Introduction

Amongst most frequently prescribed More than 40 drugs available worldwide About 20 drugs are available in India A broad class of pharmacologic agents that include the 1st generation, 2nd generation, & now 3rd Gen agents that inhibit the actions of histamine on H1 receptors Not receptor antagonists but are inverse agonists i.e. inverse agonists they produce the opposite effect on the receptor to histamine 1st Gen antihistamines never adequately studied for pediatric age groups: still used widely

Allergic Cascade
Second Allergen exposure IgE attachment to mast cell allergen specific mast cell

B cell
Cytokines IL-4, IL-13 IL- IL-

IgE production

1st Allergen exposure

Allergen attachment & degranulation of mast cell

Allergic Cascade

Allergic Cascade: Therapeutic Intervention Points

Allergen Allergen avoidance Antigen Presenting Cell

Allergen-specific immunotherapy

TH2 Cell

Lymphocyte

Anti-cytokine therapies

IL-4, IL-13 IL- IL-

IL-5 ILEosinophil

Anti-IgE therapies

B cell

Pharmacotherapy

Mediator release (Histamines, LTs, IL- 3, 4, 5) IL-

Histamine & Effects

Symptoms of allergic response mainly mediated by Histamine Hence Antihistamines for Tx of allergic diseases H1 Receptor antagonism is the basis for use Antihistamines refers to H1 antihistaminic drugs only, in general Negligible potency at H2 and little at H3 receptor. E.g. Histamine induced contraction of bronchiolar or GI smooth muscles can be completely blocked by these, but effects on gastric acid secretion & heart are unmodified 45% homology with human muscarinic receptor, hence some antimuscarinic action with some compounds

Nelson Textbook of Pediatrics, 18th Ed, 2008, Pg 944

Histamine & Effects

The histamine H1-receptor, like other G-protein coupled H1Greceptors, may be viewed as cellular switches, which cellular switches, exist as an equilibrium between inactive or off state and active or on state. In the case of H1-receptor, histamine H1crosscross-links sites on transmembrane domains to stabilize the receptor in its active conformation, thus causing the equilibrium to swing to the on position. H1-AH, which are H1not structurally related to histamine, do not antagonize the binding of histamine but bind to different sites on the receptor to produce the opposite effect. Thus, H1-antihistamines are not receptor antagonists but H1are inverse agonists in that they produce the opposite inverse agonists effect on the receptor to histamine. Consequently, the preferred term to define these drugs is H1H1antihistamines rather than histamine antagonists
World Allergy Organization Journal: March 2011 - Volume 4 - Issue 3 - pp S22-S27 S22-

Histamine & Effects

AH-G1 derive from the same chemical stem from which AHcholinergic muscarinic antagonists, tranquilizers, antipsychotics, & antihypertensive agents were also developed, they have poor receptor selectivity and often interact with receptors of other biologically active amines causing antimuscarinic, anti -adrenergic, & anti antiserotonin effects AH-G2 are minimally sedating or nonsedating because of AHtheir limited penetration of the blood-brain barrier. In bloodaddition, these drugs are highly selective for the histamine H1-receptor and have no anticholinergic effects H1-

Nelson Textbook of Pediatrics, 18th Ed, 2008, Pg 944

Histamine & Effects

1st Gen AH are more lipophilic, readily cross the BBB & interfere with histaminergic transmission Histamine is an important neuromediator in brain which contains approximately 64,000 histamine-producing histamineneurons, located in the tuberomamillary nucleus. When activated, these neurons stimulate H1-receptors in all of H1the major parts of the cerebrum, cerebellum, posterior pituitary, & spinal cord where they increase arousal in the circadian sleep/wake cycle, reinforce learning and memory, and have roles in fluid balance, suppression of feeding, control of body temperature, control of the cardiovascular system, and mediation of stress-triggered stressrelease of adreno-corticotrophic hormone & -endorphin adrenofrom the pituitary gland. It is not surprising then that antihistamines crossing the blood-brain barrier interfere bloodwith all of these processes
World Allergy Organization Journal, March 2011 - Volume 4 - Issue 3 - pp S22-S27 S22-

Histamine & Effects

Physiologically, the release of histamine during the day causes arousal whereas its decreased production at night results in a passive reduction of the arousal response. AHWhen taken during the day, AH-G1, even in the manufacturers' recommended doses, frequently cause doses, daytime somnolence, sedation, drowsiness, fatigue, and impaired concentration & memory. When taken at night, AHAH-G1 increase the latency to the onset of REM sleep and reduce the duration of REM sleep. The residual effects of sleep. poor sleep, including impairment of attention, vigilance, working memory, & sensory-motor performance, are still sensorypresent the next morning. The detrimental central nervous system effects of 1st Gen H1-antihistamines on learning & H1examination performance in children and on impairment of the ability of adults to work, drive, and fly aircraft have been reviewed in detail in a recent review
World Allergy Organization Journal, March 2011 - Volume 4 - Issue 3 - pp S22-S27 S22-

Histamine & Effects

The anti-inflammatory effects of AH is a class effect antimediated through the H1-receptor. Hence AH have ability H1to reduce nasal congestion & hyper-reactivity, which result hyperfrom the sensitization of sensory neurones in the nose by allergic inflammation. However, as nasal congestion is more slowly relieved than other nasal symptoms, continuous rather than on demand therapy is required for its treatment AH prevent the effects of H1-receptor activation through H1reversible, competitive inhibition of histamine by binding to the H1-receptor. As a result, antihistamines work best in H1preventing rather than reversing the actions of histamine and are most effective when given at doses and dosing intervals resulting in the persistent saturation of target organ tissue histamine receptors
World Allergy Organization Journal, March 2011 - Volume 4 - Issue 3 - pp S22-S27 S22-

Histamine & Effects

Source of release Receptor H1 H1 Site of receptor Smooth muscles Endothelium
1. 2. 1. 2.

Effect Bronchoconstriction Contraction of GIT Vasodilatation Increased capillary permeability leading to edema Pain and itch

Mast cells (hypersensitivity)

H1 H2 H4

Sensory nerve endings Smooth muscles of blood vessels (only in large doses) Immune active cells (as eosinophils) Oxyntic cells of the stomach Post synaptic neurons at all areas of the rain

1.

1- Vasodilatation
1.

Chemotaxis HCL secretion 1- Arousal Decreased appetite

ECL - cells in the stomach

H2 H1 and H2

1.

1. 2.

Brain (histaminergic neurons cell bodies of these neurons are found in the hypothalamus and axons extend to all areas of the brain)

H3

Presynaptic histaminergic neurons in the brain

1.

2.

