DR MOHD ZAWAWI ABU BAKAR KK NABAWAN KURSUS PSR PKK KENINGAU 12/4/2012

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

Morbidity & Mortality

Of all antihistamine exposures reported to

US poison control centers in 2007 (NPDS data), 2817 (3.6%) resulted in moderateto-major toxicity and 69 (0.090%) resulted in fatality. The vast majority of fatalities were associated with diphenhydramine.

Morbidity & Mortality

First-generation H1-receptor antagonists, such as diphenhydramine, may be particularly dangerous because they may cause pronounced agitation and seizures, resulting occasionally in rhabdomyolysis and acidosis. Also, a quinidinelike sodium channel blocking effect, and at high doses, a potassium channel blocking effect (HERG1K), may cause delayed conduction (prolonged QRS) and repolarization (prolonged QT) and contribute to ventricular dysrhythmias.

Morbidity & Mortality

Second-generation H1-receptor antagonists, such as terfenadine and astemizole (now removed from the US market), may result in QT interval prolongation and life-threatening polymorphic ventricular tachycardia (torsade

de pointes), particularly when combined with erythromycin.

Morbidity & Mortality

From 1990-2005 the Civil Aerospace Medical

Institute (CAMI) reported that antihistamines were found in 338 of 5383 pilot fatalities. It was felt that antihistamines were a factor in or the cause of 50 and 13 cases, respectively. The prevalence of antihistamine use among fatal crashes increased from 4% to 11% over this time span, indicating a worrisome trend. Reports of delayed pulmonary edema from antihistamine overdose have been reported.

Morbidity & Mortality

Famotidine has been shown to cause a significant increase in serum phosphate levels among hemodialysis patients taking calcium carbonate (even at the recommended dose of 10 mg/d). In severely ill patients, an administration of intravenous cimetidine can result in bradycardia and hypotension that can progress to cardiac arrest. USFDA reported serious adverse events including 7 deaths & 22 cases of respiratory depression assoc. with promethazine usage in children < 2 yrs (not directly related to wt based dosing).

Antihistamine usage-age
According to the 2007American Association of Poison

Control Centers' National Poison Data System(NPDS) data, the greatest number of toxic antihistamine exposures is associated with patients younger than 6 years (35,550 or 44%), though the relationship between ingested dose and severity of symptoms has been shown in one retrospective review to be insignificant. The 2007 NPDS data also indicate that antihistamines were the 10th most frequently reported exposure among children younger than 5 years. A positive association between depression symptoms among elderly persons (>65 y) and H2 blocker use has been reported. Inappropriate use of antihistamines for URI symptoms and otitis media may unnecessarily expose children to the potential side effects of this class of medication. Furthermore, no study has shown a benefit in the management of these conditions with either antihistamines or decongestants.

Structural classes of H1 antihistamine

1.

2.
3. 4. 5.

6.

Alkylamines (eg, brompheniramine, chlorpheniramine, dexchlorpheniramine, pheniramine, triprolidine) Ethanolamines (eg, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine) Ethylenediamines (eg, pyrilamine, tripelennamine) Phenothiazines (eg, methdilazine, promethazine, trimeprazine) Piperidines (eg, cyproheptadine, fexofenadine, loratadine), terfenadine and astemizole have been recalled from the US market Piperazines (eg, cetirizine, cyclizine, hydroxyzine, levocetirizine, meclizine)

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

Ethanolamine derivatives
Eg, diphenhydramine, dimenhydrinate
Strong atropine-like activity, drowsiness common Diphenhydramine assoc. with prolongation of

QT(not shown to cause Torsades de pointes) Massive ingestion seizures and cardiac conduction delays Doxylamine can cause rhabdomyolysis & renal failure

Ethylenediamine derivatives
Eg. Antazoline(eye drops), oxymetazoline(nasal drops) 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

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

Piperidine derivatives
Eg. Loratidine, desloratidine, fexofenadine Selectively binds H1 receptor & low binding

affinity for cholinergic & alfa adrenergic receptor Long half life- up to 24 hrs Terfenadine-recalled fr market(1992) dt assoc. with torsade de pointes both in acute overdose and therapeutic dose Prolonged QT syndrome & cardiac arrythmias rarely assoc. with loratidine

Piperazines derivatives
eg, cetirizine,levocetirizine,
Similar pharmacokinetic property to piperidine Cetirizine & levocetirizine-non sedative

Hydroxyzine & meclizine-sedative

No reported cardiac events

Anticholinergic S/E
Peripheral dry mouth, blurring of vision, flushed skin,

less sweating, dilated pupils, loss accommodation,intestinal ileus, urinary retention Central CNS- disorientation, agitation, delirium, short term memory impairment, incoherent speech, meaningless motor activity(eg. repetitive picking) & visual hallucination-*(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)

CVS S/E
Commonest Sinus tachycardia, rarely, vent. Tachycardia, torsade de pointes, hypotension(high dose) Antihistamine w anticholinergic effects slows cardiac Na channels & decrease cardiac conduction & myocardial contractility(pump failure in

overdose)- 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.

Resp. S/E
Resp. depression and apnea esp. with

phenothiazine(promethazine) High risk group- peads< 2yrs, not directly related to wt based dosing Pulmonary congestion secondary to cardiogenic shock & ventricular failure-most common in diphenhydramine toxicity

 Skin-fixed drug eruption(rare)-cetirizine Musculoskeletal-rhabdomyolysis in high dose of doxylamine Renal failure- secondary to doxylamine induced rhabdomyolysis

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, blood disorder, gyneacomastia, impotence

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 plasma concentration of terfenadine Alcohol intake increases antihistamine sedative effects

Caution & contraindication

1. 2. 3. 4.

High risk groups Children( esp < 2yrs)- resp. depression Elderly-fall, CNS,CVS Renal dis.- adjusted dose Liver dis.- sedative antihist. Contraindicated in severe liver dis. 5. Asthma, COPD, Chronic lung dis. 6. BPH & urinary retention 7. Acute glaucoma 8. Pyloric outflow obstruction 9. Epilepsy

 Pregnancy & lactation

-1st gen. antihistamine- no evidence of teratogenicity(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)

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