Renal pharm

• Why are NSAIDS contraindicated with ACE inhibitors?

  Both drugs act to reduce GFR which could lead to acute renal failure
• Hypertension often exhibits no symptoms, and is risk factor for stroke, heart failure and coronary heart disease.
• TPR (temperature, pressure, respiration) is the predominant determinant of BP
• Secondary hypertension is when high BP is secondary to an abnormality or drug.
• long term hypertension causes target organ damage; exacerbates tissue inflammation, oxid stress, hormones (Ang II)
• Commonly used CV (antihypertensive) drugs

  Angiotensin converting enzyme inhibitors & angiotensin antagonists

  Beta blockers

  Calcium channel blockers

  Diuretics (thiazides, loop, K+ sparing)
• Resistant HTN

  Difficult to lower BP with ≥3 drug types, includes a diuretic

  nonadherence, 2nd HTN, efficacy, adverse effects

  use different drugs

  • Renal denervation of sympathetic nerves in renal artery → decreased BP
• Triple whammy- to avoid

  Potential for acute renal failure in elderly/high risk pt with

  RASi + NSAID + diuretic
• Aliskiren- competitive inhibitor of human renin, inhibits upstream of other RAS components
• Endothelin receptor antagonists cause vasoconstriction and increased blood pressure. Not effective in primary hypertension, used in pulmonary hypertension
• Pulmonary hypertension

  Poor prognosis

  Don't generally respond well to vasodilators, use endothelin blockers such as sildenafil or prostacyclins
• Sympathetic inhibitors for hypertension

  blocks post-synaptic alpha 1 adrenoceptors in smooth muscle vasodilators; add on therapy
• CNS-mediated sympathetic inhibitors

  Brain alpha 2 receptors: reduce CNS sympathetic outflow causing vasodilation

  eg methyl dopa -used in pregnancy-related hypertension (Aldomet)
• Sodium excretion can be increased by:

  increasing filtration

  reducing Na+ reabsorption (which all clinically useful diuretics act on through contraction of extra-cellular fluid compartment)
• Loop diuretics, such as furosemide, act at the thick ascending limb
• Thiazides, such as hydrochlorothiazide, act on the distal convoluted tubule
• K+ sparing diuretics, such as spironolactone, act on the collecting tubule
• Loop or high ceiling diuretics

  Act at the thick ascending limb of the Loop of Henle to block Na+/K+/2Cl- cotransporter

  Blocks 15-25% filtered sodium reabsorption, class with greatest diuretic efficacy

  Causes unwanted potassium loss
• Clinical uses of loop diuretics

  • salt/water (volume) overload associated with oedema:

  • acute pulmonary oedema (emergency), CHF, liver cirrhosis, renal

  failure, (hypertension)

  • used if other diuretics lack sufficient efficacy

  • can be used in combination with thiazides or K-sparing diuretics
• Thiazide

  Act on distal convoluted tubule

  Inhibits NaCl cotransporter

  Modest increase in sodium excretion(5-10%)

  Enhances calcium reabsorption

  Potassium loss
• Therapeutic uses of thiazides

  mild to moderate hypertension

  oedema due to mild to moderate congestive heart failure
• Side effects common to both thiazides and loops include hypokalaemia and hyperuricaemia
• Side effects more common for loops include hypovolaemia (dizziness, weakness, nausea, cramps, hypotension), hearing loss, increased Mg, Ca excretion.
• Drug interaction: Digoxin toxicity increased with loops and thiazides, use K+ supplementation or K+ sparing diuretics
• Symptoms of hypokalaemia

  Cardiac: arrhythmias, increased digoxin toxicity

  Neuromuscular: muscle weakness, constipation

  Neurological: drowsiness, irritability, confusion, dizziness, etc
• To regulate K+ efflux, Na+ is reabsorbed. Aldosterone released from adrenal cortex binds to mineralcorticoid receptor to increase protein synthesis of more Na+ channels, which facilitates in increased Na+ reabsorption, which drives K+ efflux
• Loops and thiazides block upstream at the TAL and DCT respectively. This means there is increased Na+ in the lumen of CT. This drives Na+ reabsorption at the expense of K+ loss (excretion)
• The two classes of potassium-sparing diuretics are aldosterone antagonists (eg spironolactone and eplerenone) and sodium channel blockers (eg amiloride). These act at the late distal tubule / collecting duct
• Aldosterone antagonists block ability of aldosterone to make more Na+ pumps so stopping stopping secretion of K+
• Clinical uses of spironolactone:

  -used in combination with thiazide or loop diuretics to produce diuresis without hypokalaemia

  -used particularly in conditions associated with hyperaldosteronism

  -can be an add-on therapy for treatment of resistant hypertension
• Adverse effects of spironolactone

  hyperkalaemia

  decreased libido, impotence

  menstrual disturbances

  Drug interactions

  other K+ sparing diuretics, K+ supplements, RAS inhibitors
• Eplerenone is a 2nd generation aldosterone receptor antagonist that also decreases mortality/morbidity in CHF

  Furthermore, blocks aldosterone's promotion of fibrosis(ECM deposition)
• Amiloride clinical uses

  -blocks sodium channels in DCT

  -to achieve a potassium-sparing effect in the absence of aldosterone

  -used in combination with loops or thiazide to prevent hypokalaemia during diuretic therapy
• Main adverse effect of amiloride is hyperkalaemia
• Renin angiotensin system inhibition leads to reduced secretion of aldosterone, leading to hyperkalaemia
• K+ balance determined in collecting tubules; depends on:

  -serum concentration K+

  -Na+ concentration presented at the distal tubule

  -level of aldosterone
• Thiazide and loop diuretics cause hypokalaemia

  Aldosterone antagonists and RAS inhibitors cause hyperkalaemia
• Osmotic diuretics

  eg Mannitol

  • acts in whole nephron
  • tubular Na+ diluted and Na+ resorption rate reduced
• Uses of osmotic diuretics

  • not for generalised oedema
  • for localised oedema raised intracranial pressure or glaucoma
• Sodium-glucose cotransporter 2

  • antidiabetic indication
  • diuretic properties because glucose and sodium are linked