Inhibit histamine release producing sleep Modulate the release of other neurotransmitters

Histamine & Effects

Actions Not Caused by H1 Receptor Blockade

Sedation: Mostly with AH-G1 (Basis for Sleep-aids) Sedation: AHSleepAntinausea & Antiemetic actions (antimuscarinic): for motion sickness (preventive) Antiparkinsonism effects (antimuscarinic): can be used in EPS or acute dystonic reactions e.g. diphenhydramine Anticholinoceptor Actions: Atropine like effects Adrenoceptor-blocking Actions Orthostatic Adrenoceptorhypotension with promethazine Serotonin-blocking Actions (Cyproheptadine) SerotoninLocal Anesthesia (Blockade of Sodium channels) diphendydramine & promethazine All H1-antihistamines have anti-inflammatory effects but H1antiit requires regular daily dosing rather than dosing on demand for this action to be clinically demonstrable

Histamine & Effects

Lippincott's Illustrated Reviews: Pharmacology, 4th Edition, 2009

Different ClassificationChemical Stricture

Lippincott's Illustrated Reviews: Pharmacology, 4th Edition, 2009

Classification
H1H1-antagonists Type III Type IV Type V Type VI Type II Type I Ethylenedia ethanolami alkylamines piperazines piperidines phenothiazi nes ones mines
1st Gen. 1st Gen. 1st Gen. Carbinoxamin Bromphenira Antipolice mine Pyrilamine Clemastine Tripelennamin Diphenhydra Chlorphenira mine mine Triprolidine Doxylamine 2nd Gen. Acrivastine 1st Gen. Cyclizine Meclizine Hydroxyzine 1st Gen. 1st Gen. Promethazine Azatidine Cyproheptadi Methdilazine ne Buclizine
Astemizole Levocabastin Loratadine Terfenadine Fexofenadine

Cetirizine

Ebastine

Levocetirizine Desloratidine Norastemizole

Development Objectives


General trend: improve tolerability and safety (less to no sedation; reduce the cholinergic effects)
Targeted Molecules for improvement

Class

Type of Improvement
Active metabolite Isomer Purification

Objective

Piperidine Piperazine Piperidine

Piperidine

Azatadine
Hydroxyzine

Loratadine Cetirizine Fexofenadine Tecastemizole

Desloratadin Levocetirizin

PK, lower drug-drug interactions Receptor affinity and selectivity, efficacy Safety, lower cardiotoxicity

Terfenadine
Astemizole

not even designed as an antihistamine; discovered during research of calcium channelblocking agents

Classification
Inhalational Antihistamines (AH-G2) (AHAzelastine
> 12 years 140 mg/nostril twice daily

Olopatadine
> 6/12 years (TN Olamyst, Fourrts, Nasopat, 0.6%, Ajanta)

Levocabastine
> 12 years 0.05% 2 sprays/ nostril twice daily. Max for 4 weeks

Nasal spray: indicated for the symptomatic treatment of allergic rhinitis (sneezing, itchy nose, runny nose) The benefit is the potential for a rapid onset of action within 15-30 min. Azelastine, which is systemically absorbed and can cross the blood-brain barrier, has been shown to cause central nervous system effects in some Used in conjunction with inhalational steroids

Pharmacokinetics
All antihistamines are well absorbed following oral administration Most achieve peak plasma concentrations within 3 hours with the onset of symptoms occurring between 30 minutes & 2 hours of ingestion Duration of action ranges from 3 hours to more than 24 hours (for meclizine & AH-G2) AHAll 1st gen antihistamines, as well as most 2nd gen drugs, are metabolized in the liver by the P450 cytochrome enzyme system Cetirizine is excreted largely unchanged in the urine, & fexofenadine is excreted largely unchanged in the feces Tolerance to the action has not been observed Cyclosporin A and rifampicin may decrease hepatic uptake of fexofenadine

Adverse Effects
Antimuscarinic CNS
Depression Paradoxical excitation Dizziness In coordination Paresthesias Convulsions Central anticholinergic syndrome Extra pyramidal SE Depression Tinnitus Spasms Aggressivity Palpitations Arrhythmias Postural Hypotension

Skin & Misc.

Hypersensitivity Rashes Bronchospasm Angioedema Anaphylaxis Hair Loss Fixed drug eruptions

GI
Nausea Vomiting Diarrhea Epigastric pain Anorexia Increased appetite with some

Blood
Agranulocytosis Leucopenia Hemolytic anemia Thrombocytopenia Jaundice (Phenothiazines)

Dry mouth Dry eyes Blurred vision Urinary retention Constipation Sinusoidal Tachycardia Erectile dysfunction Thickened respiratory secretions Increased GER

Cardiac

Adverse Effects

N Engl J Med 2004;351:2203-17 2004;351:2203-

A Word About Sedation

CNS depression: effects varying from slight drowsiness to deep sleep to coma Type of drug: At recommended doses, levocetirizine is less sedating than cetirizine & desloratadine causes negligible somnolence, Fexofenadine least sedating Dose dependant & independent: Cetirizine, Desloratadine vs. 1st Gen Subjective at times: A few patients treated with nonnonsedating antihistamines have experienced drowsiness. It is prudent to exercise caution before driving or operating machinery When sedative effects do occur they are most apparent at the start of treatment and often diminish after a few days despite continued use Sedation caused by alcohol or other CNS depressants is enhanced (with AH-G1) AH-

A Word About Cardiotoxicity

Astemizole & terfenadine block the IKr current, and prolong the QT interval, and can potentially cause serious polymorphic ventricular arrhythmias such as torsades de pointes. pointes. Hence these drugs no longer approved by regulatory agencies in most countries Some AH-G1, such as promethazine, brompheniramine, & AHpromethazine, brompheniramine, diphenhydramine, diphenhydramine, may also be associated with a prolonged QTc and cardiac arrhythmias when taken in large doses or overdoses No clinically significant cardiac effects have been reported for the AH-G2 loratadine, fexofenadine, ebastine, AHazelastine, cetirizine, desloratadine, & levocetirizine

Overdose
1st Gen AH are potentially lethal in case of overdose because of their action upon different types of receptors (histaminic, serotoninergic, cholinergic, dopaminergic), and both deaths & serious toxicity have been documented in pediatric patients CNS effects are similar to atropine poisoning with some histamines When CNS stimulation predominates over CNS depression (more likely in children) it causes ataxia, excitement, tremors, psychoses, hallucinations, and convulsions; hyperpyrexia may also occur. Deepening coma and cardiorespiratory collapse may follow. Barbiturates contraindicated Treatment supportive

Overdose
Gastric emptying: beneficial only if done within hour of emptying: ingestion Activated charcoal 1 gm/kg can be given to prevent the absorption, prn 2-4h 2Benzodiazepines may be used for agitation or seizures Although benzodiazepines often are considered firstfirstline, physostigmine [0.02 mg/kg/dose slow IVP (not to exceed 0.5 mg/min); may repeat q5-10min PRN, not to q5exceed cumulative dose of 2 mg] is safe and effective for the treatment of antihistamine-induced agitated antihistaminedelirium/hallucination / agitation, provided that the ECG does not demonstrate conduction disturbances (ie, PR and QRS prolongation). Always have atropine at bedside when using physostigmine in order to reverse excessive cholinergic activity (eg, bradycardia, salivation) Manage hyperthermia, cardiac monitoring

