chapter 18: autocoids and antihistamines copyright © 2011, 2007 mosby, inc., an affiliate of...

Chapter 18:Chapter 18:

Autocoids and AntihistaminesAutocoids and Antihistamines

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

22Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 18 OutlineChapter 18 Outline

Autocoids and antihistaminesAutocoids and antihistamines Histamine (HHistamine (H1 1 or Hor H22))

Antihistamines (HAntihistamines (H11-receptor antagonists)-receptor antagonists)

Peripheral (nonsedating) HPeripheral (nonsedating) H11-receptor antagonists-receptor antagonists

Other autocoidsOther autocoids


Autocoids and AntihistaminesAutocoids and Antihistamines

Haveles (p. 234)Haveles (p. 234) Autocoids all occur naturally in the body, are Autocoids all occur naturally in the body, are

produced by many tissues, and are formed by produced by many tissues, and are formed by the tissues on which they actthe tissues on which they act Agonists or antagonists include HAgonists or antagonists include H11- and H- and H22--

receptor antagonists (H-RAs) or blockers, the receptor antagonists (H-RAs) or blockers, the eicosanoids (prostaglandins [PGs], thromboxanes eicosanoids (prostaglandins [PGs], thromboxanes [TXs], and leukotrienes [LTs]), serotonin agonists, [TXs], and leukotrienes [LTs]), serotonin agonists, angiotensin inhibitors, and cytokininsangiotensin inhibitors, and cytokinins


HistamineHistamine

Haveles (pp. 234-235)Haveles (pp. 234-235) Pharmacologic effectsPharmacologic effects Adverse reactionsAdverse reactions UsesUses

cont’d…cont’d…


HistamineHistamine

Haveles (pp. 234-235) (Fig. 18-1)Haveles (pp. 234-235) (Fig. 18-1) A ubiquitous biogenic amineA ubiquitous biogenic amine

Almost all mammalian tissues contain or can Almost all mammalian tissues contain or can synthesize histaminesynthesize histamine

In humans, histamine is stored in mast cells, In humans, histamine is stored in mast cells, intestinal mucosa, and in the central nervous intestinal mucosa, and in the central nervous system (CNS) (mast cell in tissue = basophil system (CNS) (mast cell in tissue = basophil in the bloodstream)in the bloodstream) During an allergic reaction, mast cells degranulate During an allergic reaction, mast cells degranulate

and histamine is releasedand histamine is released


Pharmacologic Effects of Pharmacologic Effects of HistamineHistamine

Haveles (p. 234)Haveles (p. 234)

HH11-agonist effects: vasodilation, increased -agonist effects: vasodilation, increased

capillary permeability, bronchoconstriction, capillary permeability, bronchoconstriction, and pain or itching in cutaneous nerve endingsand pain or itching in cutaneous nerve endings

HH22-agonist effects: increased gastric acid -agonist effects: increased gastric acid

secretionsecretion



Pharmacologic Effects of Pharmacologic Effects of HistamineHistamine

Haveles (pp. 234-235)Haveles (pp. 234-235) Agents that block or antagonize the effects of Agents that block or antagonize the effects of

histamine at the Hhistamine at the H11-receptors are known as -receptors are known as

HH11-blockers -blockers oror H H11-RAs-RAs, and at the H, and at the H22--

receptors they are receptors they are HH22-blockers -blockers oror H H22-RAs-RAs


Adverse Reactions of HistamineAdverse Reactions of Histamine

Haveles (p. 235) Haveles (p. 235) When an allergic reaction occurs, an antibody-When an allergic reaction occurs, an antibody-

antigen reaction causes release of histamine antigen reaction causes release of histamine and other autocoidsand other autocoids

Anaphylaxis is a serious and sometimes fatal Anaphylaxis is a serious and sometimes fatal reaction to a foreign protein or drug introduced reaction to a foreign protein or drug introduced into the bodyinto the body Anaphylaxis may involve difficulty in breathing due to Anaphylaxis may involve difficulty in breathing due to

bronchoconstriction, convulsions, lapses into bronchoconstriction, convulsions, lapses into unconsciousness, and deathunconsciousness, and death

