Histamine and Antihistamine ppt / Histamine and Antihistamine Classification PHARMACOLOGICAL ACTIONS / Histamine and Antihistamine pharmacology action

Histamine and Antihistamine

Qualitatively all H1 antihistaminics have similar actions, but there are quantitative differences, especially in the sedative property.

1. Antagonism of histamine : 

                                                The H1 antagonists effectively block histamine induced bronchoconstriction, contraction of intestinal and other smooth muscle and triple response— especially wheal, flare and itch. Fall in BP produced by low doses of histamine is blocked, but additional H2 antagonists are required for complete blockade of that caused by higher doses. Pretreatment with these drugs protects animals from death due to i.v. injection of large doses of histamine. Release of Adr from adrenal medulla in response to histamine is abolished. Constriction of larger blood vessel by histamine is also antagonized. Action of histamine on gastric secretion is singularly not affected by these drugs. Cyproheptadine had additional 5-HT2 receptor blocking activity (see p. 189).

2. Antiallergic action :

                                                  Many manifestations of immediate hypersensitivity (type I reactions) are suppressed. Urticaria, itching and angioedema are well controlled. Anaphylactic fall in BP is only partially prevented. Asthma in man is practically unaffected, though anaphylactic bronchoconstriction in guinea pig is largely prevented. This tissue and species dependence of response probably reflects extent of involvement of histamine in the reaction. It is now well established that leukotrienes (LTC4 , LTD4 ) and PAF are more important mediators for human asthma.

                                                 

3. CNS :

                    The older antihistamines produce variable degree of CNS depression. This appears to depend on the compound’s ability to penetrate the blood-brain barrier and its affinity for the central (compared to peripheral) H1 receptors. Individual susceptibility to different agents varies considerably. The same drug and dose may incapacitate some subjects, while others may remain alert. An overall grading of the sedative property of H1 antihistaminics is presented in Table 11.2. Some individuals also experience stimulant effects like restlessness and insomnia. Excitement and convulsions are frequently seen at toxic doses. The second generation antihistaminics are practically nonsedating.

              Certain (see below) H1 antihistamines are effective in preventing motion sickness. It is not clear whether this is due to antagonism of histamine in the brain or reflects antimuscarinic property of these drugs. Promethazine also controls vomiting of pregnancy and other causes.

           Promethazine and few other antihistaminics reduce tremor, rigidity and sialorrhoea of parkinsonism. Anticholinergic and sedative properties underlie the benefit.

 Some older antihistamines, especially cyproheptadine, have appetite stimulating effect.

 Some H1 antihistamines are also effective antitussives (see Ch. 16).

4. Anticholinergic action :

                                                     Many H1 blockers in addition antagonize muscarinic actions of ACh. The antimuscarinic action can be graded as:

If used concurrently with atropine or its substitutes, phenothiazines, tricyclic antidepressants or disopyramide, the anticholinergic action adds up.

5. Local anaesthetic :

                                              Some drugs like pheniramine, promethazine, diphenhydramine have strong while others have weak membrane stabilizing property. However, they are not clinically suitable local anaesthetics because they cause irritation when injected s.c.

Membrane stabilizing activity confers antiarrhythmic property to these compounds.

6. BP :

               Most antihistaminics cause a fall in BP on i.v. injection (direct smooth muscle relaxation or α adrenergic blockade). Promethazine has significant α blocking activity. However, this is not evident on oral administration, though postural hypotension can occur in susceptible individuals.

PHARMACOKINETICS :

                                                                   The conventional H1 antihistaminics are well absorbed from oral and parenteral routes, metabolized in the liver and excreted in urine. They are widely distributed in the body and enter brain. The newer compounds penetrate brain poorly accounting for their low/absent sedating action. Duration of action of most agents is 4–6 hours, except meclozine, chlorpheniramine, mesolastine, loratadine, cetirizine and fexofenadine which act for 12–24 hours or more. The H1 antihistaminics are mainly administered orally, but few are available for i.m./i.v. use as well.  

SIDE EFFECTS AND TOXICITY :

                                                         Side effects of first generation H1 antihistaminics are frequent, but generally mild. Individuals show marked differences in susceptibility to side effects with different drugs. Some tolerance to side effects develops on repeated use.

