows the damaged organ: intravenous labetalol by bolus and infusion is the general-purpose agent, nicardipine or clevidipine titrate smoothly, nitroglycerin is used with myocardial ischaemia or pulmonary oedema, esmolol is used in dissection, hydralazine and labetalol are the pregnancy agents, and phentolamine is used for a catecholamine crisis such as phaeochromocytoma.
Sodium nitroprusside is the fastest-acting and the most hazardous: it is light-sensitive so the bag and tubing are wrapped, it needs continuous arterial pressure monitoring, and it accumulates as thiocyanate and cyanide in renal or hepatic impairment or after prolonged high-dose use, producing metabolic acidosis, confusion and collapse.
Shortcuts are unsafe: sublingual nifedipine capsules cause an uncontrolled precipitous fall and are no longer used, and an oral loading dose given in a corridor is not a substitute for a titratable infusion in a monitored bed.
Monitoring: continuous ECG with either an arterial line or cuff readings every 5 to 15 minutes while the infusion is titrated, hourly urine output aiming above 0.5 mL/kg/hour, hourly neurological observation, and serial creatinine, electrolytes, troponin and fundoscopy — and the baseline pressure is written down first so the 25% floor can be calculated.
Once the crisis is controlled the cause is addressed: stopping medication is by far the commonest reason in Indian practice, and secondary causes such as renal artery stenosis, primary aldosteronism, phaeochromocytoma, cocaine or other sympathomimetics and pre-eclampsia are looked for before discharge.
The transition matters too: oral therapy is started and overlapped before the infusion is weaned, and the patient leaves with a written plan, a supply of tablets and an explanation that stopping them is what brought them in.

Beta-blockers — cautions

Beta-blockers competitively occupy beta-adrenergic receptors, so beta-1 blockade slows the heart, weakens contraction, delays atrioventricular conduction and reduces renin release, while beta-2 blockade constricts the airway and blunts the body's recovery from hypoglycaemia. They matter at the bedside because the pulse and blood pressure taken before each dose are what prevent harm, because they are dangerous in an asthmatic and in decompensated heart failure, and because stopping them suddenly causes a rebound that can end in myocardial infarction.

Selectivity decides safety: cardioselective beta-1 agents are metoprolol, bisoprolol, atenolol, nebivolol and esmolol; non-selective agents are propranolol, nadolol, timolol and sotalol; and labetalol and carvedilol also block alpha receptors — but selectivity is relative and is lost at high dose.
Common adult doses are metoprolol succinate 25 to 200 mg once daily, bisoprolol 2.5 to 10 mg once daily, atenolol 25 to 100 mg once daily and propranolol 40 mg two or three times daily; for rate control under monitoring, intravenous metoprolol is given as 5 mg by slow injection repeated at 5-minute intervals to a total of 15 mg, and in heart failure the starting dose is very small and is doubled no sooner than every two weeks.
Onset and duration: oral beta-blockade begins within 1 to 2 hours and the once-daily agents last a full day, while intravenous esmolol acts within about a minute and is gone within about 10 minutes, which is why it is chosen when the block may have to be withdrawn quickly.
The adverse effects that decide nursing action are bradycardia and heart block, hypotension, bronchospasm in the patient with airway disease, decompensation of heart failure when the dose is raised too fast, fatigue, cold extremities, vivid dreams and low mood, sexual dysfunction, and the masking of every warning symptom of hypoglycaemia except sweating.
The antidote in symptomatic bradycardia or overdose is atropine first and then glucagon, which raises heart rate and contractility by bypassing the blocked receptor; high-dose insulin with euglycaemia, calcium, vasopressors and pacing follow if that fails.
Monitoring before every dose: count the apical pulse for a full minute and take the blood pressure, and withhold the dose and inform the doctor if the pulse is below about 60 per minute or the systolic pressure below about 100 mmHg unless the prescriber has written a different limit; in heart failure weigh daily and watch for rising weight, oedema and breathlessness during up-titration.
Contraindications and cautions: severe asthma or active bronchospasm for the non-selective agents, second- or third-degree heart block and sick sinus syndrome without a pacemaker, marked sinus bradycardia, cardiogenic shock and decompensated heart failure; they worsen peripheral arterial disease and Raynaud phenomenon, and they are avoided in cocaine-associated chest pain because of unopposed alpha stimulation.
A beta-blocker is never stopped abruptly: withdrawal causes rebound tachycardia, hypertension, angina and even infarction, so the dose is tapered over one to two weeks and the patient is taught never to run out of tablets.
In a diabetic on insulin a non-selective beta-blocker hides the tremor and palpitations of a hypo and can prolong the episode, so a cardioselective agent is preferred and the patient is taught to rely on sweating and on glucose testing rather than on how they feel.