The predominant feature is bronchoconstrictionThe predominant feature is bronchoconstrictioncont’d…cont’d…



Other effects involve vasodilation and Other effects involve vasodilation and increased capillary permeability, both of increased capillary permeability, both of which lead to decreased blood pressure which lead to decreased blood pressure followed by shock and cardiovascular followed by shock and cardiovascular collapsecollapse




The drug of choice for anaphylaxis is The drug of choice for anaphylaxis is parenteral epinephrineparenteral epinephrine A physiologic antagonist that dilates bronchioles A physiologic antagonist that dilates bronchioles

via via ββ22-receptors rather than an antihistamine-receptors rather than an antihistamine

• An antihistamine is a pharmacologic antagonist that An antihistamine is a pharmacologic antagonist that blocks bronchoconstriction produced by histamine at the blocks bronchoconstriction produced by histamine at the same Hsame H11-receptor-receptor

• Antihistamines antagonize only some of the effects of Antihistamines antagonize only some of the effects of histamine, and they work competitively, whereas histamine, and they work competitively, whereas epinephrine acts as a direct epinephrine acts as a direct ββ22-agonist-agonist


Uses of HistamineUses of Histamine

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

established established


AntihistaminesAntihistamines(H(H11-Receptor Antagonists) -Receptor Antagonists)

Haveles (pp. 235-238)Haveles (pp. 235-238) Pharmacologic effectsPharmacologic effects Adverse reactionsAdverse reactions ToxicityToxicity UsesUses



AntihistaminesAntihistamines(H(H11-Receptor Antagonists) -Receptor Antagonists)

Haveles (p. 235)Haveles (p. 235)

Antihistamine refers to agents that are Antihistamine refers to agents that are HH11--

RAs or HRAs or H11-receptor blockers-receptor blockers Many patients have seasonal allergic reactionsMany patients have seasonal allergic reactions A mild allergic reaction to a drug may be treated A mild allergic reaction to a drug may be treated

with antihistamineswith antihistamines Patients taking antihistamines may experience side Patients taking antihistamines may experience side

effects such as xerostomiaeffects such as xerostomia Antihistamines interact with many other drug groups Antihistamines interact with many other drug groups

and are additive with other CNS depressantsand are additive with other CNS depressants


Pharmacologic Effects of Pharmacologic Effects of AntihistaminesAntihistamines

Haveles (pp. 235-236) (Fig. 18-2; Table 18-1)Haveles (pp. 235-236) (Fig. 18-2; Table 18-1)

Older HOlder H11-RAs have several pharmacologic -RAs have several pharmacologic

effects, including antihistaminic, effects, including antihistaminic, anticholinergic, antiserotonergic, and sedative anticholinergic, antiserotonergic, and sedative effectseffects Effects can be divided into those caused by Effects can be divided into those caused by

blocking histamine at the Hblocking histamine at the H11-receptor and those -receptor and those

independent of this effectindependent of this effect


HH11-Receptor Blocking Effects of -Receptor Blocking Effects of

AntihistaminesAntihistamines Haveles (p. 235)Haveles (p. 235)

Drugs that are HDrugs that are H11-antagonists competitively block or antagonize -antagonists competitively block or antagonize histamine’s effect at the following siteshistamine’s effect at the following sites Capillary permeability: blocking capillary permeability Capillary permeability: blocking capillary permeability

produced by histamine reduces tissue edemaproduced by histamine reduces tissue edema Vascular smooth muscle (vessels): antihistamines block Vascular smooth muscle (vessels): antihistamines block

dilationdilation Nonvascular (bronchial) smooth muscle: because other Nonvascular (bronchial) smooth muscle: because other

autocoids are also released in an anaphylactic reaction, autocoids are also released in an anaphylactic reaction, antihistamines are not effective in counteracting all the antihistamines are not effective in counteracting all the bronchoconstriction presentbronchoconstriction present

