Egészségügy | Farmakológia » Pharmacology of Antihistamines

Source: http://www.doksinet Pharmacology of antihistamines Source: http://www.doksinet Autacoids – local hormons endogenous peptides  PGs  LTs,  Cytokines  and biologically active amines (histamine, serotinin)  2011.0516 2 Source: http://www.doksinet History Dale and Laidlow 1910, 1911 – smooth muscle stimulation and vasodepressor action  Best et al. 1927 isolated H from liver and lung  Greek word for tissue = histos  Lewis’ “H-substance” liberates from cell after skin injury, 1927  2011.0516 3 Source: http://www.doksinet     Three distinct classes of receptors: H1 (1966), H2 (1972), H3 (1983) H1 blockers: antihistamines, second generation antagonists: nonsedating antihistamines H3 function: feedback inhibition of H1 receptor-mediated action Chemistry       Histamine = -aminoethylimidazole 2-methylhistamine: H1 agonist 4-methylhistamine: H2 agonist Betazole and impromidine agonists at H2 and

antagonists at H3 H3 agonist: (R)--methylhistamine (crosses BBB), imetit, immepip H3 antagonist: thioperamide, clobenpropit (crosses BBB) 2011.0516 4 Source: http://www.doksinet Initial events of a local acute inflammation 2011.0516 PAMP: Pathogen Associated Molecular Pattern 5 Source: http://www.doksinet Phases of asthma 2011.0516 6 Source: http://www.doksinet Effects of histamine  Nervous system     Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. H1-mediated urticarial response (insect and nettle stings) Respiratory neurons signaling inspiration and expiration are modulated by H1 receptors Presynaptic H3 receptors play important roles in modulating transmitter release in the nervous system. H3 agonists reduce the release of acetylcholine, amine, and peptide transmitters in various areas of the brain and in peripheral nerves. 2011.0516 7 Source: http://www.doksinet Effects of histamine

- cardiovascular system   Injection causes a decrease in systolic and diastolic blood pressure and an increase in heart rate - direct vasodilator action on arterioles and precapillary sphincters; the increase in heart rate involves both stimulatory actions of histamine on the heart and a reflex tachycardia Flushing, headache consistent with the vasodilation. Vasodilation elicited by small doses of histamine is caused by H1-receptor activation and is mediated primarily by release of nitric oxide from the endothelium. The decrease in blood pressure is usually accompanied by a reflex tachycardia. Higher doses of histamine activate the H2-mediated cAMP process of vasodilation and direct cardiac stimulation.  Histamine-induced edema results from the action of the amine on H1 receptors in the vessels of the microcirculation, especially the postcapillary vessels. The effect is associated with the separation of the endothelial cells, which permits the transudation of fluid and

molecules as large as small proteins into the perivascular tissue.  Increased contractility and increased pacemaker rate. These effects are mediated chiefly by H2 receptors. In human atrial muscle, histamine can also decrease contractility; this effect is mediated by H1 receptors. 2011.0516 8 Source: http://www.doksinet Effects of histamine – bronchial smooth muscle     Causes bronchoconstriction (H1). Patients with asthma are very sensitive to histamine. Hyperactive neural response Methacholine provocation is more commonly used, tests using increasing doses of inhaled histamine have been used in the diagnosis of bronchial hyperreactivity in patients with suspected asthma or cystic fibrosis. Such individuals may be 100- to 1000-fold more sensitive to histamine (and methacholine) than are normal subjects. A few species (eg, rabbit) respond to histamine with bronchodilation, reflecting the dominance of the H2 receptor in their airways. 2011.0516 9 Source:

http://www.doksinet Effects of histamine - Gastrointestinal tract smooth muscle    Histamine causes contraction of intestinal smooth muscle Histamine-induced contraction of guinea pig ileum is a standard bioassay for this amine. The human gut is not as sensitive as that of the guinea pig, but large doses of histamine may cause diarrhea, partly as a result of this effect. This action of histamine is mediated by H1 receptors. 2011.0516 10 Source: http://www.doksinet Effects of histamine – secretory tissue     Histamine is a stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. The effect is caused by activation of H2 receptors on gastric parietal cells and is associated with increased adenylyl cyclase activity, cAMP concentration, and intracellular Ca2+ concentration. Other stimulants of gastric acid secretion such as acetylcholine and gastrin do not increase cAMP even though their maximal