Drug Interactions
Antihistamines that produce sedation can potentiate CNS depressants (e.g., barbiturates, opiates, general anesthetics, & alcohol) Antihistamines that possess anticholinergic actions can produce excessive blockade if given with anticholinergic drugs (e.g., dry mouth, constipation, or blurred vision) Many metabolized by the cyt P450 system. Elimination system. may be reduced in patients with hepatic impairment or by the simultaneous ingestion of inhibitors of pathway, such as erythromycin and other macrolide antibiotics, ciprofloxacin, ketoconazole, itraconazole, and certain antidepressants such as nefazodone and fluvoxamine Metabolism may be increased by inducers of Cyt P450 system like benzodiazepines Theophylline decreases clearance of Cetirizine

Precautions
Drowsiness is a major problem with the sedating antihistamines and those affected should not drive or operate machinery; alcohol should be avoided. In the case of non-sedating antihistamines, although nondrowsiness is rare, it can occur and may affect the performance of skilled tasks Because of their antimuscarinic actions the sedating antihistamines should be used with care in conditions such as angle-closure glaucoma, urinary retention, or anglepyloroduodenal obstruction Occasional reports of convulsions: a need for caution in patients with epilepsy/CNS disorders Many are excreted in the urine in the form of active metabolites so dosage reduction may be necessary in renal impairment. Caution is also needed in hepatic impairment, notably with phenothiazine antihistamines

Precautions
Antihistamines should not be given to neonates because the latter are more susceptible to antimuscarinic effects. It has also been recommended that antihistamines should be avoided in young children Topical preparations containing antihistamines should not be used on broken or eczematous skin
Currently desloratadine, fexofenadine & loratadine are the only oral H1 antihistamines for which pilots can receive a waiver for use from the Federal Aviation Administration

Common Uses
1. Allergic rhinitis 2. Allergic dermatoses: can control itching associated dermatoses: with insect bites 3. Outpatient procedures for preanesthetic sedation and prevention of nausea and vomiting (Promethazine). It also inhibits salivary and bronchial secretions and can be used as a local anesthetic 4. Antiemetic: prevention or treatment of nausea and Antiemetic: vomiting (Doxylamine with pyridoxine) 5. Other uses: a. Reduction of tremors and muscle rigidity uses: in Parkinson's disease b. treatment of migraine No use in angioedema & persistent bronchial asthma!
Goodman & Gilmans Manual of Pharmacology & Therapeutics, 11th Ed, 2008

Allergic Rhinitis
1st first line of treatment for allergic rhinitis must be identification & avoidance of the relevant allergens Antihistamines are effective in allergic rhinitis, which comprises approximately 80% of rhinitis found in children and 30% in adults They are effective against rhinorrhoea, itch and sneezing but have little effect on nasal obstruction MetaMeta-analysis reveals that antihistamines are inferior to corticosteroids in allergic rhinitis therapy Their place in therapy is probably as sole agent in mild, intermittent rhinitis and in combination with topical corticosteroids in more severe disease not controlled by corticosteroids alone Common Cold: Despite persistent popular belief, H1 antagonists are without value in combating the common cold Clin Exp Allergy. 1999 Jul;29 Suppl 3:77-81 3:77-

Pruritus
There is conflicting evidence, but several studies show that older antihistamines that cause more somnolence are actually more effective at alleviating pruritus than newer, longer-acting longerantihistamines Reports of toxic encephalopathy in patients with skin syndromes (atopic dermatitis, varicella) involving damage to the skin barrier, in whom AH-G1 were applied topically AHExcept for pruritus seen with insect bites and urticaria, use of topical antihistamines for pruritus or rash that is widespread should be discouraged

Caladryl: 8% Calamine + 1% Diphendydramine, Camphor 1%, Spirit 2.3 % v/v Abroad: 8% Calamine + 1% Praloxine HCl [Local anesthetic like benzocaine/lidocaine] 5-Minute Pediatric Consult, 4th Edition, 2005

Acute Urticaria
Reassurance Avoidance of the cause (where possible) Antihistamines: Proven efficacy; controversial in atopic efficacy; dermatitis & other pruritic dermatoses in which efficacy may be due to sedative action of 1st Gen According to the EAACI/GA2LEN/EDF/WAO management firstguideline 2009, first-generation sedating antihistamines should no longer be used as the first choice therapy except where AH-G2 are not available or where their AHbenefits outweigh their risks Commonly used first-generation agents include firstdiphenhydramine, hydroxyzine, chlorpheniramine, & cyproheptadine
European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO)

Acute Urticaria
The newer second-generation antihistamines are secondnonsedating in most patients, with very few adverse effects reported (cetirizine can cause drowsiness in up to 10% of patients). Therefore, many specialists prefer the use of these agents for chronic urticaria, with firstfirstgeneration agents reserved for acute or refractory cases  H2 antagonists: are usually used to decrease gastric acid secretion. They are not effective when used as single agents for urticaria (may even increase the lesions); however, the combination of an H1 antagonist with an H2 antagonist has been shown to be more effective than an H1 antagonist alone (although the efficacy of this intervention has not been clearly established in children). Any of the H2 blockers can be used e.g. ranitidine, famotidine

Acute Urticaria
The EAACI/GA2LEN/EDF/WAO management guideline recommends the use of corticosteroids only in severely affected patients. A short course of an oral corticosteroid (administered daily for 5-7 d, with or without a taper) or a 5taper) single dose of a long-acting injectable steroid is not longusually associated with long-term sequelae and can be longhelpful when used for an acute episode of urticaria nonresponsive to antihistamines Can two antihistamines be combined? Usually acute combined? urticaria responds within 24 hours. If it doesnt, doses can be increased & 1st Gen & 2nd Gen can be combined to enhance the effect in refractory cases. E.g. Levocetirizine + Pheniramine maleate, Loratadine + Hydroxyzine

Expert Opinion on Pharmacotherapy, August 2004, Vol. 5, No. 8 : Pages 1807-1813 1807-

Chronic Urticaria (> 6 weeks)

Up to 75% of patient with chronic urticaria referred to tertiary centers may require higher than conventional antihistamine doses. These higher nonsedating doses. antihistamine doses improved quality of life but did not increase somnolence. Long-term systemic corticosteroids Longare not recommended. If high-dose nonsedating highantihistamine therapy is not effective, than switching to a different nonsedating antihistamine could be considered or a leukotriene antagonist can be added. Nonresponders to 20 mg of desloratadine may benefit from 20 mg of levocetirizine. Guidelines suggest increasing doses of AH-G2 up to 4AH4difficult-tofold to improve symptom control of difficult-to-treat chronic urticaria before trying other therapeutic options. (Duration can range from 6 mo to 2 years). AH-G1 avoided years). AHbecause they reduce the duration of REM sleep & interfere with growth! JACI March 2010 / Volume 125, No. 3

Respiratory Tract Infections

Formulations containing antihistamines only, or in combination with other drugs (antitussive agents, systemic decongesting drugs, etc.), are widely used for symptoms control & the treatment of RTIs in children. A meta-analysis has reviewed the usefulness: as metamonotherapy in adults and children afford no clinical relief of nasal congestion, rhinorrhea or sneezing, and do not subjectively improve the common cold. Moreover, 1st Gen antihistamines induced more side effects than placebo, particularly increased sedation in the patients with a common cold.