 

                                                          Sedation, diminished alertness and concentration, light headedness, motor incoordination, fatigue and tendency to fall asleep are the most common. Objective testing shows impairment of psychomotor performance. Patients should be cautioned not to operate motor vehicles or machinery requiring constant attention. Alcohol synergises in producing these effects as do other CNS depressants. Few individuals, however, become restless, nervous and are unable to sleep. Second generation compounds are largely free of CNS effects. 

                                            Regular use of conventional antihistamines is not advisable in children, because the CNS depressant property may interfere with learning and academic tasks. 

                                       Dryness of mouth, alteration of bowel movement, urinary hesitancy and blurring of vision can be ascribed to anticholinergic property of older antihistaminics.

                                                Epigastric distress and headache may be felt. Local application can cause contact dermatitis. Some drugs like hydroxyzine, cyclizine and fexofenadine are teratogenic in animals; but there is no evidence of excess malformations in humans. Caution is nevertheless to be exercised in prescribing an antihistaminic during pregnancy.

                                                Acute overdose produces central excitation, tremors, hallucinations, muscular incordination, convulsions, flushing, hypotension, fever and some other features of belladonna poisoning. Death is due to respiratory and cardiovascular failure.

SECOND GENERATION ANTIHISTAMINICS :

                                                  The second generation antihistaminics (SGAs) may be defined as those H1 receptor blockers marketed after 1980 which have one or more of the following properties:

•  Absence of CNS depressant property. 
•  Higher H1 selectivitiy: no anticholinergic side effects. 
• Additional antiallergic mechanisms apart from histamine blockade: some also inhibit late phase allergic reaction by modifying release/ action of leukotrienes, platelet activating factor (PAF) and cytokines, etc.

As per an international consensus group of experts, no compound developed so far merits labelling as ‘third generation antihistaminic’.

                                           These newer drugs have the advantage of not impairing psychomotor performance (driving, etc. need not be contraindicated), produce no subjective effects, no sleepiness, do not potentiate alcohol or benzodiazepines. Some patients do complain of sedation, but incidence is similar to that with placebo. However, they have a narrow spectrum of therapeutic usefulness which is limited by the extent of involvement of histamine (acting through H1 receptors) in the disease state. Their principal indications are:

 (i) Allergic rhinitis and conjunctivitis, hay fever, pollinosis: they control sneezing, runny but not                 blocked nose, and red-watering-itchy eyes. 

 

(ii) Urticaria, dermographism, atopic eczema. 

(iii) Acute allergic reactions to drugs and foods. 

The SGAs have poor antipruritic, antiemetic and  antitussive actions.

Fexofenadine :

                                 It is the active metabolite of terfenadine, the first nonsedating SGA that was withdrawn because of several deaths due to polymorphic ventricular tachycardia (Torsades de pointes) occurring with its higher doses or when it was coadministered with CYP3A4 inhibitors (erythromycin, clarithromycin, ketoconazole, itraconazole, etc.). This toxicity is based on blockade of delayed rectifier K+ channels in the heart at higher concentrations. Astemizole is another SGA banned for the same reason. Fexofenadine has a low propensity to block delayed rectifier K+ channels, does not prolong QTc interval. Since it is minimally metabolized, no interaction with CYP3A4 inhibitors have been reported. It is largely free of arrhythmogenic potential, but some cases of ventricular arrhythmia in patients with preexisting long QT interval have been reported. Thus, it is not entirely safe in patients with long QT, bradycardia or hypokalemia.

                            Fexofenadine penetrates blood-brain barrier poorly; produces minimal sedation or impairment of psychomotor performance. It is free of atropinic side effects. oral absorption is rapid. It is mainly excreted unchanged in urine and bile, has plasma t½ 11–16 hours and duration of action 24 hours.

Dose: For allergic rhinitis 120 mg OD; for urticaria and other skin allergies 180 mg OD.

