Term
| First Generation H2 antagonists |
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Definition
| Chlorpheniramine (chlortrimeton), diphenyhydramine (benadryl), demenhydrinate (dramamine) |
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Term
| 2nd generation H2 antagonists |
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Definition
| loratadine (claritin), fexofenadine (claritin) |
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Term
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Definition
| cimetidine (tagmet), ranitidine (zantac), famotidine (pepcid) |
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Term
| nonreceptor antihistamines |
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Definition
| cromolyn sodium (nasalcrom) |
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Term
| chlorpheniramine (chlortrimeton) |
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Definition
a. Dose: 4-8 mg
b. Duration: 4-6 hr
c. Anti-ACh: +
d. Sedation: ++
e. Other: in OTC cold medication |
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Term
| diphenhydramine (benadryl) |
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Definition
a. Dose: 25-50 mg
b. Duration: 4-6 hr
c. Anti-ACh: +++
d. Sedation: +++
e. Other: anti-motion sickness, OTC sleep aid |
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Term
| demenhydrinate (dramamine) |
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Definition
a. Dose: 50 mg
b. Duration: 4-6 hr
c. Anti-ACh: +++
d. Sedation: +++
e. Other: anti-motion sickness |
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Term
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Definition
a. Dose: 10 mg
b. Duration: 12-24 hr
c. Anti-ACh: none
d. Sedation: +/- |
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Term
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Definition
a. Dose: 60 mg
b. Duration: 6-12 hr
c. Anti-ACh: none
d. Sedation: +/- |
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Term
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Definition
1. Relative potency: 1
2. Dose to suppress >50% acid over 24 hr: 400-800 mg |
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Term
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Definition
1. Relative potency: 4-10
2. Dose to suppress >50% acid over 24 hr: 150 mg |
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Term
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Definition
1. Relative potency: 20-50
2. Dose to suppress >50% acid over 24 hr: 20 mg |
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Term
| cromolyn sodium (nasocrom) |
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Definition
1. Mast cell stabilizers – cromolyn sodium; nedocromil
a. Directly inhibit mast cell degranulation
b. Cromolyn available as nasal spray (Nasalcrom®); inhaler (Intal®); eye drops (Opticrom®); nedocromil as nasal spray (Alocril®; Tilade®)
c. Requires 3-4 times daily dose; not additive w/ steroid inhalers |
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Term
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Definition
a. Autacoids: compounds that are released and act locally in periphery – histamine, serotonin, PGs, leukotrienes, kinins
b. Histamine roles: immune responses, control stomach acid, neurotransmitter |
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Term
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Definition
i. periphery: widespread, esp. skin and lungs
1. mostly synthesized and stored in mast cells and basophils
ii. GI: in enterochromaffin-like cells (ELC) of stomach fundus
iii. CNS: NT – cell bodes in ventral posterior hypothalamus |
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Term
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Definition
| histidine to histamine, histidine decarboxylase and pyridoxal phosphate |
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Term
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Definition
| i. rapidly broken down to inactive metabolites |
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Term
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Definition
| i. Newly synthesized histamine is either rapidly degraded or is stored bound to heparin in storage granules |
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Term
| Histamine immunological release |
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Definition
i. Exposure of a previously sensitized (exposed) subject to an antigen can trigger an immediate allergic reaction, causing mast cell degranulation and histamine release – Type 1-hypersensitivity
ii. Degranulation also releases other chemical mediators / autacoids:
1. ATP; eicosanoids; kinins; cytokines; serotonin; PAF
iii. Negative feedback control: histamine can modulate its own release from many mast cells via H2 receptors |
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Term
| Histamine mechanical release |
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Definition
| i. Physical or chemical injury to skin or mucosal can cause immediate release of histamine from mast cells |
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Term
| Drugs that effect histamine release |
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Definition
i. Morphine, acetylcholine, tubocurarine; radiocontrast media; plasma expanders
ii. Release inhibited by methylxanthines, b-agonists (epinephrine), prostaglandins |
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Term
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Definition
i. A food borne illness that results from eating spoiled fish. It is the second most common type of seafood poisoning
ii. Cause: histidine in bacteria on fish skin converted to histamine
1. lack of refrigeration accelerates reaction
iii. Occurs 15-60 min after meal; can last 4-6 hrs
iv. Symptoms resemble allergy attack: skin flushing, throbbing headache, oral burning, abdominal cramps, nausea, diarrhea, palpitation, tachycardia
v. Treated w/ antihistamines |
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Term
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Definition
| Smooth muscle, endothelium, brain Increase IP3, DAG, NO, Ca2+ (Gq) |
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Term
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Definition
| Gastric mucosa, cardiac muscle, mast cells, brain Increase cAMP, Ca2+ (Gs) |
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Term
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Definition
Presynaptic: brain, myenteric plexus, sympathetic neurons
Decrease cAMP, Ca2+ |
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Term
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Definition
| Eosinophils, neutrophils, CD4 T cells Decrease cAMP, Ca2+ |
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Term
| tissue effects of histamine |
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Definition
i. Stimulates nerve endings: itch, pain (probably H1 & H3)
1. Part of response to injury & inflammation |
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Term
| Histamine and Central nervous system |
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Definition
i. Cell bodies in ventral posterior hypothalamus
ii. These circuits help regulate several important functions, including arousal (wakefulness), drinking, appetite, body temperature, blood pressure via post-synaptic H1 and/or H2
1. some evidence for CNS pain regulation: H2 blockers as analgesics?