ACE inhibitors — side effects

ACE inhibitors block angiotensin-converting enzyme so that less angiotensin II is formed: arterioles dilate, aldosterone falls, sodium and water are lost and potassium is retained. Because the same enzyme also degrades bradykinin, that peptide accumulates, and it is bradykinin — not the blood pressure effect — that produces the two adverse effects the nurse must recognise, the dry cough and the airway-threatening angio-oedema.

The agents are the -pril group: enalapril 2.5 to 20 mg twice daily, ramipril 1.25 to 10 mg once daily, lisinopril 2.5 to 40 mg once daily and captopril 6.25 to 50 mg three times daily; the first dose is small and often given at bedtime because of first-dose hypotension, and captopril alone is taken an hour before food.
Onset and duration: captopril acts within 15 to 30 minutes and lasts 6 to 8 hours, while enalapril, ramipril and lisinopril act over 1 to 2 hours and last a full day, so the once-daily agents are used for maintenance and captopril when a short-acting trial is wanted.
They are first-line in hypertension, in heart failure with reduced ejection fraction and after myocardial infarction, and they slow the progression of diabetic and proteinuric kidney disease — which is why a small early rise in creatinine after starting them is expected rather than a reason to stop.
The adverse effects that decide nursing action are angio-oedema of the lips, tongue and larynx (life-threatening, commonest in the first weeks but possible after years of use), a persistent dry irritating cough in up to a fifth of patients, hyperkalaemia, first-dose and postural hypotension, acute kidney injury in bilateral renal artery stenosis or volume depletion, taste disturbance and rash with captopril, and fetal injury in pregnancy.
There is no specific antidote: the drug is stopped, angio-oedema is managed as an airway emergency with oxygen, intramuscular adrenaline as ordered and early anaesthetic help — recognising that the response may be poor because the swelling is bradykinin-mediated rather than histamine-mediated — and hyperkalaemia is treated with calcium gluconate, then insulin with dextrose, then a potassium binder.
Monitoring: check serum potassium and creatinine before starting and again within one to two weeks of starting or of any dose increase; a creatinine rise of up to about 30% above baseline is acceptable and the drug is continued, while a larger rise, or a potassium above 5.5 mEq/L, means the dose is withheld and the doctor informed, and blood pressure is measured lying and standing after the first dose.
Absolute contraindications are pregnancy in any trimester (fetal renal failure, oligohydramnios, skull hypoplasia and death), previous angio-oedema on any ACE inhibitor, and bilateral renal artery stenosis; an ACE inhibitor is not combined with an angiotensin receptor blocker, and a 36-hour washout is required before starting sacubitril-valsartan because the overlap causes angio-oedema.
Interactions that matter on the drug round: potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes and trimethoprim all raise the potassium, lithium levels rise, and the combination of an ACE inhibitor, a diuretic and an NSAID is the triple whammy that precipitates acute kidney injury.
The dry cough is a class effect that does not respond to antitussives, and the correct action is to switch to an angiotensin receptor blocker such as losartan or telmisartan, which blocks the receptor without raising bradykinin.

Warfarin — INR targets

Warfarin is an oral vitamin K antagonist: it blocks vitamin K epoxide reductase so the liver cannot carboxylate clotting factors II, VII, IX and X or proteins C and S, and its effect is measured entirely by the INR because there is no fixed dose. It matters at the bedside because the therapeutic window is narrow, because dozens of drugs and a change in green vegetables will move the INR, and because the difference between a target INR and a high one is the difference between a prevented stroke and an intracranial bleed.

