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63 Cards in this Set

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Where is the major storage site of histamine?
In most tissues, found in mast cells or its circulating counterpart, the basophil. In these cells, histamine is syn and stored in granules
Where do the largest numbers of mast cells exist?
Nasal mucosa
**these storage sites are the ones most involved
Where else is histamine synth?
-- In non-mast cells of the gastric mucosa and epidermis
-- appears to be neurotransmitter in parts of CNS
-- turnover is also very high in rapidly growing tissues (embryonic tissue and granulation assoc w/ wound healing)
-- been suggested that hist exerts anabolic effect on growth and repair
What about histamine ingested in the diet?
It is rapidly degraded by the GI tract and does not reach systemic circ
-- inhibition of enzyme monoamine oxidase does not affect degradation of histamine
How is histamine released from mast cells and basophils?
-- re-exposure to an offending Ag causes IgE bridges to form on the surface of the mast cell
-- bridging results in increase in the intracellular conc of the Ca (probably via IP3) which in turn causes degranulation of the mast cell
-- degranulation results in release of histamine and other inflamm promoters (eosinophil and PMN chemotactic factors) and destructive enzymes (proteases and acid hydroxylases)
-- also causes de novo synth of bronchoconstrictors PGD2, LTC4, and LTD4 (latter two being slow reacting substance of anaphylaxis)
The majority of the inflamm and tissue damage caused by mast cell degran is actually mediated by…?
Heinous cmpds OTHER THAN histamine
-- other cmpds account for fact that antihistamines are only partially effective in reversing inflamm rxns involved in hypersensitivity

**Thus it is better to prevent degranulation
What about mechanical injury?
If mech injury produces destruction of mast cells, it also causes histamine release
-- scratching of the skin causes cytolytic release of histamine resulting in redness and itching
What type of drugs can elicit histamine release?
Radiocontrast media
Dextran plasma expanders
How can we inhibit AG-induced histamine release?
Selective B2-adrenoceptor agonists such as albuterol
Chromolyn sodium, nedocromil, and olopatadine
How does epinephrine and albuterol inhibit histamine release?
They stimulate an adrenoceptor-sensitive adenylate cyclase in the mast cell mbrn
-- Resulting increase in cAMP blocks histamine release by preventing the increase in intracellular Ca concentration caused by formation of IgE bridges
How does theophylline inhibit histamine release?
Increases cAMP conc by inhibiting cAMP phosphodiesterase
-- increased cAMP prevents the increase in intracellular Ca conc caused by formation of IgE bridges
How does cromolyn sodium, nedocromil, and olopatadine inhibit histamine release?
It inhibits mast cell degran by preventing the increase in intracellular Ca conc caused by formation of IgE bridges
Histamine and second messenger systems: H1 receptors
H1 receptors: ↑IP3 --> ↑ intracellular Ca causing contraction of:
1. vascular endothelial cells of postcapillary venules --> extravasation of plasma

2. bronchial smooth muscle --> decreased ventilation

3. GI smooth muscle --> bowel cramping, involuntary defecation
Histamine and second messenger systems: H1-receptors on vascular endothelial cells of resistance arterioles
Causes synth of NO --> activation of guanyl cyclase --> ↑CGMP --> relaxation of vascular smooth muscle --> vasodilation --> decreased TPR --> hypotension
Histamine and second messenger systems: H2 receptors coupled to adenyl cyclase
1. vascular smooth muscle cells of arterioles --> ↑cAMP --> relaxation --> vasodilation --> decreased TPR --> hypotension

2. gastric parietal cells: ↑cAMP  ↑calcium  ↑ acid secretion
Histamine and vasodilation: H1 receptor mediated vs. H2 receptor mediated
H1-receptor mediated = rapid onset and offset

H2-receptor mediated = slow onset and offset
Where do we find H1 histamine receptors?
1. vascular smooth muscle

2. capillary endothelial cells

3. bronchial smooth muscle

4. GI smooth muscle = food allergy

5. sensory nerve ending
Result of H1 histamine receptors in vascular smooth muscle?
1. relaxation of resistance arterioles and venules