iii. H3 receptors are presynaptic on these neurons and those of other NTs, including acetylcholine and peptides
1. Activation of H3 by histamine inhibits release of transmitter
2. H3 receptors important for metabolic balance: animals w/out H3 have increased food intake, decreased energy output, obesity, insulin resistance |
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Term
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Definition
i. Vasodilation of arterioles, relaxation of precapillary sphincters BP
1. Mediated mostly by H1, some H2; release of NO from endothelium
2. Flushing, sense of warmth, headache may accompany vasodilation
ii. Increased heart rate & contractility
1. Primarily due to reflex tachycardia
2. At higher doses, can get direct stimulation of heart (H2)
iii. Increased capillary permeability in post-capillary venules (H1)
1. contributes to edema w/ inflammation
iv. Note: cardiac responses typically are NOT seen w/ endogenous histamine, as release is local and little reaches or remains intact in circulation for more than a few seconds. |
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Term
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Definition
i. stimulates gastric acid secretion via H2 receptors on parietal cells
1. also stimulates secretion in intestine
2. can also stimulate contraction of intestinal smooth muscle |
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Term
| Histamine and bronchiolar smooth muscle |
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Definition
i. Bronchoconstriction (H1)
1. Normally not marked, but asthmatics are very hypersensitive to histamine-induced bronchoconstriction (and to other stimuli) |
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Term
| Histamine and the immune system |
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Definition
i. “Triple Response” to intradermal histamine: localized red spot; edema or “wheal”; spreading flush or “flare”
1. vascular smooth muscle relaxation: vasodilation = red spot
2. vascular endothelium permeability: fluid leak = swelling, edema
3. stimulation of free nerve endings, and axon reflex: red, irregular flare surrounding spot (and hypersensitivity to touch)
ii. Histamine released by allergic response or injury contributes significantly to the inflammatory response
1. triple response
2. sensory nerve activation (pain, itch)
3. leakage of complement, C-reactive protein, other mediators
4. chemotactic attraction for inflammatory cells (neutrophils, eosinophils, basophils, monocytes, lymphocytes)
5. May regulate cytokine production in leukocytes
a. latter 2 effects probably mediated by H4 receptors |
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Term
| General description of antihistamines |
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Definition
a. History; general description
i. Competitive antagonists to histamine’s smooth muscle effects have been available for >60 yrs (= H1 antagonists)
ii. Widely used for allergies; in many OTC preparations
iii. Some pt. differences in therapeutic responses and adverse effects
1. e.g. CNS excitation instead of sedation
iv. Don’t work against all symptoms of allergic response (other autacoids)
1. e.g. anaphylactic bronchospasm mediated by leukotrienes |
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Term
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Definition
i. 2nd generation drugs have less sedation, fewer autonomic effects
ii. H1 antagonism is a side effect of MANY other drugs
1. Esp. antipsychotics, antidepressants |
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Term
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Definition
| i. have become mainstay of treatment for peptic acid hypersecretion |
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Term
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Definition
| i. potential in analgesia, appetite & weight control |
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Term
| H1 antihistamines general properties |
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Definition
1. Pharmacodynamics
a. competitive antagonists, or inverse agonists, at H1 (little or no effect at H2 or H3)
2. Most 1st generation drugs also block other receptors:
a. muscarinic cholinergic
b. some at a1, 5-HT, local anesthetic receptors
3. ADME (absortion, distribution, metabolism, excretion)
a. rapidly absorbed, peak 1-2 hrs; widely distributed
b. 1st generation drugs penetrate BBB; 2nd generation drugs do not
i. Thus, difference in sedative effects
c. many extensively metabolized; some produce active metabolites
d. Some 2nd generation drugs use CYP3A4; subject to drug interactions
e. 1st generation drugs typically have duration 4-6 hrs; 2nd generation drugs longer-lasting (see table) |
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Term
| H1 antihistamines indications |
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Definition
1. Allergic rhinitis, conjunctivitis: usually v. effective
a. Drugs of choice for prevention or to treat symptoms
b. For continued use, minimizing sedation valuable
c. Some find diminished response over time; may need to switch to different AH
2. Itching, pruritis: useful
3. Atopic & contact dermatitis: some utility
a. sedative properties can be useful
4. Drug reactions (w/ itch, urticaria, angioedema): useful