Mechanism and delay: the clotting factors already in the circulation must be cleared before warfarin works, so the INR starts to move in 24 to 36 hours as factor VII falls but full antithrombotic effect takes 3 to 5 days until prothrombin is depleted; after stopping, the effect persists 2 to 5 days, which is why elective surgery needs the drug stopped about 5 days beforehand.
Dose and route: maintenance in an adult is usually 2 to 10 mg orally once daily at the same time each evening, started without a loading dose in most patients and adjusted entirely on the INR result.
Protein C has a short half-life and falls first, so the first days of warfarin are transiently prothrombotic and can cause skin necrosis; a patient with acute thrombosis is therefore overlapped with heparin or low-molecular-weight heparin for at least 5 days and until the INR has been 2 or above for 24 hours.
Target INR is 2.0 to 3.0 for atrial fibrillation, venous thromboembolism and a bioprosthetic valve, and 2.5 to 3.5 for most mechanical valves, particularly in the mitral position; the INR is checked frequently at initiation and, once stable, at intervals of up to about 4 weeks.
The adverse effect that decides nursing action is bleeding — gum and nose bleeding, bruising, haematuria, melaena and heavy menstrual loss, with intracranial and retroperitoneal haemorrhage as the dangerous forms; the other effects are warfarin-induced skin necrosis in the first days, purple toe syndrome and embryopathy.
The antidote is vitamin K (phytomenadione), with the dose and route chosen by the situation: a low oral dose for a very high INR without bleeding, and slow intravenous vitamin K together with four-factor prothrombin complex concentrate — or fresh frozen plasma where concentrate is unavailable — for serious or life-threatening bleeding, while a moderately raised INR without bleeding is usually managed by withholding doses alone.
Monitoring is the INR derived from the prothrombin time, and nothing else: daily at initiation, then twice weekly, then up to monthly when stable, with the result acted on before the next dose is due and every result written where the prescriber will see it.
Warfarin has more clinically important interactions than almost any other drug: it is potentiated by amiodarone, metronidazole, fluconazole, co-trimoxazole, ciprofloxacin, NSAIDs and binge alcohol, and antagonised by rifampicin, carbamazepine, phenytoin and a sudden increase in vitamin K rich foods such as spinach, cabbage and broccoli — the teaching is a steady intake, not avoidance.
Contraindications are pregnancy, especially the first trimester and near delivery, active major bleeding, severe uncontrolled hypertension, and a patient who cannot attend for INR monitoring; intramuscular injections are avoided in anyone taking it, and the patient carries an anticoagulant card.

Heparin — monitoring

Heparin is an indirect anticoagulant: it binds antithrombin and accelerates its inactivation of thrombin and factor Xa several thousandfold, so an existing clot is prevented from growing while the body's own fibrinolysis clears it. It matters at the bedside because unfractionated heparin has an unpredictable response that must be steered by the activated partial thromboplastin time, and because its immune complication, heparin-induced thrombocytopenia, presents as new clotting rather than as bleeding.

Mechanism and difference between preparations: unfractionated heparin inhibits both thrombin (IIa) and factor Xa, low-molecular-weight heparins such as enoxaparin act mainly on Xa, and fondaparinux acts only on Xa; none of them dissolves an existing clot, so a thrombolytic is a different class altogether.
Dose and route: treatment with unfractionated heparin is a weight-based intravenous bolus followed by a continuous infusion titrated on a nomogram, while prophylaxis is 5000 units subcutaneously every 8 to 12 hours; unfractionated heparin is the agent chosen in renal failure and when the effect may have to be switched off quickly.
Onset and duration: intravenous unfractionated heparin acts immediately and its effect is gone within 1 to 2 hours of stopping the infusion, whereas subcutaneous low-molecular-weight heparin peaks at 3 to 5 hours and lasts about 12 hours, which is why it is given once or twice a day.
Monitoring unfractionated heparin is the activated partial thromboplastin time with a therapeutic target of about 1.5 to 2.5 times the laboratory control value; it is checked about 6 hours after starting and 6 hours after every rate change, then at least daily once stable, and the result is seen before the rate is altered.
Low-molecular-weight heparin has a predictable dose-response and needs no routine monitoring; anti-factor-Xa activity is measured only in pregnancy, obesity, renal impairment and children, and the dose is reduced when the creatinine clearance falls below about 30 mL/min.
The adverse effects that decide nursing action are bleeding, heparin-induced thrombocytopenia, and, on long-term use, osteoporosis and hyperkalaemia from aldosterone suppression; a baseline platelet count is taken and monitored during therapy.
Heparin-induced thrombocytopenia is an immune reaction appearing at day 5 to 10 (sooner on re-exposure) with a fall in platelets of 50% or more, and its danger is thrombosis rather than bleeding; every source of heparin including flushes and heparin-bonded lines is stopped, a non-heparin anticoagulant such as argatroban or fondaparinux is started, and platelets are not transfused.
The antidote is protamine sulfate, roughly 1 mg for every 100 units of unfractionated heparin given in the preceding hours, injected slowly because rapid injection causes hypotension, bradycardia and anaphylactoid reactions; it only partly reverses low-molecular-weight heparin and does not reverse fondaparinux.
Contraindications are active major bleeding, previous heparin-induced thrombocytopenia, severe uncontrolled hypertension and recent neurosurgery or intracranial haemorrhage; unlike warfarin, heparin does not cross the placenta and is the anticoagulant of choice in pregnancy.
Administration detail matters: subcutaneous heparin goes into abdominal fat at least 5 cm from the umbilicus at 90 degrees, without aspirating and without massaging afterwards, with sites rotated, and it is never given intramuscularly because of haematoma.