J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 28-40 28-

Respiratory Tract Infections

The combinations of antihistamines with decongestants are not effective in young children. In older children and in adults, most studies report a beneficial effect in terms of general recovery, as well as in the nasal symptoms, when these combinations are used. However, the metaanalysis also concludes that the clinical relevance of these effects is not clear. In another study designed to determine whether continued treatment with a non-sedating antihistamine (loratadine) non(loratadine) is able to prevent upper airways infections, the only conclusion was that children suffered fewer respiratory exacerbations during the active treatment phase than the placebo group - though this protective effect disappeared on suspending the treatment. This study concluded that treatment. the URI rate in children at risk of suffering such infections qes considerably with age, and is not significantly influenced by treatment with loratadine.

Anaphylaxis
Diphenhydramine 12 mg/kg up to 50 mg, can be given intramuscularly or intravenously. Intravenous antihistamines should be infused over a period of 510 5 minutes to avoid inducing hypotension. Addition of hypotension. ranitidine, an H2-blocker, 1 mg/kg up to 50 mg H2intravenously, may be more effective than an H1-blocker H1alone, especially for hypotension, but histamine blockers should be considered second-line treatment for secondanaphylaxis Premedication is useful in preventing anaphylactoid reactions because of radiocontrast media

Current Diagnosis & Treatment: Pediatrics (CDTP) 19th Ed, 2008

Antihistamines in Asthma

Goodman & Gilmans Manual of Pharmacology & Therapeutics, 11th Ed, 2008

Antihistamines in Asthma
Histamine is an important inflammatory mediator within the respiratory tract. Following provocation by an inhaled allergen, it has been demonstrated that plasma histamine levels increase, coinciding with the immediate and late response phases of the allergic reaction. A rise in plasma histamine also has been reported during asthma attacks. Children under 14 years of age with bronchial asthma, antihistamine treatment was indicated in up to 30% of cases Antihistamines such as ketotifen, cetirizine & loratadine have shown a range of effects upon asthma: they reduce exerciseexercise-induced asthma attacks, improve cough in children with pollen allergy during the pollinic season, & improve asthma symptoms in children
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 28-40 28-

Antihistamines in Asthma
Ketotifen has been shown to be effective in preventing the development of asthma in children with a family history of respiratory allergy and high IgE levels, & Cetirizine prevents the development of asthma in children with atopic dermatitis sensitized to aeroallergens. Moreover, such preventive effects persist for 18 months after discontinuing the treatment Loratadine has been shown to reduce the number of respiratory exacerbations during the treatment period in a group of children with repeated ear, nose and throat infections (5 or more), without prior asthma

J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 28-40 28-

Antihistamines in Asthma
Antihistamines are not considered effective in the management of asthma and their use has often been contracontra-indicated in patients with asthma because of fears that they may cause airway obstruction. However, antihistamineantihistamine-induced airway obstruction has rarely been noted clinically and many patients with asthma tolerate concurrent treatment with antihistamines without obvious adverse effects. Therefore the American Academy of Allergy and Immunology has recommended that antihistamines are not contra-indicated in patients contrawith asthma, unless an adverse reaction has previously been demonstrated

J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 28-40 28-

Cough
The mechanism of antitussive action of AH may involve reduction in cholinergic nerve transmission or may simply result from their sedative effects; reduction of nasal secretions may be of value in treating cough caused by postnasal drip Antihistamines should not be used to treat productive coughs because reduction in bronchial secretions may cause formation of viscid mucus plugs. The sedative effects of antihistamines may prove troublesome for daytime use but may be a short-term advantage for night shortcoughs Antihistamines may be useful in the management of children with an acute allergic cough in the pollen season. They may also be used, with allergen avoidance and intranasal corticosteroids, in children with a chronic throat clearing type of cough and signs of allergic rhinitis J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 28-40 28-

Cough
Prolonged nonspecific cough: On the basis of the cough: existing scientific evidence, empirical treatment with these drugs cannot be recommended - in contraposition to the recommendations in adults. If antihistamine treatment is decided, it should be discontinued if no response is elicited within two weeks. Acute Cough: antihistamines in combination with Cough: decongestants (brompheniramine/phenylpropanolamine & brompheniramine/phenylephrine/propanolamine) was no superior to placebo in the two studies included, and that antihistamines alone (clemastine and chlorpheniramine) afforded no greater benefit than placebo in another study AH may induce cough by drying the secretion of oral cavity & respiratory tract ( Bronchospasm) Bronchospasm)
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 28-40 28-

Migraine
Prophylactic medication: Cyproheptadine medication: H1 receptor & serotonin agonist 0.20.4 mg/kg hs (Max 0.5 mg/kg/24 hr) 0.2 Cyproheptadine is an antihistaminic medication with serotoninserotonin-blocking activity that is taken at a dose of 2 to 4 mg two to three times daily. Adverse effects may include sedation, increased appetite, and occasionally, in longer term therapy, depression caused by serotonin blockade Only two drugs have been subjected to rigorous controlled studies to test the efficacy and tolerability of prophylactic agents in reducing the severity and frequency of childhood migraine; propranolol, a blocker, and flunarizine, a calcium channel blocking flunarizine, agent
Nelson Textbook of Pediatrics, 18th Ed, 2007

Insomnia
Some of the older sedating antihistamines including diphenhydramine and promethazine, have been promoted to the public for occasional insomnia, although their long duration of action may cause hangover effects Promethazine was formerly popular for children but the use of hypnotics in this age group is not usually justified. justified. Moreover a possible association between phenothiazines and sudden infant death syndrome contributed to the recommendation that such antihistamines should not be used in young children Deaths reported with use of diphenhydramine below 2 years of age
Nelson Textbook of Pediatrics, 18th Ed, 2007

Lytic Cocktail
A mixture of drugs injected intravenously to produce sedation, analgesia, amnesia, hypotension, hypothermia, and blockade of the functions of the sympathetic and parasympathetic nervous systems during surgical anesthesia Premedication Lytic Cocktail: Demerol {Pethidine}, Phenergan {Promethazine}, and Thorazine {Chlorpromazine}(DPT) for the Sedation of Children: contains a long-acting longopiate with a tendency to activate seizures and two longlongacting neuroleptics 1 ml contains pethidine 28 mg, promethazine 7 mg, chlorpromazine 7 mg administered intramuscularly or rectally Not recommended these days!
Pediatr Clin North Am. 1989 Oct;36(5):1285-91 Oct;36(5):1285-

Extrapyramidal Side Effects (EPS)

Drugs: Neuroleptics [Haloperidol (Serenace), thioridazine, Trifluoperazin, Risperidone], Metoclopramide (Reglan), Antiemetics [Promethazine (Phenergan), Prochlorperazine (Stemetil)]
South African Medical Journal, 55, 328 (1979)

Extrapyramidal Side Effects (EPS)