a. Not useful against anaphylactic reactions
b. urticaria
i. usually effective
c. angioedema
i. initially effective, but don’t last
5. Asthma & anaphylaxis
a. antihistamines not effective (other autacoids)
6. Motion sickness, antiemetic: specific agents useful (see table)
a. Primarily useful as prophylactics
b. Anti-motion sickness
i. Several 1st generation drugs effective
1. Diphenhydramine, promethazine
2. Piperazines (cyclizine, meclizine, hydroxyzine) also effective, less sedative (but contraindicated in pregnancy)
3. All more effective when combined w/ stimulant (ephedrine, amphetamine)
c. Antiemetic
i. Promethazine used to counteract drug-induced nausea
ii. Doxylamine (in Bendectin®) was used to treat morning sickness
1. Withdrawn 1983: associated with teratogenic effects (unproven)
2. Still available as OTC sleep aid
7. Common cold: no demonstrated utility
a. Some symptom relief? (anticholinergic effects dry up secretions)
8. Local anesthetic: when patient allergic to other anesthetics
9. Sleep aid: widely used OTC
a. Common response (>50%) to most 1st generation antihistamines
i. 2nd generation drugs do not penetrate BBB (<7 % incidence)
b. Can limit daytime use
i. Enhanced by alcohol use
ii. Little evidence of abuse; different mechanism than traditional sedative hypnotics
c. Some children (adults rarely) experience CNS excitation
i. Toxic doses produce stimulation, agitation, even convulsions
d. Several sold OTC as “sleep aids”
10. Anti-cholinergic
a. Prominent w/ several 1st generation (see table)
b. Dry mouth, blurred vision, urinary retention
c. This effect may contribute to anti-Parkinson’s activity
d. It may also contribute to symptom relief in common cold (?)
i. Inhibits nasal secretions (non-allergic rhinorrhea)
11. Local anesthesia
a. Some 1st generation drugs block Na+ channels in same manner as procaine & lidocaine
b. Diphenhydramine & promethazine can be used when patients are allergic to standard local anesthetics
12. Other
a. Cetirizine inhibits mast cell release of histamine
b. Cyproheptadine blocks some 5-HT receptors (anti-migraine)
c. Promethazine blocks a1 receptors (orthostatic hypotension) |
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Term
| H1 antihistamines side effects/toxicity |
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Definition
1. CNS effects: sedation, etc.
a. Mainly w/ 1st generation drugs
b. Additive w/ alcohol, other CNS depressant drugs
c. Also can cause dizziness, uncoordination, fatigue;
i. can impair performance in mental and physical tasks
2. Anticholinergic
a. Limited to 1st generation drugs
b. Dry mouth, urinary retention, tachycardia, blurred vision
c. At higher doses, CNS confusion, hallucinations, convulsions
3. Less common toxicities
a. GI: nausea, vomiting, diarrhea; loss of appetite
b. CNS excitation (even at therapeutic doses in some)
i. Primarily in children; rarely adults
ii. This is the primary issue in overdose
c. Insomnia, nervousness, tremors
d. Allergic response to topical application |
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Term
| H2 antihistamines general properties |
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Definition
1. Histamine released from enterochromaffin-like cells (ELC) of stomach fundus
2. Activates H2 histamine receptors on parietal cells
a. Increases cAMP; inhibits H+-K+-ATPase (“proton pump”)
b. Gastrin, ACh do same, but via increased intracellular Ca2+
c. PPIs (proton pump inhibitors) like omeprazole act directly on ATPase
3. H2 antagonists are specific, reversible, competitive inhibitors
a. Suppress histamine-stimulated acid secretion
b. Also suppress parietal cell response to gastrin and ACh
c. Best effects on nocturnal acid secretion
d. Modest effects on meal-stimulated acid secretion |
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Term
| H2 antihistamines indications |
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Definition
1. GERD (Gastro-esophageal reflux disease)
a. Should be taken prior to meals
2. Duodenal ulcer; gastric ulcer
a. Promote healing; prophylaxis inhibits recurrence
b. With recognition of role of H. Pylori in ulcer disease, the use of H2 blockers has declined
3. Hyper-secretory states
a. Zollinger-Ellison: gastrin-secreting tumor (can be fatal)
b. H2 blockers (@ high doses) useful prior to surgery |
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Term
| H2 antihistamines adverse effects |
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Definition
1. Safe drugs, high TI
2. <3% incidence: diarrhea, headache, constipation, fatigue, myalgia
3. When used i.v., possible mental status changes in elderly (confusion, hallucinations, agitation)
4. Cimetidine has unique hormonal effects (esp. at high doses)
a. increases prolactin, inhibits estradiol metabolism; inhibits dihydrotesterone receptor binding
b. can cause male gynecomastia, impotence; female galactorrhea |
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Term
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Definition
1. 1st pass metabolism, 50% bioavailability (except nizatidine)
2. T1/2 1-4 hrs, but duration of action longer (4-8 hrs)
3. Dose reduction necessary w/ renal and hepatic insufficiency
4. Ranitidine can suppress 1st past metabolism of ethanol
5. Significant drug interactions w/ cimetidine (inhibits CYP1A2, CYP2C9, CYP2D6, CYP3A4) |
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