Dopaminergic drugs, Triptans, ARBs, Loop diuretics

Levodopa, ropinirole, and pramipexole are examples of....?

Dopaminergic drugs

What are the common indications for dopaminergic drugs?

1) To improve motor symptoms in Parkinson’s disease.

2) Treating secondary parkinsonism (parkinsonian symptoms due to a cause other than idiopathic Parkinson’s disease)

What is the preferred dopaminergic drug used for PD if motor symptoms are impacting quality of life?

Levodopa

What is the MOA of levodopa in the treatment of PD?

In PD, there is a dopamine deficiency in the nigrostriatal pathway.

L-dopa is a precursor of dopamine that can cross the BBB via membrane transporter.

What is the MOA of ropinirole and pramipexol in the treatment of PD?

They are relative selective agonists for the D2 receptor, which predominated in the striatum.

What are the common side effects of ALL dopaminergic drugs?

Nausea and hypotension.

What side effects are more common with dopamine agonists than levodopa?

Sleepiness, confusion and hallucinations.

What side effect is more common with levodopa agonists than dopamine agonists?

Excessive and involuntary movements (dyskinesias) and the wearing-off effect (worsening of symptoms at the end of dosage interval).

What is the on-off effect and how can you improve its control?

1) A complication of advanced PD causing sudden, unpredictable switches between good mobility (“on”) and severe immobility/ symptoms (“off”).

2) Modified-release formulations may improve control by providing a more continuous supply of dopamine.

When is the use of dopaminergic drug use cautioned? Why?

1) In older people and those with cognitive/psychiatric disease- due to the risk of confusion and hallucinations.

2) In cardiovascular disease due to the risk of hypotension.

Which drugs should not be used with dopaminergic drugs? Why?

First/second generation antipsychotics or metoclopramide because of their opposing effects on dopamine receptors.

Levodopa is always co-formulated with ...? Why?

1) With a peripheral dopa-decarboxylase inhibitor: either benserazide (co-beneldopa) or carbidopa (co-careldopa).

2) To prevent peripheral conversion to dopamine- increases brain availability and reduces side effects.

What should be monitored with dopaminergic drugs?

Blood pressure (especially those with CVD).

Why should you NEVER stop dopaminergic therapy abruptly?

This can precipitate neuroleptic malignant syndrome.

What action may be taken when a patient who normally takes a dopaminergic drug becomes nil-by-mouth/oral route becomes unavailable?

A transdermal dopamine-agonist preparation may be useful.

What is the indication for sumatriptan/zolmitriptan?

To treat the severe symptoms of acute migraine (with or without aura).

MOA of triptans?

1) Inhibiting neurotransmission in the peripheral trigeminal nerve and in the trigeminocervical complex (via 5-HT1B and 5-HT1D receptors).

2) Constricting cranial blood vessels (via 5-HT1B receptors).

What are the common adverse effects of triptans?

Chest and throat discomfort as well as vomiting, tiredness, dizziness and transient high blood pressure.

Rarely, triptans can cause MI and angina, how?

Due to coronary vasospasm.

Due to their vasoconstrictor properties, triptans should NOT be used in which conditions?

IHD, cerebrovascular disease, peripheral vascular disease, uncontrolled HTN, hemiplegic migraine or migraine with brainstem aura.

Triptans may increase the risk of serotonin toxicity and serotonin syndrome when in combination with ... ?

Other serotonergic drugs: MAO inhibitors, tramadol, SSRIs and TCAs.

How should you take oral sumitriptan?

Tablets should be swallowed whole with water.

Can you take paracetamol and/or ibuprofen with triptans?

Yes.

Can you prevent triptans to prevent a migraine attack?

No, it can only be used to treat when a migraine as already started.

What are the first-line preventative treatment options for migraine?

Propranolol, amitriptyline, topiramate and valproate.

What is used if the first-line preventative treatment options for migraine are ineffective?

Monoclonal antibodies that target CGRP (galcanezumab) or its receptor (erenumab), but only under specialist direction.

What are the common indication for ARBs?

1) HTN

2) Chronic HF

3) Secondary prevention of MACE

4) Diabetic neuropathy and CKD with proteinuria.

MOA of ARBs in HTN?

Angiotensin II is a vasoconstrictor and stimulates aldosterone secretion.

Blocking its action reduces peripheral vascular resistance (afterload), which lowers blood pressure

MOA of ARBs in CKD?

Dilates the efferent glomerular arteriole, which reduces intraglomerular pressure and slows the progression of CKD.

MOA of ARBs in CHF?

Reducing aldosterone concentration promotes sodium and water excretion.

This can help to reduce venous return (preload), which has a beneficial effect in heart failure.

What are the main adverse effects of ARBs?

Hypotension (especially after the first dose), hyperkalaemia, and renal failure.