Appear to result from drug-induced alteration of drugdopaminergicdopaminergic-cholinergic balance in the nigrostriatum (ie, basal ganglia). Most drugs produce dystonic reactions by nigrostriatal dopamine D2 receptor blockade, which leads to an excess of striatal cholinergic output Occasionally dose related, more often idiosyncratic & unpredictable Acute Dystonia: Tonic muscular contractions localized to Dystonia: one or several muscle groups: Eye manifestations include spasm of EOM (oculogyric crisis), Neck torticollis, Back (opisthotonus), Pharyngeal muscle spasm or laryngospasm can be life-threatening lifeGeneralized rigidity, Hypokinesia/ Dyskinesia, tremors, irritability, involuntary movement, apparent marked crying/screaming, distress with constant crying/screaming, whimpering, agitation Pediatr Clin North Am. 1989 Oct;36(5):1285-91 Oct;36(5):1285-

Extrapyramidal Side Effects (EPS)

Metoclopramide: incidence is 0.2%, as high as 20% in Metoclopramide: children with high doses. Most often Acute dystonia, usually within the first 24-72 hours after initiation of 24medication, and often subside within 24 hours after withdrawal from therapy. Delayed signs may develop, most profound is tardive dyskinesia: reported rarely & usually occurs after prolonged use (months to years) Dystonic reactions are likely to occur if the recommended dose is exceeded (0.5 mg/kg/d), but individual susceptibility to metoclopramide and the cumulative effect of repeated doses of the drug may also be important Sudden onset, usually within minutes to days of initiating onset, or increasing dose of causative agent. Vital signs normal & mental status unaffected
Pediatr Clin North Am. 1989 Oct;36(5):1285-91 Oct;36(5):1285-

Extrapyramidal Side Effects (EPS)

Dystonia can include pharyngeal or laryngospasm which results in upper airway obstruction AIRWAY MANAGEMENT Medication: IV or IM diphenhydramine, diazepam or Medication: benzotropine (>3 yrs: 0.02-0.05 mg/kg/dose IV/IM/PO 0.02qDay/BID) Continue medication* for 48-72 hours to prevent relapse. 48Benztropine/ Diphenhydramine/ Trihexyphenidyl Cases where diagnosis is uncertain the administration of diazepam is a good therapeutic trial. Diazepam given IV trial. causes the patients to fall asleep immediately and to wake within an hour, free from all symptoms IV: route of choice, with S & S often resolving within 10 minutes. minutes. IM, if an IV line cannot be established will take 30 min to be absorbed. >1 dose may be necessary for complete resolution http://emedicine.medscape.com/article/814632http://emedicine.medscape.com/article/814632-followup

Evidence Supporting Antihistamines

Allergic Rhinoconjunctivitis Urticaria Atopic Dermatitis Upper Respiratory Infections Otitis Media Asthma Anaphylaxis
1= randomized controlled trials 2= case control cohort study 3= consensus of expert groups A= Good evidence for use B= Some evidence for use C= Evidence neither for or against use D= Strong evidence against use
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 28-40 28-

1A 1A 1B 3D 3D 1C 3B

Evidence Supporting Antihistamines

Young children experience an average of six to eight colds per year. The use of antihistamines and decongestants in children with acute sinusitis cannot be recommended Many people self-prescribe OTC cough preparations & health selfpractitioners often recommend their use for the initial treatment of cough. The results of review suggest that there is no good evidence for or against the effectiveness of OTC medications in acute cough Antihistamines alone are not an effective treatment for the common cold, but might have a small effect in combination with decongestives: this review has been withdrawn Children with asthma can find using inhaled treatments medication difficult and so oral medication such as ketotifen, which is an antihistamine, can be used to help control symptoms. The review found that mild asthma symptoms were well-controlled in the studies wellof 4 to 32 week duration with reduction in use of rescue bronchodilator, rescue oral steroids and in exacerbations as well as clear perception of effectiveness from physicians, parents and children

Common Drugs & Doses: AH-G1 AHStructural Class

1. Ethanolamine
(Prototype: Diphenhydramine) Clemastine

Characteristics
Significant antimuscarinic activity Sedation, somnolence (50%) q Incidence of GI symptoms Effective in emesis & motion sickness

Dosages
(Cap. Benadryl 25/50mg, syr. 12.5 mg/5ml, inj. 50 mg/ml amp. & 10 mg/ml vial) BENADRYL COUGH FORMULA [J & J] Syr: diphenhydramine 14.08 mg, NH4Cl 0.138 g, sodium citrate 57.03 mg, menthol 1.14 mg 5 mg/kg/d q6h IM/IV/PO, Adult 25-50 mg tds (Max. 300 25mg/d) For Anaphylaxis or Phenothiazine overdose: 1-2 1mg/kg slow iv Caution in bronchial asthma

2.Ethylenediamine/ Ethylamine
Pyrilamine Mepyramine Pyranesamine

Most specific H1 antagonist Reduced Anticholinergic activity Feeble CNS effects Somnolence GI s/s common

Common Drugs & Doses: AH-G1 AHStructural Class Characteristic s

3.Alkylamine (Prototype Chlorpheniramine)
Most potent Not so prone to develop drowsiness More suitable for older patients Sedation/CNS stimulation

Dosages
Chlorpheniramine Maleate: (Tab. Piriton/Cadistin 4 mg) 0.35 mg/kg/d, Adult 2-4 mg tds/qid 2Nelson: 2-6 yrs: 1 mg, 6-12 yrs: 2 26mg, > 12 yrs: 4 mg q4-6h q4Paradoxical excitation, constipation, caution in asthma Dexchlorpheniramine Maleate: (Tab. Polaramine 2,6 mg, Syr. 0.5 mg/5ml) Age Based: 2-5 yrs: 0.5 mg q6-8h 2q6(max 3 mg/d), 6-11 yrs: 1 mg q6-8h 6q6(max 6 mg/d), Adult: 2 mg tds or 4-6 4mg hs Pheniramine Maleate: (Tab. Avil 25/50 mg, Inj. 22.75 mg/mL, 2 mL amp, 10 mL vial) 0.3 0.5 mg/kg/day q8h, PO,IM,IV Adult: PO 25 mg BID-TID (up to 100 BIDmg/d), IM/IV 22.5-45 mg BID 22.5Vial preparation is for IM use only

Common Drugs & Doses: AH-G1 AHStructural Class Characteristics

3.Alkylamine (Prototype Chlorpheniramine)

Dosages
Pheniramine Maleate: (Tab. Avil 25/50 mg, Inj. 22.75 mg/mL, 2 mL amp, 10 mL vial) 1.5 mg/kg IV/IM can be given in case of Acute Urticaria. [Medical Emergencies in Children; Meharban Singh, 3rd Ed] BromPpeniramine Maleate: For PO/IV/IM/SC Use
Triprolidine: (Syr. Recofast-Shreya RecofastTriprolidine 2.5 mg + Phenylephrine 5 mg per 5 mL)

4 mo-2 yrs: 0.313 mg q4-6h (max moq41.25 mg/d) 2-4 yrs: 0.625 mg q4-6 h (max 2.5 q4mg/d) 4-6 yrs: 0.938 mg q4-6h (max 3.7 q4mg/d) 6-12 yrs: 1.25 mg q4-6 h (max 5 q4mg/d) Adult: 2.5 mg q4-6h (Max 10 mg/d) q4Ref. Merck Manual, 18th Ed, 2006

