Whys & Wherefores in Clinical Pharmacology (1)

1. WHYS AND WHEREFORES IN CLINICAL
PHARMACOLOGY (1)
DR HTET HTET

2. WHY THIAZIDE AND LOOP
DIURETICS CAUSE HYPOKALAEMIA?

3.  Loop diuretics/thiazide
diuretics increase urinary
Na+ excretion
 increased Na+ delivery to the
distal tubule
 increase urinary K+ excretion

4. WHY SPIRONOLACTONE CAUSES
HYPERKALAEMIA?

5.  late distal tubule and collecting duct have a limited capacity to reabsorb
solutes;
 Na+ channel blockade in this part of the nephron increases Na+ and
Cl− excretion rates only mildly (∼2% of filtered load)
 Blockade of Na+ channels hyperpolarizes the luminal membrane
 As a result, opposes cation reabsorption and facilitates cation secretion,
 decreases K+, H+, excretion

6. WHY ACEI CAUSES DRY COUGH?

7. 1.ACE inhibitors
2.Angiotensin receptor blockers
3.Direct renin inhibitors
Cough
• In 5%–20% of patients, ACE inhibitors induce a
bothersome, dry cough mediated by the
accumulation in the lungs of bradykinin,
substance P, or PGs.
• Thromboxane antagonism, aspirin, and iron
supplementation reduce cough induced by ACE
inhibitors.
• ACE dose reduction or switching to an ARB is
sometimes effective.
• Once ACE inhibitors are stopped, the cough
disappears, usually within 4 days.

8. WHY ACEI CAUSES
HYPERKALAEMIA?
Hyperkalemia
Significant K+ retention is rarely encountered in patients with normal renal function. However, ACE
inhibitors may cause hyperkalemia in patients with renal insufficiency or diabetes or in patients
taking K+-sparing diuretics, K+ supplements, β receptor blockers, or NSAIDs.

11. WHY ACEI ARE CI IN RENAL ARTERY
STENOSIS?

12. The blood coming to glomerulus is
supplied by afferent arterioles and
blood going out of glomerulus is
carried by efferent arterioles.
The rate of glomerular filtration
depends on intraglomerular pressure
which in turn depends on the
pressure difference between efferent
and afferent arterioles.

13. For an optimal glomerular filtration rate
(GFR), afferent arterioles should have
low pressure and efferent arterioles
should have high pressure.
At afferent arterioles, prostaglandin I2
commonly called as prostacyclin
maintains low blood pressure by
vasodilatation.
Similarly at efferent arterioles AT II
maintains high blood pressure by
vasoconstriction.
If this physiological mechanism is
disturbed by any drugs may lead to fall in
GFR and subsequent renal failure on long
term.
In renal artery stenosis, the afferent pressure is
reduced by the narrowed vessel, hence autoregulation
is almost exclusively dependent on changes in post-
glomerular arteriolar tone.
Because ACE inhibitors interfere with the production of
angiotensin II, autoregulation is impaired, glomerular
perfusion falls, renal ischaemic nephropathy develops
and renal failure ensues.

16. HOW ACEI CAN DELAY CARDIAC
REMODELING PROCESS?

17.  prevents or delays the progression of heart failure, decreases the incidence of sudden death
and myocardial infarction, decreases hospitalization, and improves quality of life.
 reduces afterload and systolic wall stress, and both cardiac output
 Cause better hemodynamic performance
 increased exercise tolerance and suppression of the sympathetic nervous system
 In heart failure, ACE inhibitors reduce ventricular dilation and tend to restore the heart to its
normal elliptical shape
 ACE inhibitors may reverse ventricular remodeling via changes in preload/afterload by
preventing the growth effects of AngII on myocytes and by attenuating cardiac fibrosis
induced by AngII and aldosterone.

18. WHY ACEIs ARE DRUG OF FIRST
CHOICE FOR HYPERTENSION WITH
DM/NEPHROPATHY?

19.  ACE inhibitors prevent or delay the progression of renal disease, affording renoprotection, as defined by
changes in albumin excretion.
 attenuate the progression of renal insufficiency in patients with a variety of nondiabetic nephropathies.
 Activation AT1 receptor by Ang II
 ctivation of protein kinase signaling cascades,
 cytoskeletal rearrangements,
 retraction of podocyte processes, and
 a reduction in proteins of the slit diaphragm,
 all resulting in increased permeability of the renal epithelium to proteins (proteinuria)
 ACE inhibitors reduce these effects of AngII

20. REFERENCES
 Jackson EK. Drugs Affecting Renal Excretory Function. In: Brunton LL, Hilal-Dandan R, Knollmann
BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill;
. http://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170270388. Accessed March
21, 2019.
 Hilal-Dandan R. Renin and Angiotensin. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman &
Gilman's: The Pharmacological Basis of Therapeutics, 13eNew York, NY: McGraw-Hill;
. http://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170106980. Accessed March
21, 2019.
 https://www.quora.com/Can-clonazepam-cause-hyperkalemia
 https://docksci.com/queue/drug-induced-hyperkalemia_5ac962c9d64ab288796deb68.html
 https://egpat.com/questions/why-potassium-levels-should-be-monitored-in-patients-using-ace-inhibitors
 https://www.gponline.com/ace-inhibitors-renal-artery-stenosis/cardiovascular-system/article/914629