Nerve endings: antihistamines can suppress itching and pain Nerve endings: antihistamines can suppress itching and pain associated with histamine-mediated reaction at cutaneous associated with histamine-mediated reaction at cutaneous nerve endingsnerve endings


Other Effects (Unrelated to HOther Effects (Unrelated to H11-Blocking -Blocking

Effects) of AntihistaminesEffects) of Antihistamines Haveles (pp. 235-236)Haveles (pp. 235-236)

CNS: antihistamines produce varying degrees of CNS: antihistamines produce varying degrees of CNS depression (may be used to induce sleep)CNS depression (may be used to induce sleep)

Anticholinergic: can be used to dry up secretionsAnticholinergic: can be used to dry up secretions Antiemetic: some antihistamines, such as Antiemetic: some antihistamines, such as

meclizine (Dramamine, Bonine), have meclizine (Dramamine, Bonine), have pronounced antiemetic or antimotion sickness pronounced antiemetic or antimotion sickness activityactivity Also effective in controlling dizziness, nausea, and Also effective in controlling dizziness, nausea, and

vomiting with Mvomiting with Ménière’s syndromeénière’s syndrome Local anesthesia: may be used to provide some Local anesthesia: may be used to provide some

local anesthesialocal anesthesia


Adverse Reactions of Adverse Reactions of AntihistaminesAntihistamines

Haveles (pp. 236-237) (Fig. 18-2)Haveles (pp. 236-237) (Fig. 18-2) Vary in relative amounts among the different Vary in relative amounts among the different

agentsagents CNS depression: can be a pharmacologic effect CNS depression: can be a pharmacologic effect

or adverse reactionor adverse reaction Sedation is the most common side effect associated Sedation is the most common side effect associated

with older antihistamines; may be accompanied by with older antihistamines; may be accompanied by dizziness, tinnitus, incoordination, blurred vision, and dizziness, tinnitus, incoordination, blurred vision, and fatiguefatigue

When antihistamines are combined with When antihistamines are combined with decongestants, CNS depression of the antihistamine decongestants, CNS depression of the antihistamine is counteracted by CNS stimulation of the is counteracted by CNS stimulation of the decongestantdecongestant



Adverse Reactions of Adverse Reactions of AntihistaminesAntihistamines

Gastrointestinal (GI) complaints associated Gastrointestinal (GI) complaints associated with antihistamines include anorexia, nausea, with antihistamines include anorexia, nausea, vomiting, and constipationvomiting, and constipation

Anticholinergic: HAnticholinergic: H11-RAs have varying -RAs have varying

anticholinergic effectsanticholinergic effects Anticholinergic effects lead to xerostomiaAnticholinergic effects lead to xerostomia


Toxicity of AntihistaminesToxicity of Antihistamines

Haveles (p. 237)Haveles (p. 237) Antihistamine poisoning has become more Antihistamine poisoning has become more

common in recent yearscommon in recent years Excitation predominates in small children, and Excitation predominates in small children, and

sedation can occur in adultssedation can occur in adults Death usually results from coma with cardiovascular Death usually results from coma with cardiovascular

and respiratory collapseand respiratory collapse


Uses of AntihistaminesUses of Antihistamines

Haveles (pp. 237-238)Haveles (pp. 237-238) Allergic reactions: allergic rhinitis and seasonal Allergic reactions: allergic rhinitis and seasonal

hay fever can be controlled by antihistamineshay fever can be controlled by antihistamines Acute urticarial attacks can be treatedAcute urticarial attacks can be treated

Nausea and vomiting: used to prevent and Nausea and vomiting: used to prevent and treat motion sickness and to control treat motion sickness and to control postoperative vomiting and vomiting induced postoperative vomiting and vomiting induced by radiation therapyby radiation therapy



Uses of AntihistaminesUses of Antihistamines

Haveles (pp. 237-238)Haveles (pp. 237-238) Preoperative sedation: because of their Preoperative sedation: because of their

sedative effectssedative effects Over-the-counter sleep aids: diphenhydramine Over-the-counter sleep aids: diphenhydramine