Common Drugs & Doses: AH-G1 AHStructural Class

4. Piperazine (Cyclizine Hydroxyzine Cetirizine)

Characteristics
Moderate sedative & significant antiemetic actions Cyclizine and meclizine have been used primarily to counter motion sickness, although promethazine and diphenhydramine (dimenhydrinate) are more effective

Dosages
Hydroxyzine HCL (Tab. Atarax/Hicope/Prugo 10/25mg, Syr. 10 mg/5ml, Dps 6 mg/ml, Inj. 25 mg/ml) 2 mg/kg/d q6-8h PO, q60.50.5-1 mg/kg/dose q4-6h IM q4Nelson: 0.5-0.6 mg/kg/dose 6 0.5hourly, Adult: 10-100 mg/dose tid10tidqid {1 ml/kg/day divided 6-8 6hourly}, > 1 yea/ 6 mo Nausea & V: 0.25-1 mg/kg/dose 0.25q4q4-6h PO/iv/im/PR Cholinergic urticaria can be treated with hydroxyzine and dermographism with hydroxyzine or diphenhydramine. Cyproheptadine HCL (Tab. Ciplactin/PCL 4 mg, syr. 2 mg/5 ml) 0.25-0.5 mg/kg/d q8-12h 0.25q8Nelson: 2-6 yrs: 2 mg/dose q82q812h, >7 yrs/adults: 4 mg/dose q8q812h (Max. 0.5 mg/kg/24hr) Esp. Cold Urticaria: DOC (0.5 q8h), not appetite stimulant

5. Piperidines (Cyproheptadine, Phenindamine, Azatadine)

Highly selective H1 Moderate to low sedation Cyproheptadine uniquely has both antihistamine and antiserotonin activity. Cyproheptadine can cause drowsiness & significant anticholinergic effects

Common Drugs & Doses: AH-G1 AHStructural Class

6. Phenothiazines (Prototype: Promethazine)

Characteristics
Significant sedative, and pronounced antiemetic & antimuscarinic effects Photosensitivity reactions

Dosages
Promethazine HCl: (Tab. Phena/Phenergan/Avomine MD 25 mg theoclate 10,25 mg, Syr. 5 mg/5ml, Inj. 25 mg/ml) Antihistaminic: 0.5 mg/kg/d (max 12.5 mg/dose) q6-8h,OR q60.5 mg/kg hs PRN (max 25 mg)PO, > 2 yrs Sedation: 0.5-1 mg/kg/dose 0.5(max 50 mg) q6h PRN Motion Sickness: 0.5 mg/kg/dose q8-12h PO (1st q8dose to 1 hr before journey) Nausea & Vomiting: 0.25-1 0.25mg/kg/dose q4-6h PO/iv/im/PR q4Photosensitizer, Vague muscle spasm IM preferable to IV. IV should be diluted to a max of 25 mg/mL. SC can cause skin necrosis. Potential for fatal respiratory depression <2 years age

Common Drugs & Doses: AH-G2 AHSecondSecond-Generation Piperazines (Cetirizine) A metabolite of Hydroxyzine, Cetirizine is the only drug in this class. It has minimal anticholinergic effects. It also has negligible penetration into the brain but is associated with a somewhat higher incidence of drowsiness than the other second-Gen. secondNo reported cardiac side effects. Cetirizine (Tab. Alerid/Cetzine/Zyrtec 10 mg, Syr. 5 mg/5ml, Drops Zyrtec 10 mg/mL) 6 mo-2 yrs: 2.5 mg/d, 2-5 yrs: 2.5 mg/d q12-24h, 6 yr: 5mo2q12510 mg/d, Adult 10-20 mg/d, 0.25 mg/kg/d for < 6 yrs 10[Reduce dose with renal disease] Levocetirizine (Syr. Levocet/Lazine/1-AL 2.5 mg/5 mL) Levocet/Lazine/16 mo-5 yrs: 1.25 mg (2.5 mL once daily) in the evening, 6mo611 yrs: 2.5 mg/d, u 12 yrs: 5 mg/d
Goodman & Gilmans Manual of Pharmacology & Therapeutics, 11th Ed, 2008

Common Drugs & Doses: AH-G2 AHSecondSecond-Generation Piperidines (Prototype: Loratadine) Highly selective for H1 receptors, lack significant anticholinergic actions, & penetrate poorly into the CNS. Loratidine: (Tab. Alaspan/Loridin 10 mg, Syr. 5 mg/5ml) 2-5 yrs: 5 mg OD, 0.2 mg/Kg/d, 6 yrs: 10 mg OD 30 Kg: 5 mg OD, > 30 Kg 10 mg OD Desloratidine: (Syr. Desloratidine: (Syr. Rodera/Desent/Aerius 2.5 mg/5ml) 6-11 mo. 2 ml OD (1 mg), 12 mo-5 yrs 2.5 ml OD, 6-11 yrs 5 mo6ml OD : usfda guidelines Fexofenadine: (Tab. Allegra 30/120/180 mg, Syr. Fexy/Histafree/Fexidine 30 mg/5 ml) 6 mo-2 yrs (for CIU): 15 mg (2.5 mL) BD, 2-11 yrs 30 mg (5 mo2mL) BD. For Seasonal Allergic Rhinitis 2-11 yrs: 30 mg (5 2mL) BD 12 yrs & adults: SAR 120 mg OD, CIU 180 mg OD SE: Headache, fatigue, nausea dizziness

Miscellaneous Drugs
Terfenadine (Tab. Terfed/Trexyl 60 mg, Syr. 30 mg/5 mL): 3-6 yrs: 15 mg BID, 6-12 yrs 30 mg BID, > 12 yrs & adults 60 mg BID 6CI: Concomitant admn with erythromycin & other macrolides, ketoconazole, metrogyl. May prolong Qt interval & fatal arrhythmias. Avoid below 3 yrs. Astemizole (Tab. Stemiz/Histeese/Histalong 10 mg, Syr 5 mg/5 mL): < 6 yrs: 0.2 mg/kg OD, 6-12 yrs: 5 mg OD, >12 yrs & adults 10 mg OD (up 6to 30 mg OD by weekly increase) Same precaution as with Terfenadine. Caution hepatic disease. Azatadine (Tab. Zadine 1 mg, Syr 0,5 mg/5 mL): > 12 yrs & adults: 1-2 mg/dose BID 1Clemastine (Tab. Tavegyl 1.34 mg, Syr. 0.67 mg/5 mL, Tab. Clamist 1 mg, Syr. 0.5 mg/5 mL) 1-6 yrs: 0.05 mg/kg/d q8-12h (max 1 mg/d), 6-12 yrs: 0.5 mg/dose BID q86(max 3 mg/d), >12yrs & adults: 1 mg BID (max 6 mg/d) Dimethendene Maleate (Tab. Foristal 1 mg): > 12 yrs & adults: 1-2 mg TID, or SR Tab. 2.5 mg BID (Foristal lontab) 1Methdialazine (Tab. Dilosyn 8 mg, Syr. 4 mg/5 mL): > 3 yrs: 4 mg (5 mL) BID-TID, Adults: 8 mg BID BID-