Loratadine :

                            Another long-acting selective peripheral H1 antagonist which lacks CNS depressant effects and is fast acting. It is partly metabolized by CYP3A4 to an active metabolite with a longer t½ of 17 hr, but has not produced cardiac arrhythmia in overdose, though seizures are reported. No interaction with macrolides or antifungals has been noted. Good efficacy has been reported in urticaria and atopic dermatitis.

 

Desloratadine :

                                   It is the major active metabolite of loratadine effective at half the dose. Noninterference with psychomotor performance and cardiac safety are documented.

Cetirizine :

                        It is a metabolite of hydroxyzine with marked affinity for peripheral H1 receptors; penetrates brain poorly, but mild sedation and subjective somnolence is experienced by many recipients. It is not metabolized; does not prolong cardiac action potential or produce arrhythmias when given with erythromycin/ ketoconazole.

                        Cetirizine in addition inhibits release of histamine and of cytotoxic mediators from platelets as well as eosinophil chemotaxis during the secondary phase of the allergic response. Thus, it may benefit allergic disorders by other actions as well. It attains high and longer lasting concentration in skin, which may be responsible for superior efficacy in urticaria/atopic dermatitis, as well as for once daily dosing despite elimination t½ of 7–10 hr. It is indicated in upper respiratory allergies, pollinosis, urticaria and atopic dermatitis; also used as adjuvant in seasonal asthma.

Levocetirizine :

                                  is the active R(–) enantiomer of cetirizine. It is effective at half the dose and appears to produce less sedation and other side effects.

Azelastine :

                            This newer H1 blocker has good topical activity; in addition it inhibits histamine release and inflammatory reaction triggered by LTs and PAF. After intranasal application it has been shown to down regulate intracellular adhesion molecule-1 (ICAM-1) expression on nasal mucosa. Its t½ is 24 hr, but action lasts longer due to active metabolite. Its metabolism is inhibited by CYP 3A4 inhibitors. Given by nasal spray for seasonal and perennial allergic rhinitis it provides This newer H1 blocker has good topical activity; in addition it inhibits histamine release and inflammatory reaction triggered by LTs and PAF. After intranasal application it has been shown to down regulate intracellular adhesion molecule-1 (ICAM-1) expression on nasal mucosa. Its t½ is 24 hr, but action lasts longer due to active metabolite. Its metabolism is inhibited by CYP 3A4 inhibitors. Given by nasal spray for seasonal and perennial allergic rhinitis it provides.

Mizolastine :

                            This nonsedating antihistaminic is effective in allergic rhinitis and urticaria by single daily dosing despite a t½ of 8–10 hr and no active metabolite. 

Ebastine :

                       Another newer SGA that rapidly gets converted to the active metabolite carbastine having a t½ of 10–16 hr. It is nonsedating and active in nasal and skin allergies. Animal studies have found it to prolong Q-Tc interval which makes it liable to arrhythmogenic potential and CYP3A4 interaction, but actual reports are still few.

 

Rupatadine :

                            This recently introduced antihistaminic has additional PAF antagonistic property, and is indicated in allergic rhinitis.

USES :

The uses of H1 antihistaminics are based on their ability to block certain effects of histamine released endogeneously, as well as on their sedative and anticholinergic properties.

1. Allergic disorders :

                                            Antihistaminics do not suppress AG: AB reaction, but block the effects of released histamine—are only palliative. They effectively control certain immediate type of allergies, such as itching, urticaria, seasonal hay fever, allergic conjunctivitis and angioedema of lips, eyelids, etc. However, their action is slow, therefore Adr alone is life-saving in laryngeal angioedema, while intravenously administered antihistaminic may have adjuvant value. Similarly, they cannot be relied upon in anaphylactic shock and have a secondary place to Adr. Benefits are less marked in perennial vasomotor rhinitis, atopic dermatitis and chronic urticarias; combination with an H2 antagonist succeeds in some cases of chronic urticaria not responding to H1 antagonist alone.

The antihistaminics are ineffective in bronchial asthma: reasons may be—

• Leukotrienes (LTC4 , D4 ) and PAF are more important mediators in humans than histamine. 
• Concentration of antihistamines attained at the site may not be sufficient to block high concentration of histamine released locally in the bronchi.