(Nytol) is used in over-the-counter sleep aids(Nytol) is used in over-the-counter sleep aids Local anesthesia: diphenhydramine (Benadryl) Local anesthesia: diphenhydramine (Benadryl)

can be used by injection to provide some local can be used by injection to provide some local anesthesiaanesthesia


Examples of AntihistaminesExamples of Antihistamines

Haveles (p. 236) (Table 18-1)Haveles (p. 236) (Table 18-1) EthanolaminesEthanolamines

diphenhydramine (Benadryl)diphenhydramine (Benadryl) carbinoxamine (Clistin)carbinoxamine (Clistin) clemastine (Tavist)clemastine (Tavist)

EthylenediaminesEthylenediamines tripelennamine (PBZ)tripelennamine (PBZ) pyrilamine (various)pyrilamine (various)




Haveles (p. 236) (Table 18-1)Haveles (p. 236) (Table 18-1) AlkylaminesAlkylamines

chlorpheniramine (Chlor-Trimeton)chlorpheniramine (Chlor-Trimeton) dexchlorpheniramine (Polaramine)dexchlorpheniramine (Polaramine) brompheniramine (Dimetane)brompheniramine (Dimetane)

PhenothiazinesPhenothiazines promethazine (Phenergan)promethazine (Phenergan)




Haveles (p. 236) (Table 18-1)Haveles (p. 236) (Table 18-1) PiperadinesPiperadines

cyproheptadine (Periactin)cyproheptadine (Periactin) azatadine (Optimine)azatadine (Optimine) phenindamine (Nolahist)phenindamine (Nolahist)

PiperazinesPiperazines hydroxyzine (Vistaril, Atarax)hydroxyzine (Vistaril, Atarax)


Peripheral (Nonsedating) HPeripheral (Nonsedating) H11--

Receptor AntagonistsReceptor Antagonists Haveles (pp. 226, 238) (Table 18-1)Haveles (pp. 226, 238) (Table 18-1)

No common chemical denominator, they are No common chemical denominator, they are different in origin, chemical structure, different in origin, chemical structure, solubility, and metabolic effectssolubility, and metabolic effects All block peripheral HAll block peripheral H11-receptors-receptors

Do not cross the blood-brain barrier, do not Do not cross the blood-brain barrier, do not produce sedationproduce sedation



Peripheral (Nonsedating) HPeripheral (Nonsedating) H11--

Receptor AntagonistsReceptor Antagonists Haveles (p. 236)Haveles (p. 236)

fexofenadine (Allegra): an active metabolite of fexofenadine (Allegra): an active metabolite of terfenadine (Seldane)terfenadine (Seldane) Side effects include drowsiness and viral infectionsSide effects include drowsiness and viral infections

loratadine (Claritin)loratadine (Claritin) desloratadine (Clarinex)desloratadine (Clarinex) cetirizine (Zyrtec)cetirizine (Zyrtec) acrivastine (Semprex)acrivastine (Semprex) azelastine (Astelin)azelastine (Astelin)


Other Autocoids Other Autocoids

Haveles (pp. 238-240)Haveles (pp. 238-240) PGs and TXsPGs and TXs LTsLTs KininsKinins Substance PSubstance P


Prostaglandins and Prostaglandins and ThromboxanesThromboxanes

Haveles (pp. 238-239)Haveles (pp. 238-239) Members of a group of biologically active agents Members of a group of biologically active agents

termed termed eicosanoidseicosanoids Produced in the body in response to many different Produced in the body in response to many different

stimuli and small quantities produce a large spectrum stimuli and small quantities produce a large spectrum of effects on many different body systemsof effects on many different body systems