A Word About Loratadine

Loratadine:
Inhibits the late phase allergic reaction by acting on leukotrienes or prostaglandins or by producing an antiantiplatelet activating factor (PAF) effect Loratadine is rapidly and almost completely absorbed Tmax : 1 hour, Plasma protein binding: 97% - 99% The t for loratadine and its metabolite were 14.4 and 18.7 hours, respectively Loratadine is excreted in the urine (40%) and feces (42%) over a 10-day period 10Descarboethoxyloratadine is the major active metabolite Loratadine or its metabolite have little or no accumulation after multiple once per day dosage regime Not removed by dialysis in case of poisoning

A Word About Loratadine

Loratadine:
Adverse effects: Fatigue, Dizziness, Dry mouth, Headache, Sedation, Nausea, Pruritus No cardiac toxicity Increased plasma concentrations of loratadine have been reported after concomitant use with azole (fluconazole/itra/keto), erythro/azithro/clarithro-mycin or erythro/azithro/clarithrocimetidine, but without clinically significant changes Safe in children above 2 yrs of age In severe hepatic/renal impairment: Lower initial dose 5 mg daily or 10 mg every alternate day Somnolence, tachycardia and headache have been reported with overdoses. A single acute ingestion of 160 mg produced no adverse effects in adults. Symptomatic and Supportive Treatment should be started in overdose

Second Generation Review

Drug Cetirizine Age Approved u 6 mo Sedation ? Most Potent ? Most Potent Least Sedating
Avoid in renal failure Avoid in renal failure

Levocetirizine u 6 mo Desloratidine Fexofenadine Loratidine Ebastine u 6 mo u 6 mo u 2 yr u 2 yr

Other Agents: Ebastine

Ebastine is a new piperidine-containing, relatively piperidinenonsedating AH-G2 AHEbastine has a unique chemical structure that differs from other second generation antihistamines. After oral administration, ebastine undergoes extensive first-pass firstmetabolism by hepatic cytochrome P450 3A4 into its active carboxylic acid metabolite, carebastine. This reaction has a conversion rate of 100% [Prodrug] [Prodrug] Prompt onset of action and a long duration of action, is suitable for once-daily administration to children onceDose: (Tab. Ebast DT 5 mg, 10 mg) Adult: 10-20 mg once daily, Child: >6 yr: 5 mg once daily 105 10 and 2.5 mg, appears to be efficient and can be used safely in children 6 11 and 2 5 years of age, respectively1
Expert Opinion on Pharmacotherapy, August 2004, Vol. 5, No. 8 : Pages 1807-1813 1807-

Other Agents: Rupatadine

Rupatadine is a second generation antihistamine and PAF antagonist Approved for the treatment of allergic rhinitis and chronic years. urticaria in adults and children over 12 years. The Defined Daily Dose (DDD) is 10 mg orally The efficacy of Rupatadine as treatment for allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) has been investigated in adults and adolescents (aged over 12 years) in several controlled studies, showing a rapid onset of action and a good safety profile even in prolonged treatment periods of a year

Expert Opinion on Pharmacotherapy, August 2004, Vol. 5, No. 8 : Pages 1807-1813 1807-

Other Agents: Ketotifen

Ketotifen is a ?second generation antihistamine & mast cell stabilizer This drug is available in two forms: an ophthalmic form used to treat allergic conjunctivitis or itchy red eyes and an oral form used to prevent asthma attacks Used for temporary prevention of itching due to allergic conjunctivitis Dose: Children 3 years & adults: 1 drop every 8-12 years 8It has several adverse side effects including drowsiness, weight gain, dry mouth, irritability and increased nose bleeds Tab. Ketasma (Sun)/Asthafen/Tritofen 1 mg, Syr. Tritofen 1 mg/5 mL Dose: Children > 2 years: 1 mg/day OD. Can be increased years: gradually to a max of 1 mg BD
Expert Opinion on Pharmacotherapy, August 2004, Vol. 5, No. 8 : Pages 1807-1813 1807-

Efficacy Vs Potency
No universally effective antihistamine is yet available Potency to suppress histamine induced wheal & flare response: Cetirizine > Fexofenadine > Loratadine The majority of studies found levocetirizine to be the most potent of the antihistamines tested, including the parent compound cetirizine The most potent antihistamine is probably the antiantidepressant doxepin (TCA) CPM & Diphendydramine are supposed to be most potent among 1st gen Hydroxyzine (Atarax) is most potent Antihistamine for Pruritus: Family Practice Notebook, Sedating Antihistamines, 2010 Promethazine is the most potent for motion sickness & vertigo Terfenadine: most potent for solar urticaria
Expert Opinion on Pharmacotherapy, August 2004, Vol. 5, No. 8 : Pages 1807-1813 1807-

1st Gen
Potent Multiple dosing required Acts both on central and peripheral receptors Penetrate the blood brain barrier so common side effects are sedation and anti-cholinergic action antiIngestion at bedtime may result in hangover following morning

2nd Gen
More specific blockers of H1 receptors Less lipophilic -longer therapeutic activity, Less frequent dosing Limited sedation No anticholinergic side effects Individual drawbacks like drug interactions, cardio toxicity and lack of potency

Vulnerable Populations
Infants < 6 months: no H1 antihistamine is approved Infants 6 mo 2 years: safety data for 4 drugs years: cetirizine, levocetirizine, desloratadine & fexofenadine Children 2 5 years: most are approved; but few are studied Pregnancy & lactation: Cetirizine, loratadine Elderly: Fexofenadine is the safest

Decongestants with AH
Alpha adrenergic agents (topical/oral): duration of efficacy is limited because of rebound congestion & systemic responses such as insomnia, irritability, hypertension. Useful in enhancing the efficacy of AH in relieving the nasal congestion & may diminish their sedative effects. Potency: Phenylpropalamine > Pseudoephedrine > Phenylephrine Should not be prescribed for > 7 days Avoided below 2 years of age Pseudoephedrine (PSE): More effective than Phenylephrine Dosing interval 4 6 hourly Dose: 2-12 yrs: 4 mg/kg/d [or 15 mg q4-6h for 2-6 yrs, 30 2q42mg/dose for 6-12 yrs], > 12 yrs/adults: 60 mg/dose. SR 6preparation can be given 120 mg BID or 240 mg OD Phenylephrine: Dosing interval 4 hourly Dose: 6-12 yrs: 2.5 mg 4 hourly, > 12 yrs/adults: 5 mg 4 hourly 6-

Menthol with AH
Menthol is chiefly used to relieve symptoms of bronchitis, sinusitis, and similar conditions. For this purpose it may be used as an inhalation, usually with benzoin or eucalyptus oil, oil, as pastilles, or as an ointment with camphor and eucalyptus oil for application to the chest or nostrils. However, the use of menthol in inhalations is unlikely to provide any additional benefit When applied to the skin menthol dilates the blood vessels, causing a sensation of coldness followed by an analgesic effect. It relieves itching and is used in creams, lotions, or ointments in pruritus and urticaria. It has also been applied to the forehead, presumably as a counter-irritant, for the relief of counterheadache In small doses by mouth menthol has a carminative action

