ACE inhibitors

introduction:

ACE is an enzyme that converts:
- inactive angiotensin I → vasoconstrictor peptide angiotensin II;
- vasodilator peptide bradykinin → inactive fragments;
ACE is found in endothelial cells lining all blood vessels as well as in the lung, brain, kidney, adrenals, GIT, & reproductive system;
ACE inhibition thus:
- interrupts renin-angiotensin-aldosterone cascade →
  - decr. circulating angiotensin II → vasodilatation & decr. symp.N.S.;
    - decr. aldosterone secretion → short-term natriuresis & decr. K losses;
    - ⇒ incr. renin levels;
  - decr. local tissue angiotensin II
    - → decr. GFR esp. if GFR dependent on AG-II maintaing efferent tone:
    - eg. low RBF such as renal artery stenosis esp.bilat.;
- inhibition of bradykinin breakdown → incr. PG production → vasodil.;
  - may result in bradykinin local XS:
    - coughing (1-13%);
    - angioedema (v.rare) - see hereditary angioedema (HAE);
- THUS → vasodilatation → decr. TPR → hypotension;
- NB.in HT:
  - C.O., LVEDF, HR unchanged;
  - HR not changed as decr. resetting baro. & incr. vagal
- NB. in CCF:
  - HR unchanged but decr. LVEDF → incr. C.O.
- BUT:
  - peripheral blood flow, esp. cerebral is maintained;
  - normal haemodynamic response to exercise/stress/GA maintained;
  - postural effects are minimal unless hypovolaemia is present;

ACE inhib. are effective, well tolerated in most types & grades of severity of hypertension & in mild-severe essential HT are as potent & effective single agent Rx as beta-blockers or diuretics;
Their efficacy can be improved by combination with a low Na diet, or a K-losing diuretic or Ca antagonist.
They are ideal in the elderly except care if renal impairment or extensive vascular disease;

ACE inhib. lower BP smoothly & rapidly within 20min (captopril) & 1hr (enalapril) whilst maintaining cerebral & renal blood flow but care with dosage as the hypovolaemia potentiates hypotensive effect of ACE inhib.

As HT in this case is Renin-AG dependent, ACE inhib. are very effective & the Rx of choice for unilat.renal A stenosis whilst awaiting Sx but may precipitate ARF if bilat. stenoses or stenosis to sole kidney as there will not be any compensatory incr. GFR in good kidney to maintain renal function!!

ACE inhib. effective as also maintains RBF & control BP without significant hypovolaemia & may slow the decline in renal function in diabetic nephropathy.
Not for pregnancy as teratogenic!

with diuretics:
- NEVER with K-sparing diuretics!!!!
- K-losing diuretics good in CCF or essential HT;
with calcium channel blockers:
- good in HT with IHD or if severe/resistant HT;
with beta-blockers:
- not particularly effective;
with alpha-blockers:
- potent combination (eg. prazosin);
- but rarely necessary as high risk of hypotension;

Impaired renal function:
- bilat. renal A stenosis or stenosis lone kidney → reversible ARF;
- most ACE inhib. are renally excreted;
- occasional incr. urea/CRN assoc. with ACE inhib. may indicate decr. dose needed;
Hyperkalaemia:
- avoid using K-sparing diuretics as well;
- esp. if: renal insuff.; D.M.; K supplements;
Impaired liver function:
- Reversible abn. LFT's have occurred during Rx with ACE inhib.
- Use with care if impaired liver function;
General Anaesthesia:
- Agents that produce hypotension which is normally compensated by renin release may produce uncompensated hypotension if ACE inhib.
Persistent cough esp. females & on lying down may need decr. dose or cessation;
Safety not established in children;
Best to withdraw drugs that raise plasma renin levels before commencing ACE inhibitors, for example: diuretics, potent vasodilators;

diuretics: additive effects, beware incr. K with K-sparing or oral K supplements;
lithium carbonate: lithium excretion may be decr. as well as Na;
non-steroidal anti-inflammatory drugs (NSAIDs): may decr. anti-HT effects of ACE inhib.
SPPS: as contains pre-kallikrein, may cause hypotension;

1898, renin is discovered and appeared to increase blood pressure
1939, renin was found not to cause the rise in blood pressure, but was an enzyme which catalyzed the formation of the substances that were responsible, namely, angiotensin I (Ang I) and Ang II
1976, the 1st ACEI was captopril was synthesized
- developed following research into the hypotensive effects of the Brazilian Pit Viper snake venom
enalapril, patented in 1978 and approved for medical use in 1984
lisinopril, patented in 1978 and approved for medical use in the United States in 1987
1979, saralasin synthesized as an analogue of angiotensin II but with competitive angiotensin II receptor antagonist activity
perindopril (Coversyl), patented in 1980 and approved for medical use in 1988
quinapril, patented in 1980 and came into medical use in 1989
ramipril, patented in 1981 and approved for medical use in 1989
benazepril, patented in 1981 and came into medical use in 1990
cilazapril, patented in 1982 and approved for medical use in 1990
fosinopril introduced into US in 1991 and is the 1st phosphonate ACEI (and currently the only one of this type)
trandolapril, patented in 1981, and approved for medical use in 1993
imidapril, patented in 1982 and approved for medical use in 1993
1995, 1st angiotensin II receptor blockers (ARBs) approved for medical use - losartan