Angiotensin converting enzyme inhibitors toxicity
They are widely used in treating HT,CHFeg:captopril ,cilazapril,
enalapril fosinopril, lisinopril ,ramipril,quinopril, trandalopril,alacepril….
They cause ↓BP,hyperkalemia(uncommon),cough,angioneurotic edema.
Overdose is reported with captopril, enalaprril and lisinopril.
Pharmacology and pathophysiology
Pentopril ,alacepril,rammipril and enalapril are prodrugs which are
converted to active drug in liver they have high rate of absorption and
longer duration of action than other drugs in this class.food can ↓the rate
of absorption of active drug as Captopril by 30% but has little effect on
prodrug absorption. Enalapril is converted to enalprilat which have poly -
phasic elimination kinetic,the prolonged elimination terminal kinetic
phase is related to persistent binding of the drug toACE, after minor over
dose of enalapril the plasmaACEactivity didn’t normalize for 147hr
,captopril is eliminated from the body more rapidly ,ramiprolat(the active
metabolite of ramipril)is eliminated more slowly than other ACEIs the
primary route of elimination for all is the kidney ,the pathophysiological
effects are related to the mechanism by which these drugs ameliorate
HT,ACEIs work by blocking ACE in pulmonary vascular endothelium
which is important enzyme in rennin –angiotensin system (RAS).All
ACEIs bind ACE § prevent the conversion of angiotensinI to
angiotensinII which is the º1antihypertensive effect .Ang II directly acts
on bl. vessels § causes vasoconstriction It is also stimulate aldosteron
secretion causing salt§ water retention § participate in the breakdown of
bradykinin to inactive form .ACEIs result in accumulation of bradykinin
which may further↓BP by either direct vasodilation or by stimulate PG
synthesis .Unlike other vasodilatorts ACEIs don’t produce reflex
tachycardia ,this is likely due to centrally mediated effect .Angioedema
is a rare life threatening complication associated with the use of ACEIs
,marked edema of the tongue can obstruct the airway resulting in
respiratory arrest ,this is mediated by kallikrein-kinin system .The
hemodynamic response to ACEIs is mediated by substances that bind to
opiate receptors . ↓BP can occur with 1st therapeutic dose of ACEIs § this
effect can be blocked by naloxone administration .ACEIs can cause renal
damage by: 1) ↓ glumerular filtration pressure. 2) ↓ renal blood flow due
to systemic ↓ Bp. Reduced aldosterone production result in electrolyte
abnormality like hyper K ,hypo Na and metabolic acidosis .
CLINICAL PRESENTATION
Within 6-hr post ingestion BP↓with the 1 st therapeutic dose ,syncope
MI, hypoperfusion (with subsequent acute reversible renal failure)hyper
k ,hypoNa ,hyperPO4,metabolic acidosis . Adverse effect of therapeutic
use of ACEIs : Angioedema, nephrotic syndrome, ↓ BP ,chronic
cough,azotemia, rhinitis,rash ,arthralgia, agranulocytosis, the tongue and
the soft tissue of the neck are affected ,some cases will resolve with
treatment for allergic reaction like antihistamine ,corticosteroids.Other
cases progress .fatality reported (in this case the massive edema led to
airway obstruction requiring surgical interference, severe hypokalemia
occur if ACEIs are taken with K supplement or K –sparring diuretic .
captopril accentuate the respiratory depressive and the analgesic property
of morphine .
TREATMENT
1)Maintain airways by ventilator 2) Activated charcoal 3)0.9 %Nacl
(crystalloid)
4)NE IV infusion or EP or DA infusion .
5)Naloxone to ↑BP ,angiotensinamide infusion or ang II infusion to↑BP
6)Hemodialysis esp in renal failure.
7) for angioedema use antihistamine , corticosteroids.