Martindale, The Complete Drug Reference, 36th Ed, 2009

Mucolytics with AH
Bromhexine is a mucolytic used in the treatment of respiratory disorders associated with productive cough. Bromhexine is usually given orally in a dose of 8 to 16 mg of the hydrochloride three times daily [Children 2-5 yrs: 2 2mg/dose TID, 6-12 yrs: 4 mg TID, >12 yrs: 8 mg TID] 6Bromhexine hydrochloride is rapidly absorbed from the gastrointestinal tract; peak plasma concentrations occur after about 1 hour. Bromhexine undergoes extensive first-pass firstmetabolism in the liver: its oral bioavailability is stated to be only about 20% Ambroxol is a metabolite of bromhexine and is used similarly as a mucolytic. It is given in a usual oral daily dose of 60 to 120 mg of the hydrochloride (* 1.5 2 mg/kg/d) in 2 divided doses. It can also been given by inhalation, injection, or rectally
Martindale, The Complete Drug Reference, 36th Ed, 2009

Guaifenesin with AH
Guaifenesin is licensed for use as an expectorant in children; however, over-the-counter cough and cold over-thepreparations containing expectorants (including guaifenesin) should be used with caution in children and generally avoided in those under 2 years of age. Typical licensed oral doses, given every 4 hours, are: hours, 6 months to 2 years, 25 to 50 mg 2 to 6 years, 50 to 100 mg 6 to 12 years, 100 to 200 mg UK preparations suggest that these doses be given up to a maximum of 4 times daily, although in other countries higher total doses may be given A small study found that guaifenesin also appeared to reduce cough reflex sensitivity in patients with upper respiratoryrespiratory-tract infections, which produce a transient infections, increase in sensitivity, although it had no effect on cough reflex in healthy subjects

Coloring Agents with AH

Tartrazine, Quinolone yellow & Sunset yellow (Yellow), Cramoisine & Ponceau 4R (Red) Meta-analysis results support the hypothesis that artificial Metafood colors promote hyperactivity in hyperactive children as measured on behavioral ratings. Food Standards Agency (FSA) studies have shown that eating foods or drinks containing these can cause urticaria, urticaria, dermatitis, asthma, dermatitis, asthma, or rhinitis. Under EC guidelines, rhinitis. medicines should carry a warning that additives may cause may allergic reactions. Foods and drinks carry no such warning, reactions. despite been consumed in much greater quantities. All these are banned from all foods and drinks for the under threes in UK Sodium Benzoate (Preservative): Sodium benzoate is banned from all foods and drinks for the under threes, but is allowed in medicines aimed at children of the same age

Some Cough & Cold Preparations

Syr. Brand
Sinarest (Centaur) Wikoryl (Wallace)

Anti-H1 Anti-

Decongestant Antipyretic
125 mg PCM 125 mg PCM 125 mg PCM

Misc.
60 mg Na Citrate Menthol base Carmoisine

1 mg CPM 5 mg Phenylephrine 1 mg CPM -dodo-

2 mg CPM 5 mg SolvinCold Phenylephrine (Ipca), Delcon PLUS (Veritaz) Maxtra P (Zuventus) Febrex Plus (Indoco) 1 mg CPM 5 mg Phenylephrine 1 mg CPM 2.5 mg Phenylephrine

Carmoisine

125 mg PCM 125 mg PCM 60 mg Na Citrate

Sunset Yellow FCF

Tartrazine, carmoisine

*contents per 5 mL of preparation

Some Cough & Cold Preparations

Syr. Brand
Sinarest PLUS (Centaur) WikorylWikoryl-DS (Wallace) Fluzet (Rexcel) AlexAlex-P (Glenmark) SinarestSinarest-PD (Centaur) Coldman (Dyota Numandis)

Anti-H1 Anti2 mg CPM

Decongestant Antipyretic
5 mg Phenylephrine 5 mg Phenylephrine 5 mg Phenylephrine 2.5 mg Phenylephrine 2.5 mg Phenylephrine 5 mg Phenylephrine 250 mg PCM 250 mg PCM 250 mg PCM 170 mg PCM 125 mg PCM 250 mg PCM

Misc.
60 mg Na Citrate Menthol base

2 mg CPM

60 mg Na Citrate

Menthol base, Sunset yellow FCF Menthol base, Sunset yellow FCF PonceauPonceau4R Menthol base

2 mg CPM

10 mg Dextrmeth orphan 5 mg Dextromet horphan 60 mg Na Citrate

1.5 mg CPM 1 mg CPM 2.5 mg Cetirizine

Some Cough & Cold Preparations

Syr. Brand
Coldsol (Synchem) Coldsol DM (Synchem) NamcoldNamcold-Z (Lincoln) NamcoldNamcold-ZForte TussinTussin-DMR (Synchem)

Anti-H1 Anti1.25 mg Cetirizine 1.25 mg Cetirizine 0.5 mg Desloratadi ne 1.25 mg Desloratadi ne 5 mg Cetirizine

Decongestant Antipyreti c
2.5 mg Phenylephrine 2.5 mg Phenylephrine 2.5 mg Phenylephrine 5 mg Phenylephrine 10 mg Phenylephrine 125 mg PCM 125 mg PCM 125 mg PCM 250 mg PCM 30 mg Ambroxol

Misc.
25 mg Na Citrate Dextrome thorphan 10 mg 7.5 mg Ambroxol 15 mg Ambroxol Dextrome thorphan 15 mg
1 mg Menthol, Erythrocine, Carmoisine 1 mg Menthol, PonceauPonceau-4R

5 mg Zinc Gluconate, Carmoisine

10 mg Zinc Gluconate, Carmoisine

75 mg Na Citrate,
Sunset Yellow FCF

Some Cough & Cold Preparations

Syr. Brand Anti-H1 AntiDecongestant Antipyretic
12.5 mg PPA 12.5 mg PPA 15 mg PSE 125 mg PCM 125 mg PCM 125 mg PCM
Carmoisine

Misc.

Rinostat Plus 1 mg CPM (RPG(RPG-LS) OnsetOnset-CF (Medley) HatricHatric-3 (Aristo) 2.5 mg Cetirizine 1 mg CPM

Most of the preparations have irrational combination Dose can not be standardized for a particular child Side effects limit the usefulness in young children May cause bronchospasm & aggravate cough

FDA warns of giving children cough, cold meds

An FDA review of side-effect records filed with the sideagency between 1969 and September 2006, found 54 reports of deaths in children associated with decongestant medicines made with Pseudoephedrine, Phenylephrine or ephedrine. 69 reports of deaths associated with antihistamine medicines containing diphenhydramine, brompheniramine or chlorpheniramine. Most of the deaths in children younger than 2. The Consumer Healthcare Products Association, which Association, represents makers of over-the-counter medicines, backs over-thethe recommendation that the cold and cough treatments not be used in children younger than 2 Evidence suggests the drugs are not only risky but also dont work in the very young
http://www.fda.gov/forconsumers/consumerupdates/ucm048682.htm

Summary
 Second-generation antihistamines are the Seconddrugs of choice for the recommended treatment indications  Many 1st Gen drugs alone or in combination are OTC, hence potential for toxicity  First-generation drugs should be held in Firstreserve for infrequent situations where their adverse effects may prove desirable, or when parenteral dosing is required

Thanks