Antihistamine Toxicity

8/2/2019 Antihistamine Toxicity

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DR MOHD ZAWAWI ABU BAKAR

KK NABAWAN

KURSUS PSR PKK KENINGAU

12/4/2012


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Class of antihistamine

Human Histamine receptors- H1, H2, H3, H4

Clinical use : H1 and H2

H3 & H4 : under research H1 receptor antagonists- 1st generation sedating

antihistamine & 2nd generation non sedating antihistamine

H2 receptor antagonists- cimetidine, ranitidine, famotidine


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Morbidity & Mortality

Of all antihistamine exposures reported toUS poison control centers in 2007 (NPDSdata),2817 (3.6%) resulted in moderate-to-major toxicityand 69 (0.090%)

resulted in fatality. The vast majority offatalities were associated withdiphenhydramine.


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First-generation H1-receptor antagonists, suchas diphenhydramine, may be particularly

dangerous because they may cause pronouncedagitation and seizures, resulting occasionally inrhabdomyolysis and acidosis. Also, a quinidinelikesodium channel blocking effect, and at high doses,

a potassium channel blocking effect (HERG1K),may cause delayed conduction (prolongedQRS) and repolarization (prolonged QT) andcontribute to ventricular dysrhythmias.


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Second-generation H1-receptor antagonists,such as terfenadine and astemizole (now removedfrom the US market), may result in QT intervalprolongation and life-threatening

polymorphic ventricular tachycardia (torsadede pointes),particularly when combined witherythromycin.


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From 1990-2005 the Civil Aerospace MedicalInstitute (CAMI) reported thatantihistamines were found in 338 of 5383pilot fatalities. It was felt that

antihistamines were a factor in or the causeof 50 and 13 cases, respectively. Theprevalence ofantihistamine use amongfatal crashes increased from 4% to 11%

over this time span, indicating a worrisometrend.Reports of delayed pulmonary edema from

antihistamine overdose have been reported.


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Famotidine has been shown to cause a significantincrease in serum phosphate levels amonghemodialysis patients taking calcium carbonate(even at the recommended dose of 10 mg/d).

In severely ill patients, an administration ofintravenous cimetidine can result in bradycardiaand hypotension that can progress to cardiacarrest.

USFDA reported serious adverse eventsincluding 7 deaths & 22 cases of respiratorydepression assoc. with promethazine usage inchildren < 2 yrs (not directly related to wt baseddosing).


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Antihistamine usage-age

According to the 2007American Association of PoisonControl Centers' National Poison Data System(NPDS) data,

the greatest number of toxic antihistamine exposuresis associated with patients younger than 6 years(35,550 or 44%), though the relationship between ingesteddose and severity of symptoms has been shown in oneretrospective review to be insignificant.

The 2007 NPDS data also indicate that antihistamines werethe 10th most frequently reported exposure amongchildren younger than 5 years.

A positive association between depression symptomsamong elderly persons (>65 y) and H2 blocker use has been

reported. Inappropriate use of antihistamines for URI symptoms andotitis media may unnecessarily expose children to thepotential side effects of this class of medication.Furthermore, no study has shown a benefit in themanagement of these conditions with eitherantihistamines or decongestants.


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Structural classes of H1 antihistamine

1. Alkylamines (eg, brompheniramine, chlorpheniramine,dexchlorpheniramine, pheniramine, triprolidine)

2. Ethanolamines (eg, carbinoxamine, clemastine,dimenhydrinate, diphenhydramine, doxylamine)

3. Ethylenediamines (eg, pyrilamine, tripelennamine)

4. Phenothiazines (eg, methdilazine, promethazine,trimeprazine)

5. Piperidines (eg, cyproheptadine, fexofenadine,loratadine), terfenadine and astemizole have been

recalled from the US market6. Piperazines (eg, cetirizine, cyclizine, hydroxyzine,levocetirizine, meclizine)


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Alkylamines derivatives

eg. chlorpheniramine, dexchlorpheniramine,triprolidine.

Among most potent antihistamine Produce more CNS stim. & less drowsiness

Chlorpheniramine suppress visuospatial cognition& visuomotor coordination-may cause fall


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Ethanolamine derivatives

Eg, diphenhydramine, dimenhydrinate

Strong atropine-like activity, drowsiness common

Diphenhydramine assoc. with prolongation ofQT(not shown to cause Torsades de pointes)

Massive ingestion seizures and cardiacconduction delays

Doxylamine can cause rhabdomyolysis & renalfailure


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Ethylenediamine derivatives

Eg. Antazoline(eye drops), oxymetazoline(nasaldrops)

Weak CNS effects

Ppt angle closure glaucoma Interacts with monoamine oxidase inh.

