Pulmonary oedema

Question 1

Loop diuretics

Common indication

Answer 1

1. Relief of breathlessness in acute pulmonary oedema in conjunction with oxygen and nitrates
2. Symptomatic treatment of fluid overload in chronic HF
3. Treatment of fluid overload in other oedematous states e.g. liver or renal disease

Question 2

Loop diuretics

MOA

Answer 2

• As their name suggests, loop diuretics act principally on the ascending limb of the loop of Henle, where they inhibit the Na+/K+/2Cl−cotransporter.
• This protein is responsible for transporting sodium, potassium and chloride ions from the tubular lumen into the epithelial cell.
• Water then follows by osmosis. Inhibiting this process has a potent diuretic effect.
• In addition, loop diuretics have a direct effect on blood vessels, causing dilatation of capacitance veins.
• In acute heart failure, this reduces preload and improves contractile function of the ‘overstretched’ heart muscle.
• Indeed, this is probably the main benefit of loop diuretics in acute heart failure, as illustrated by the fact that the clinical response is usually evident before a diuresis is established.

Question 3

Loop diuretics

Adverse effects

Answer 3

• Water losses due to diuresis can lead to dehydration and hypotension. Inhibiting the Na+/K+/2Cl− co-transporter increases urinary losses of sodium, potassium and chloride ions.
• Indirectly, this also increases excretion of magnesium, calcium and hydrogen ions.
• You can therefore associate loop diuretics with almost any low electrolyte state (i.e. hyponatraemia, hypokalaemia, hypochloraemia, hypocalcaemia, hypomagnesaemia and metabolic alkalosis).
• A similar Na+/K+/2Cl− co-transporter is responsible for regulating endolymph composition in the inner ear. At high doses, loop diuretics can affect this too, leading to hearing loss and tinnitus.

Question 4

Loop diuretic

Warnings

Answer 4

• Loop diuretics are contraindicated in patients with severe hypovolemia or dehydration.
• They should be used with caution in patients at risk of hepatic encephalopathy (where hypokalaemia can cause or worsen coma) and those with severe hypokalaemia and/or hyponatraemia.
• Taken chronically, loop diuretics inhibit uric acid excretion and this can worsen gout.

Question 5

Loop diuretics

Interactions

Answer 5

• Loop diuretics have the potential to affect drugs that are excreted by the kidneys.
• For example, lithium levels are increased due to reduced excretion.
• The risk of digoxin toxicity may also be increased, due to the effects of diuretic-associated hypokalaemia.
• Loop diuretics can increase the ototoxicity and nephrotoxicity of aminoglycosides
• NB- only monitoring needed is U&E regularly in treatment

Question 6

Nitrates

Common indications

Answer 6

1. Short-acting nitrates (glyceryl trinitrate) are used in the treatment of acute angina and chest pain associated with the acute coronary syndrome.
2. Long-acting nitrates (e.g. isosorbide mononitrate) are used for prophylaxis of angina where a β-blocker and/or a calcium channel blocker are insufficient or not tolerated.
3. Intravenous nitrates are used in the treatment of pulmonary oedema, usually in combination with furosemide and oxygen.

Question 7

Nitrates

MOA

Answer 7

• Nitrates are converted to nitric oxide (NO). NO increases cyclic guanosine monophosphate (cGMP) synthesis and reduces intracellular Ca2+ in vascular smooth muscle cells, causing them to relax.
• This results in venous and, to a lesser extent, arterial vasodilatation. Relaxation of the venous capacitance vessels reduces cardiac preload and left ventricular filling.
• These effects reduce cardiac work and myocardial oxygen demand, relieving angina and cardiac failure.
• Nitrates can relieve coronary vasospasm and dilate collateral vessels, improving coronary perfusion.
• They also relax the systemic arteries, reducing peripheral resistance and afterload. However, most of the anti-anginal effects are mediated by reduction of preload.

Question 8

Nitrates

Adverse effects

Answer 8

• As vasodilators, nitrates commonly cause flushing, headaches, light-headedness and hypotension.
• Sustained use of nitrates can lead to tolerance, with reduced symptom relief despite continued use.
• This can be minimised by careful timing of doses to avoid significant nitrate exposure overnight when it tends not to be needed.

Question 9

Nitrates

Warnings

Answer 9

• Nitrates are contraindicated in patients with severe aortic stenosis, in whom they may cause cardiovascular collapse.
• This is because the heart is unable to increase cardiac output sufficiently through the narrowed valve area to maintain pressure in the now dilated vasculature.
• Nitrates should also be avoided in patients with haemodynamic instability, particularly hypotension.

Question 10

Nitrates

Interactions

Answer 10

• Nitrates must not be used with phosphodiesterase inhibitors (e.g. sildenafil) because these enhance and prolong the hypotensive effect of nitrates.
• Nitrates should also be used with caution in patients taking antihypertensive medication, in whom they may precipitate hypotension.