Chapter 18: Autocoids and Antihistamines Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 18 Outline Autocoids and antihistamines Histamine (H1 or H2) Antihistamines (H1-receptor antagonists) Peripheral (nonsedating) H1-receptor antagonists Other autocoids

Autocoids and Antihistamines Haveles (p. 234) Autocoids all occur naturally in the body, are produced by many tissues, and are formed by the tissues on which they act Agonists or antagonists include H1- and H2-receptor antagonists (H-RAs) or blockers, the eicosanoids (prostaglandins [PGs], thromboxanes [TXs], and leukotrienes [LTs]), serotonin agonists, angiotensin inhibitors, and cytokinins

Histamine Pharmacologic effects Adverse reactions Uses Haveles (pp. 234-235) Pharmacologic effects Adverse reactions Uses cont’d…

Histamine A ubiquitous biogenic amine Haveles (pp. 234-235) (Fig. 18-1) A ubiquitous biogenic amine Almost all mammalian tissues contain or can synthesize histamine In humans, histamine is stored in mast cells, intestinal mucosa, and in the central nervous system (CNS) (mast cell in tissue = basophil in the bloodstream) During an allergic reaction, mast cells degranulate and histamine is released

Pharmacologic Effects of Histamine Haveles (p. 234) H1-agonist effects: vasodilation, increased capillary permeability, bronchoconstriction, and pain or itching in cutaneous nerve endings H2-agonist effects: increased gastric acid secretion cont’d…

Pharmacologic Effects of Histamine Haveles (pp. 234-235) Agents that block or antagonize the effects of histamine at the H1-receptors are known as H1-blockers or H1-RAs, and at the H2-receptors they are H2-blockers or H2-RAs

Adverse Reactions of Histamine Haveles (p. 235) When an allergic reaction occurs, an antibody-antigen reaction causes release of histamine and other autocoids Anaphylaxis is a serious and sometimes fatal reaction to a foreign protein or drug introduced into the body Anaphylaxis may involve difficulty in breathing due to bronchoconstriction, convulsions, lapses into unconsciousness, and death The predominant feature is bronchoconstriction cont’d…

Adverse Reactions of Histamine Other effects involve vasodilation and increased capillary permeability, both of which lead to decreased blood pressure followed by shock and cardiovascular collapse cont’d…

Adverse Reactions of Histamine The drug of choice for anaphylaxis is parenteral epinephrine A physiologic antagonist that dilates bronchioles via β2-receptors rather than an antihistamine An antihistamine is a pharmacologic antagonist that blocks bronchoconstriction produced by histamine at the same H1-receptor Antihistamines antagonize only some of the effects of histamine, and they work competitively, whereas epinephrine acts as a direct β2-agonist

Uses of Histamine No clinical uses of histamine have been established Haveles (p. 235) No clinical uses of histamine have been established

Antihistamines (H1-Receptor Antagonists) Haveles (pp. 235-238) Pharmacologic effects Adverse reactions Toxicity Uses cont’d…

Antihistamines (H1-Receptor Antagonists) Haveles (p. 235) Antihistamine refers to agents that are H1-RAs or H1-receptor blockers Many patients have seasonal allergic reactions A mild allergic reaction to a drug may be treated with antihistamines Patients taking antihistamines may experience side effects such as xerostomia Antihistamines interact with many other drug groups and are additive with other CNS depressants

Pharmacologic Effects of Antihistamines Haveles (pp. 235-236) (Fig. 18-2; Table 18-1) Older H1-RAs have several pharmacologic effects, including antihistaminic, anticholinergic, antiserotonergic, and sedative effects Effects can be divided into those caused by blocking histamine at the H1-receptor and those independent of this effect

H1-Receptor Blocking Effects of Antihistamines Haveles (p. 235) Drugs that are H1-antagonists competitively block or antagonize histamine’s effect at the following sites Capillary permeability: blocking capillary permeability produced by histamine reduces tissue edema Vascular smooth muscle (vessels): antihistamines block dilation Nonvascular (bronchial) smooth muscle: because other autocoids are also released in an anaphylactic reaction, antihistamines are not effective in counteracting all the bronchoconstriction present Nerve endings: antihistamines can suppress itching and pain associated with histamine-mediated reaction at cutaneous nerve endings

Other Effects (Unrelated to H1-Blocking Effects) of Antihistamines Haveles (pp. 235-236) CNS: antihistamines produce varying degrees of CNS depression (may be used to induce sleep) Anticholinergic: can be used to dry up secretions Antiemetic: some antihistamines, such as meclizine (Dramamine, Bonine), have pronounced antiemetic or antimotion sickness activity Also effective in controlling dizziness, nausea, and vomiting with Ménière’s syndrome Local anesthesia: may be used to provide some local anesthesia

Adverse Reactions of Antihistamines Haveles (pp. 236-237) (Fig. 18-2) Vary in relative amounts among the different agents CNS depression: can be a pharmacologic effect or adverse reaction Sedation is the most common side effect associated with older antihistamines; may be accompanied by dizziness, tinnitus, incoordination, blurred vision, and fatigue When antihistamines are combined with decongestants, CNS depression of the antihistamine is counteracted by CNS stimulation of the decongestant cont’d…