Why can ARBs cause renal failure?

They reduce efferent arteriole constriction, which is needed to maintain glomerular filtration.

Why is renal artery stenosis a particular risk with ARBs?

Because constriction of the efferent glomerular arteriole is required to maintain GFR in renal artery stenosis.

Why do ARBs cause less cough and angioedema than ACE inhibitors?

They do not inhibit ACE and therefore do not affect bradykinin metabolism.

Why may ARBs be preferred in Black people of African or Caribbean origin?

They have a higher risk of angioedema with ACE inhibitors.

Which drugs interact with ARBs? What is the interaction?

Potassium-elevating drugs such as potassium supplements, aldosterone antagonists, and potassium-sparing diuretics.

Combination risks hyperkalemia.

What is the effect of combining NSAIDs with ARBs?

Increased risk of nephrotoxicity.

When should ARBs be avoided?

In renal artery stenosis, AKI and in women who are/can become pregnant or breastfeeding.

When is the best time to take the first dose of losartan/candesartan/irbesartan? Why?

Before bed- to reduce symptomatic hypotension.

How should the efficacy of ARBs be monitored clinically?

By assessing symptoms (e.g. breathlessness in HF) and blood pressure in HTN.

What safety checks are required before starting ARBs?

Electrolytes and renal function.

When should renal function and electrolytes be rechecked after starting or increasing ARBs?

1-2 weeks after initiation and after each dose increase.

What rise in serum creatinine requires stopping ARBs?

An increase of more than 30%.

What fall in eGFR requires stopping ARBs?

A decrease of more than 25%.

What should be done if serum potassium rises above 5.0 mmol/L on ARBs?

Stop other potassium-elevating and nephrotoxic drugs.

What action should be taken if potassium remains >5.0 mmol/L despite stopping interacting drugs?

Reduce the ARB dose.

When should ARBs be stopped due to hyperkalaemia?

If serum potassium exceeds 6.0 mmol/L.

In which patients may ARB doses be reduced or discontinued over time?

Those aged over 80, or who develop frailty or multimorbidity.

What are common indications for loop diuretics?

1) Relief of breathlessness in acute pulmonary oedema with oxygen/nitrates.

2) Symptomatic treatment of fluid overload in CHF.

3) Fluid overload in other oedematous states (renal or liver disease), sometimes combined with other diuretics.

What is the primary site and target of loop diuretics?

Ascending limb of the loop of Henle; they inhibit the Na⁺/K⁺/2Cl⁻ co-transporter.

How does inhibition of the Na⁺/K⁺/2Cl⁻ co-transporter cause diuresis?

Sodium, potassium, and chloride reabsorption is blocked; water follows by osmosis → potent diuretic effect.

What vascular effect do loop diuretics have that is particularly useful in acute heart failure?

Dilation of capacitance veins → reduces preload → improves contractile function of overstretched heart muscle.

What are the common adverse effects of loop diuretics?

Dehydration, hypotension and almost low electrolyte state (hyponatraemia, hypokalaemia, hypochloremia, hypocalcaemia, hypomagnesaemia, and metabolic alkalosis).

How can high doses of loop diuretic affect hearing?

At high doses, they can affect the inner ear Na⁺/K⁺/2Cl⁻ cotransporter → tinnitus or hearing loss.

When are loop diuretics contraindicated?

Severe hypovolemia or dehydration.

In which conditions should loop diuretics be used with caution?

Hypokalaemia, hyponatraemia, people at risk of hepatic encephalopathy (hypokalaemia may worsen coma) and gout.

How can loop diuretic worsen gout?

In chronic use, loop diuretics inhibit uric acid excretion, which can worsen gout.

How do loop diuretics affect lithium therapy?

Can increase lithium levels due to reduced renal excretion.

How do loop diuretics affect digoxin toxicity?

Risk is increased because hypokalemia potentiates digoxin toxicity.

Which drugs have increased ototoxicity or nephrotoxicity when combined with loop diuretics?

Aminoglycosides

How is efficacy of loop diuretics monitored in acute pulmonary oedema?

Improvement in breathlessness, tachycardia, BP, oxygen requirement; urine output increases later.

How is efficacy of loop diuretics monitored over several days?

Body weight (aiming for ≤1 kg/day loss).

What labs should be monitored for safety when using loop diuretics?

Serum sodium, potassium, renal function.

When should loop diuretics be stopped in simple oedema?

After a few days; encourage movement, leg raising, support stockings.

Why might bumetanide be preferred over oral furosemide in severe fluid overload, and what is the equivalent dose?

1) Furosemide absorption is unpredictable due to gut oedema, bumetanide oral bioavailability is more predictable.

2) 1 mg bumetanide ≈ 40 mg furosemide.