hypertensive crisis

Tripelennamine(US) exposure-myoclonic jerk,

hallucination, agitation

Tripelennamine + pentazocine(weak opiod) =heroin-like effects


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Phenothiazine derivatives

Eg. Promethazine

Strong anticholinergic activity

Akathisia & dystonic reaction are common similar structure to CPZ, haloperidol

Promethazine can cause fatal resp.

depression/apnea in children< 2 yrs


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Piperidine derivatives

Eg. Loratidine, desloratidine, fexofenadine

Selectively binds H1 receptor & low bindingaffinity for cholinergic & alfa adrenergic receptor

Long half life- up to 24 hrs

Terfenadine-recalled fr market(1992) dt assoc. withtorsade de pointes both in acute overdose andtherapeutic dose

Prolonged QT syndrome & cardiac arrythmiasrarely assoc. with loratidine


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Piperazines derivatives

eg, cetirizine,levocetirizine,

Similar pharmacokinetic property to piperidine

Cetirizine & levocetirizine-non sedative Hydroxyzine & meclizine-sedative

No reported cardiac events


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Anticholinergic S/E

Peripheral dry mouth, blurring of vision, flushed skin,less sweating, dilated pupils, lossaccommodation,intestinal ileus, urinary retention

Central CNS- disorientation, agitation, delirium, short

term memory impairment, incoherent speech, meaninglessmotor activity(eg. repetitive picking) & visualhallucination-*(psychosis usu. Assoc. with AH, paranoia &intact sensorium)

Seizures, esp. in epilepsy and acute poisoning Others-somnolence, lethargy, EPS, anxiety

Chronic abuse(Benadryl)- withdrawal Sx with restlessness,irritability,excessive blinking(no EPS+psychosis)


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CVS S/E

Commonest Sinus tachycardia, rarely, vent.

Tachycardia, torsade de pointes, hypotension(highdose)

Antihistamine w anticholinergic effects slowscardiac Na channels & decrease cardiac conduction

& myocardial contractility(pump failure inoverdose)- diphenhydramine, chlorpheniramine &certain phenothiazine

VT 4X more in non sedating antihistamine

Prolonged QT-diphenhydramine,phenothiazine,piperidine(loratidine)

Torsades de pointes- only in piperidine, esp.terfenadine & astemizole.


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Resp. S/E

Resp. depression and apnea esp. withphenothiazine(promethazine)

High risk group- peads< 2yrs, not directly related

to wt based dosing Pulmonary congestion secondary to cardiogenic

shock & ventricular failure-most common indiphenhydramine toxicity


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Skin-fixed drug eruption(rare)-cetirizine Musculoskeletal-rhabdomyolysis in high dose of

doxylamine

Renal failure- secondary to doxylamine inducedrhabdomyolysis


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H2 receptor antagonist

Selective H2 receptor inhibitor

Not blocking H1 receptor & dont have

antimuscarinic activity Common S/E : GI(diarrhea, vomiting), dizziness,

somnolence, headache, arthralgia, rash

Rare S/E: A.pancreatitis, brady, AV block,confusion, depression, hallucination, blooddisorder, gyneacomastia, impotence


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Drugs interaction

Antihistamine enhances other antimuscarinic &sedative such as TCA, hypnotics, anxiolytics,MOAI

Co-admin. Of antifungal imidazole(eg.Ketoconazole,itraconazole) & macrolide ab.Increases plasma concentration of 2nd gen.antihistamine

Grapefruit ingestion increases plasmaconcentration of terfenadine

Alcohol intake increases antihistamine sedative

effects


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Caution & contraindication

High risk groups

1. Children( esp < 2yrs)- resp. depression

2. Elderly-fall, CNS,CVS

3. Renal dis.- adjusted dose

4. Liver dis.- sedative antihist. Contraindicated insevere liver dis.

5. Asthma, COPD, Chronic lung dis.

6. BPH & urinary retention7. Acute glaucoma

8. Pyloric outflow obstruction

9. Epilepsy


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Pregnancy & lactation

-1

st

gen. antihistamine- no evidence ofteratogenicity(cat B)

-2nd gen. antihist-limited data on safety profile(cat C)

-H2 receptor antagonist- ranitidine, cimetidine,

famotidine not known to be harmful(cat. B)


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References

BNF 58, September 2009

http://emedicine.medscape.com/article/812828-overview

http://www.patient.co.uk/doctor/Antihistamines.htm

I.Matok et al. Safety of H2 Blockers Use During Pregnancy, J Clin.Pharmacol., Jan. 2010;50(1) :81-87
http://emedicine.medscape.com/article/812828-overviewhttp://www.patient.co.uk/doctor/Antihistamines.htmhttp://www.patient.co.uk/doctor/Antihistamines.htmhttp://emedicine.medscape.com/article/812828-overviewhttp://emedicine.medscape.com/article/812828-overviewhttp://emedicine.medscape.com/article/812828-overview

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Antihistamine Toxicity