Nitroglycerin

Nitroglycerin is an organic nitrate that is denitrated inside vascular smooth muscle to nitric oxide, which raises cyclic GMP and relaxes the vessel — capacitance veins far more than arteries. It matters at the bedside because that venodilatation drops preload and so cuts myocardial oxygen demand within a minute or two, which is why it is the first drug reached for in angina and in acute pulmonary oedema; the same fall in preload is what makes it dangerous in a right-ventricular infarct or after a phosphodiesterase-5 inhibitor.

Mechanism: nitroglycerin is a prodrug — mitochondrial aldehyde dehydrogenase releases nitric oxide, which activates guanylyl cyclase, raises cyclic GMP and dephosphorylates myosin light chains; venodilatation predominates, so preload falls before afterload does.
Adult dose and route: 0.4 mg sublingually (0.5 mg is the common Indian tablet strength; the usual range is 0.3–0.6 mg), one dose repeated every 5 minutes to a maximum of three doses. If pain persists after three doses over 15 minutes treat it as an acute coronary syndrome. The intravenous infusion starts at 5 µg/min and is titrated up in 5–10 µg/min steps, and transdermal patches deliver 5–15 mg over 12 hours.
Onset and duration: sublingual onset in 1–3 minutes, peak at about 5 minutes and duration 20–30 minutes; the intravenous infusion acts within 1–2 minutes and wears off within 5–10 minutes of stopping, which is why it is the vasodilator of choice when the blood pressure may have to be taken back quickly.
The adverse effect that decides nursing action is hypotension with reflex tachycardia, along with a throbbing headache, flushing and dizziness. Give the dose with the patient seated or lying, record the blood pressure before every dose, and withhold it if the systolic pressure is below 90 mmHg or has fallen more than 30 mmHg below baseline.
Contraindications: systolic blood pressure below 90 mmHg, right-ventricular infarction complicating an inferior wall myocardial infarction (that ventricle is preload dependent), severe aortic stenosis, hypertrophic obstructive cardiomyopathy, raised intracranial pressure, and a phosphodiesterase-5 inhibitor taken within 24 hours (sildenafil, vardenafil) or 48 hours (tadalafil).
Monitoring parameter with its target: continuous blood pressure and heart rate — keep the systolic above 90 mmHg and the mean arterial pressure at 65 mmHg or more; in a hypertensive emergency lower the mean arterial pressure by no more than 25% in the first hour, and stop the infusion if the heart rate rises above 100/min with a falling pressure.
Tolerance appears within 24 hours of continuous exposure; a nitrate-free interval of 8–12 hours each day (patch off at night, eccentric oral dosing at 8 a.m. and 2 p.m.) restores the response, and abrupt withdrawal in a long-term user can provoke coronary spasm.
There is no reversal agent — the short half-life is the antidote. Nitrate hypotension is treated by stopping the drug, laying the patient flat with the legs raised and giving an intravenous crystalloid bolus; very high doses can cause methaemoglobinaemia, which is treated with methylene blue 1–2 mg/kg intravenously.
Handling: sublingual tablets are kept in the original dark glass bottle, tightly closed, away from heat and light, and are replaced every 6 months once opened; nitroglycerin is adsorbed by polyvinyl chloride, so an infusion runs in glass or non-PVC tubing through an infusion pump.

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