effects on acid output can be reduced by H2-receptor antagonists. Histamine also stimulates secretion in the small and large intestine. In contrast, H3-selective histamine agonists inhibit acid secretion stimulated by food or pentagastrin in several species. 2011.0516 11 Source: http://www.doksinet Effects of histamine- triple response  Intradermal injection causes red spot, edema, and flare response that was first described over 60 years ago (Lewis). The effect involves three separate cell types: smooth muscle in the microcirculation, capillary or venular endothelium, and sensory nerve endings. At the site of injection, a reddening appears owing to dilation of small vessels, followed soon by an edematous wheal at the injection site and a red irregular flare surrounding the wheal. The flare is said to be caused by an axon reflex A sensation of itching may accompany these effects.  Similar local effects may be produced by injecting histamine liberators (compound 48/80,

morphine, etc) intradermally or by applying the appropriate antigens to the skin of a sensitized person. Although most of these local effects can be blocked by prior administration of an H1receptor-blocking agent, H2 and H3 receptors may also be involved. 2011.0516 12 Source: http://www.doksinet Histamine Receptor Roles  H1 receptor     H2 receptor   Vasodilation Increased capillary permeability Bronchoconstriction Increase gastric acid secretion H3 receptor  Sedation Source: http://www.doksinet Antihistamines Bovet et al. 1944: pyrilamine maleate, then diphenhydramine and tripelennamine, in 1980s the non-sedating agents were developed.  All antagonists are reversible, competitive inhibitor. Contain substitute ethylamine moiety.  2011.0516 14 Source: http://www.doksinet Histamine & Antihistamine  H1 blockers:  First generation More sedating, more ANS-blocking (diphenhydramine)  Less sedatin, less ANS-blocking

(chlorpheniramine)   Second generation   (Loratadine, Astemizole, Terfenadine) H2 blockers:   Cimetidine, Ranitidine, Nizatidine, Famotidine H3 blockers (presynaptic heterorexceptor with modulatory effects on the release of other transmitters) Source: http://www.doksinet Antihistamine Agents  First generation  Sedating chlorpheniramine  diphenhydramine (Benadry®)  clemastine  promethazine (Phergan®)   Second generation  No sedating (BBB) terfenadine  fexofenadine  Loratadine  astemizole  cetirizine*  * Active metabolite Source: http://www.doksinet Pharmacological action      Smooth muscle: antagonism of bronchoconstriction in guinea pigs, in humans little or no effec (because LTs and PAF is the responsible for bronchoconstriction. Inhibits the vasoconstrictor effect in large vessels and vasodilator effect in small vessels. Inhibit capillary permeability, flare, itch and edema formation.

Actions on CNS: Central depression (diminished alertness, slowed reaction time, somnolence) Variable susceptibility to individual drugs. Ethanolamines are particularly prone to cause sedation. Second generation of H1 blockers (non-sedating antihistamines) � Do not cross BBB. They are good agains motion sickness: dimenhydrinate, diphenhydramine, various piperazine derivatives, promethazine (they have anticholinergic activities, atropine-like effects). The second generation drugs (terfenadine, astemizol, loratidine) do not have atropin-like effect. Local anaesthetic effect: some H1 blockers have, e.g promethazine 2011.0516 17 Source: http://www.doksinet Histamine Antagonists Actions  H1 receptors blockade resulting in:         inhibit smooth muscle contraction decrease wheal, flare,and itch decrease secretions: salivary and lachrymal CNS: sedation Relief of manifestations of immediate-type hypersensitivity reactions allergic rhinitis cold remedies

newer agents “selective” for peripheral H 1 receptors  less sedation (dose dependant) Source: http://www.doksinet Side effects Sedation: Concurrent ingestion of alcohol or other CNS depressant produces an additive effect. Dizziness, tinnitus, lassitude, incoordination, fatigue blurred vision, diplopia, euphoria, nervousness, insomnia, tremor, loss of appetite, nausea, vomiting, epigastric distress, diarrhoea, constipation. Dryness of the mouth and respiratory passages, cough, urinary retention and dysuria (atropin-like effect, but not for 2nd generation of H1 blockers). Sometimes increase appetite and wheight gain  Polymorphic ventricular tachycardia and torsades de pointes: 2nd generation terfenadine and astemizole cause prolongation of QTc. When CYP3A4 is not able to metabolize the parent drug (coadministration of CYP3A4 inhibitor drug, such as grapefruit juice), the parent drug, but not the metabolite, blocks delayed rectifier K+ channel as do sotalol and quinidine.