Pharmacologic Effects of Pharmacologic Effects of ProstaglandinsProstaglandins

Haveles (pp. 238-239)Haveles (pp. 238-239) Not only is there a wide spectrum of action, but also Not only is there a wide spectrum of action, but also

different PGs have different activities in different tissuesdifferent PGs have different activities in different tissues Smooth-muscle effects: vascular smooth muscle may be Smooth-muscle effects: vascular smooth muscle may be

relaxed or stimulated, depending on the specific PGsrelaxed or stimulated, depending on the specific PGs Platelets: TX stimulates platelet aggregation and is a Platelets: TX stimulates platelet aggregation and is a

vasoconstrictor; PGI inhibits platelet aggregation and is a vasoconstrictor; PGI inhibits platelet aggregation and is a vasodilatorvasodilator

Effects on reproductive organs: both PGE and PGF have Effects on reproductive organs: both PGE and PGF have oxytocic actionoxytocic action

CNS: PGs increase body temperature by releasing interleukin-CNS: PGs increase body temperature by releasing interleukin-11

Other effects: increased heart rate and cardiac outputOther effects: increased heart rate and cardiac output


Dental Implications Dental Implications

Haveles (p. 239)Haveles (p. 239) PGs have been implicated in periodontal PGs have been implicated in periodontal

diseasedisease At least two stages of periodontal disease may At least two stages of periodontal disease may

involve PGsinvolve PGs• The first is inflammation of the gingiva with erythema, The first is inflammation of the gingiva with erythema,

edema, and increase in gingival exudateedema, and increase in gingival exudate

• The second is the resorption of alveolar bone with tooth The second is the resorption of alveolar bone with tooth lossloss


Uses of ProstaglandinsUses of Prostaglandins

Haveles (p. 239)Haveles (p. 239) PGs may be used for inducing midtrimester PGs may be used for inducing midtrimester

abortionsabortions A PG agonist (misoprostol [Cytotec]) is A PG agonist (misoprostol [Cytotec]) is

available for prevention of nonsteroidal available for prevention of nonsteroidal antiinflammatory agent–induced ulcersantiinflammatory agent–induced ulcers

PGs are being studied in treatment of PGs are being studied in treatment of bronchial asthma and hypertensionbronchial asthma and hypertension


Prostaglandin AntagonistsProstaglandin Antagonists

Haveles (p. 239)Haveles (p. 239) Administration of PG antagonists may prove Administration of PG antagonists may prove

useful in the treatment of certain pathologic useful in the treatment of certain pathologic conditionsconditions Aspirin can inhibit platelet aggregation by blocking Aspirin can inhibit platelet aggregation by blocking

TXTX Indomethacin blocks the effects of PGs on ductus Indomethacin blocks the effects of PGs on ductus

arteriosusarteriosus


LeukotrienesLeukotrienes

Haveles (p. 239)Haveles (p. 239) Another complex group of autocoids that are Another complex group of autocoids that are

also derived from arachidonic acidalso derived from arachidonic acid Cause strong bronchoconstriction in humansCause strong bronchoconstriction in humans They also contract other smooth muscle such as They also contract other smooth muscle such as

the uterus and GI tractthe uterus and GI tract


KininsKinins

Haveles (pp. 239-240)Haveles (pp. 239-240) Polypeptides that are distributed in a great Polypeptides that are distributed in a great

variety of body tissuesvariety of body tissues Kallidin and bradykinin are found in plasma and Kallidin and bradykinin are found in plasma and

may play a role in dental diseasesmay play a role in dental diseases Plasma kinins may be involved in shock and Plasma kinins may be involved in shock and

acute or chronic allergic or inflammatory acute or chronic allergic or inflammatory conditions such as anaphylaxis and arthritisconditions such as anaphylaxis and arthritis


Substance PSubstance P

Haveles (p. 240)Haveles (p. 240) A peptide thought to function as a A peptide thought to function as a

neurotransmitter in the CNS and a local neurotransmitter in the CNS and a local hormone in the GI tractshormone in the GI tracts A vasodilator and produces hypotensionA vasodilator and produces hypotension Increases the action of the intestinal and bronchial Increases the action of the intestinal and bronchial

smooth musclesmooth muscle Causes secretion in the salivary glandsCauses secretion in the salivary glands

chapter 18: autocoids and antihistamines copyright © 2011, 2007 mosby, inc., an affiliate of...

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