2. vasodilation causes hypotension and reflexly-mediated tachycardia

3. rapid vasodilation is mediated by stimulation of H2-receptors
Result of H1 histamine receptors in capillary endothelial cells?
1. contraction increases capillary permeability

2. extravasation of plasma causes local edema
Result of H1 histamine receptors in bronchial smooth muscle?
1. contraction causes bronchoconstriction

2. FEV1 and PEFR are decreased
Result of H1 histamine receptors in GI smooth muscle?
1. contraction enhances peristalsis

2. bowel cramping and diarrhea result

Food allergy
Result of H1 histamine receptors in sensory nerve endings?
stimulation causes pain and itching
H2 histamine receptor locations?
Gastric parietal cells
Result of H2 histamine receptors in gastric parietal cells?
1. increased secretion of gastric acid, pepsin and intrinsic factor

2. acid secretion exacerbates GI ulcers caused by H. pylori
Explain the “triple response of Lewis”

Intradermal release of histamine produces:
Flush – localized red spot at the site of injury which appears in a few seconds

Flare – diffuse flush of the skin extending 1cm around the site of injury which appears more slowly

Wheal – edema localized at the original red spot which develops after several minutes
What, exactly, are the causes of the triple response of Lewis?
All are mediated by H1-receptors

Flush – arteriodilation caused by histamine at the site of release

Flare – activation of axonal reflexes in the branches of the sensory nerves shich cayses the surrounding blood vessels to dilate

Wheal – localized edema resulting from the increase in capillary perm caused by histamine

Histamine, PGs and bradykinin stimulate sensory nerve ending to cause sensations of pain, itching, and burning = ALGESIA
The “triple response of Lewis” can be produced by…?
1. trauma
2. sunburn
3. animal venoms and toxins
4. plant toxins (poison oak and ivy)
5. plant allergens
Describe an immediate HSN (acute allergic) rxn
1. bronchoconstriction causing severe dyspnea

2. laryngeal edema – DOC is epi which constricts laryngeal vessels

3. hypotension – (may be severe) Tx w/ i.v. combo of H1-blocker and H2-blocker (diphenhydramine + cimetidine)
Describe seasonal allergic rhinitis
1. allergic rxn of nasal mucosa and conjunctiva to pollen

2. increased nasal and ocular secretion and vasodilation
Describe asthma
1. re-exposure to allergen causes bridging of reaginic Abs (IgEs) on the surface of mast cells, including those of the nasal mucosa and bronchioles, causing degranulation

2. degranulation of mast cells elicits bronchoconstriction, respiratory tract congestion (vasodilation, increased secretion and edema) and chemotaxis of eosinophils
Describe urticaria (hives) and pruritis (itching)
1. local allergic responses

2. red itchy patches of hives represent the flush, flare, and wheal caused by local histamine release w/in the skin
Describe mast cell tumors
1. skin tumors (urticaria pigmentosa) cause local hives after mech pressure releases histamine

2. degran of mast cells in deeper tumors (mastocytosis) can produce systemic effects including increased aPTT from heparin release
Describe gastric and duodenal ulcers
1. stim of H2-receptors increases gastric acid secretion: acid promotes and/or exacerbates ulceration

2. increased acid secretion causes “stress” ulcers (i.e. in severe trauma such as burns)
Describe GERD
Gastric acid damages the mucosa of the esophagus
Name the inhibitors of mast cell degranulation
Cromolyn sodium

Cromolyn sodium use?
1. inhalation for asthma

2. ophthalmic for allergy

3. nasal for allergy

4. oral for food allergy
Olopatadine use?
1. ophthalmic for allergy

prevents mast cell degran AND blocks H1-histamine receptors
Non-prescription H1-histamine receptor antagonists?
1. brompheniramine – class B

2. chlorpheniramine – class B

3. diphendydramine – class B

4. dimenhydrinate – class B

5. loratadine – class B
Oral prescription H1-histamine receptor antagonists?
1. hydroxyzine – class C

2. cyproheptadine – class B

3. cetirizine – class B

4. fexofenadine – class C

5. desloratadine – class B

6. meclizine – class B
Other prescription H1-histamine receptor antagonists?
1. olopatadine (eye drops) – class C