Hepatic dysfunction and preexisting prolonged QTc interval are risk factors. To bypass this problem fexofenadine was evaluated, which is a carboxylated terfenadine. Terfenadine was withdrawn Carboxylated drugs: Fexofenadine, Cetirizine, Acrivastine, Levocabastine, Ebastine�Cerebastine.  CYP3A4 inhibitors: macrolide antibiotics (erythromycin, clarithromycin), antifungal agents (ketoconazole, itroconazole, grapefruit juice.  Loratidine, however metabolized by CYP3A4, does not appear to be associated with this toxicity. Cetirizine and acrivastine have not been shown to prolong QTc interval. 2011.0516 19  Source: http://www.doksinet Side effects (cont.) Drug allergy: topical application: allergic dermatitis, photosensitization. Leucopenia, agranulocytosis, hamolytic anaemia are rare.  Acute poisoning: hallucinations, excitement, ataxia, incoordination, athetosis, convulsions. Fixed, dilated pupils with flushed face, sinus tachycardia, urinary retention, dry mouth, fever

(like in atropin poisoning)  2011.0516 20 Source: http://www.doksinet Available H1 antagonists Ethanolamines (Prototype: Diphenhydramine): Significant antimuscarinic effect, sedation, somnolence  Ethylenediamines (Prototype: Pyrilamine): Central effects are feeble, low incidence of somnolence, GI side effects are common. Tripelennamine  Alkylamines (Prototype:Chlorpheniramine): Most potent H1 antagonists. Most suitable for daytime use, but cause sedation  Piperazines (Prototype: Chlorcyclizine): Prolonged action, low incidence of drowsiness. Hydroxyzine is widely used for skin allergies. Cetirizine: active metabolite of hydroxyzine, poorly penetrate BBB. Cyclizine, meclizine against motion sickness.  Phenothiazines (Prototype: Promethazine): Possess anticholinergic activity. Prominent sedative and antiemetic effect.  Piperidines (Prototype: Terfenadine): astemizole, loratidine: 2011.0516 Highly selective to H1 and devoid of atropine-like effects. Do21 

Source: http://www.doksinet Therapeutic uses           Allergy: Acute types of allergy (rhinitis, urticaria, conjunctivitis, hay fever, pollinosis). Suppress only the symptoms Not used to treat systemic anaphylaxis, angioedema (laryngeal swelling) (epinephrine is used). For topical treatment: levocabastine. Good in the treatment of pruritus, atopic and contact dermatitis, insect bite and ivy poisoning (szomorce). Used in the treatment of drug allergy Motion sickness: dimenhydrinate, meclizine (Meniere’s disease) and piperazines and promethazine (phenothiazine). Antiemetic effect: doxylamine in vomiting in pregnancy Antiparkinsonian effect: Diphenhydramine is as adjuvant treatment of Parkinson’s disease, but less effective as trihexyphenidyl Sedation: Some of them are useful as “sleep-aids”, take care children occasionally manifest excitation Anticholinoceptor action: 1st generation ethanolamine, ethylenediamine subgroups atropin-like effects

Adrenoceptor blocking effect: -receptor blockade: Phenothiazine subgroup (promethazine)� orthostatic hypotension. Serotonin blocking action: 1st generation: cyproheptadine, promoted as an antiserotonin agent Local anaesthetic effect: 1st generation: they block sodium channel, diphenhydramine and promethazine. They are useful to produce local anaesthesia if the patient is allergic to conventional local anaesthetic drugs. Other action: terfenadine, acrivastine blocks P-glycoprotein transporter found in cancer cells, epithelium of the gut, and the capillaries of the brain. 2011.0516 22