Adverse Reactions of Antihistamines Gastrointestinal (GI) complaints associated with antihistamines include anorexia, nausea, vomiting, and constipation Anticholinergic: H1-RAs have varying anticholinergic effects Anticholinergic effects lead to xerostomia

Toxicity of Antihistamines Haveles (p. 237) Antihistamine poisoning has become more common in recent years Excitation predominates in small children, and sedation can occur in adults Death usually results from coma with cardiovascular and respiratory collapse

Uses of Antihistamines Haveles (pp. 237-238) Allergic reactions: allergic rhinitis and seasonal hay fever can be controlled by antihistamines Acute urticarial attacks can be treated Nausea and vomiting: used to prevent and treat motion sickness and to control postoperative vomiting and vomiting induced by radiation therapy cont’d…

Uses of Antihistamines Haveles (pp. 237-238) Preoperative sedation: because of their sedative effects Over-the-counter sleep aids: diphenhydramine (Nytol) is used in over-the-counter sleep aids Local anesthesia: diphenhydramine (Benadryl) can be used by injection to provide some local anesthesia

Examples of Antihistamines Haveles (p. 236) (Table 18-1) Ethanolamines diphenhydramine (Benadryl) carbinoxamine (Clistin) clemastine (Tavist) Ethylenediamines tripelennamine (PBZ) pyrilamine (various) cont’d…

Examples of Antihistamines Haveles (p. 236) (Table 18-1) Alkylamines chlorpheniramine (Chlor-Trimeton) dexchlorpheniramine (Polaramine) brompheniramine (Dimetane) Phenothiazines promethazine (Phenergan) cont’d…

Examples of Antihistamines Haveles (p. 236) (Table 18-1) Piperadines cyproheptadine (Periactin) azatadine (Optimine) phenindamine (Nolahist) Piperazines hydroxyzine (Vistaril, Atarax)

Peripheral (Nonsedating) H1-Receptor Antagonists Haveles (pp. 226, 238) (Table 18-1) No common chemical denominator, they are different in origin, chemical structure, solubility, and metabolic effects All block peripheral H1-receptors Do not cross the blood-brain barrier, do not produce sedation cont’d…

Peripheral (Nonsedating) H1-Receptor Antagonists Haveles (p. 236) fexofenadine (Allegra): an active metabolite of terfenadine (Seldane) Side effects include drowsiness and viral infections loratadine (Claritin) desloratadine (Clarinex) cetirizine (Zyrtec) acrivastine (Semprex) azelastine (Astelin)

Other Autocoids PGs and TXs LTs Kinins Substance P Haveles (pp. 238-240) PGs and TXs LTs Kinins Substance P

Prostaglandins and Thromboxanes Haveles (pp. 238-239) Members of a group of biologically active agents termed eicosanoids Produced in the body in response to many different stimuli and small quantities produce a large spectrum of effects on many different body systems

Pharmacologic Effects of Prostaglandins Haveles (pp. 238-239) Not only is there a wide spectrum of action, but also different PGs have different activities in different tissues Smooth-muscle effects: vascular smooth muscle may be relaxed or stimulated, depending on the specific PGs Platelets: TX stimulates platelet aggregation and is a vasoconstrictor; PGI inhibits platelet aggregation and is a vasodilator Effects on reproductive organs: both PGE and PGF have oxytocic action CNS: PGs increase body temperature by releasing interleukin-1 Other effects: increased heart rate and cardiac output

Dental Implications PGs have been implicated in periodontal disease Haveles (p. 239) PGs have been implicated in periodontal disease At least two stages of periodontal disease may involve PGs The first is inflammation of the gingiva with erythema, edema, and increase in gingival exudate The second is the resorption of alveolar bone with tooth loss

Uses of Prostaglandins Haveles (p. 239) PGs may be used for inducing midtrimester abortions A PG agonist (misoprostol [Cytotec]) is available for prevention of nonsteroidal antiinflammatory agent–induced ulcers PGs are being studied in treatment of bronchial asthma and hypertension

Prostaglandin Antagonists Haveles (p. 239) Administration of PG antagonists may prove useful in the treatment of certain pathologic conditions Aspirin can inhibit platelet aggregation by blocking TX Indomethacin blocks the effects of PGs on ductus arteriosus

Leukotrienes Haveles (p. 239) Another complex group of autocoids that are also derived from arachidonic acid Cause strong bronchoconstriction in humans They also contract other smooth muscle such as the uterus and GI tract

Kinins Haveles (pp. 239-240) Polypeptides that are distributed in a great variety of body tissues Kallidin and bradykinin are found in plasma and may play a role in dental diseases Plasma kinins may be involved in shock and acute or chronic allergic or inflammatory conditions such as anaphylaxis and arthritis

Substance P Haveles (p. 240) A peptide thought to function as a neurotransmitter in the CNS and a local hormone in the GI tracts A vasodilator and produces hypotension Increases the action of the intestinal and bronchial smooth muscle Causes secretion in the salivary glands