2. promethazine (i.m. or rectal suppository) – class C
Pharmacological properties of antihistamines?
See pg. 46 of the syllabus
Pharmacokinetics of cetirizine, fexofenadine, loratadine, and desloratadine?
half life (h) and clearance

Cetirizine 8 50% renal 50% hepatic

Fexofenadine 14 95% renal

Loratadine 8 hepatic

Desloratadine 28 renal
Pharm effects of H1-receptor blockades?
1. prevents constrictor response to histamine at most smooth muscle (bronchial and GI)

2. inhibit the pain and itching caused by histamine at sensory nerve ending

3. antagonize the increase in capillary permeability
Pharm effects of a cholinergic muscarinic receptor blockade?
1. depresses CNS (sedation, etc)

2. inhibits nasopharyngeal secretion

3. prevents motion sickness (action in vestibular nuclei)

4. exerts an antiemetic effect
Local anesthetic pharm effect is only caused by…?
Topical diphenhydramine

-- blocks Na channels in afferent sensory pain fibers
Therapeutic uses of antihistamines?
1. seasonal and allergic rhinitis
2. acute HSN rxns
3. motion sickness
4. pre-op sedation
5. nausea and vomiting
6. vertigo (Meniere’s disease)
7. Parkinson’s disease
Tx of seasonal and allergic rhinitis?
Newer, non-sedating dugs preferred:
-- cetirizine
-- fexofenadine
-- loratadine
Tx of acute HSN rxns?
H1 blockers are adjunctive therapy
**Epi (s.c.) remains the DOC
Tx of motion sickness?
Prophylaxis = dimenhydrinate and meclizine

Treatment = promethazine
Tx for pre-op sedation?
Tx for vertigo?
If of vestibular origin
-- DIMENHYDRINATE and MECLIZINE reduce the nausea, ataxia, and nystagmus caused by spontaneous bursts of activity of the sensory nerves of the semicircular canals
Tx for Parkinson’s disease
DIPHENHYDRAMINE is used to treat the central motor disorder caused by antipsychotic drugs
Why is promethazine so great?
**antihistaminic and anticholinergic effect
** given i.m. or by rectal suppository

Used for tx of:
1. acute HSN rxns
2. allergic dermatoses (poison ivy/oak)
3. motion sickness
4. sedate anxious pts
5. prevent post-op nausea and vomiting
6. n/v assoc w/ GI infection (via rectal suppository)
Do we use H1-receptor antagonists for serous otitis media?
NOT effective and can cause ontoward effects (sedation, irritability, and restlessness)
-- after repeated rounds of antibiotic therapy, pressure equalization (PE) tubes usually solve the problem of recurrent OM
Toxicity and side-effects of antihistamines?
1. CNS depression
2. CNS excitation
3. Dizziness and tinnitus
4. Antimuscarinic effects
5. Torsade
CNS toxicity of antihistamines?
-- decreased alertness, slowed rxn times and somnolence
-- potentiates CNS depression caused by alcohol and other drugs and can lead to impaired psychomotor performance

-- paradoxical excitation can occur w/ overdose or even normal doses in children and older adults
Antimuscarinic effects of antihistamines?
1. dry mouth

2. dry respiratory tract (cough may occur)

3. urinary retention in the presence of BPH

4. exacerbation of glaucoma
Torsade effect of antihistamines?
Parent cmpd of fexofenadine (terfenadine) inhibits K repol current in ventricular muscle
-- prolongs the QT interval and can cause torsade

**drugs such as ketoconazole and the macrolide antibiotics (erythro and clarithro – not azithro) inhibit oxidation of terfenadine to fexofenadine

-- plasma conc of terfenadine increases and may precip torsade, espec in pts w/ congenitally-prolonged Q-T syndrome or patients taking other drugs which prolong the Q-T interval

***Loratadine DOES NOT cause torsade, even in the presence of CYP3A4 inhibitors, possibly b/c it is also metab by the CYP2D6 isozyme
H1-histamine antagonists found in OTC products?
Diphenhydramine – Nytol, Sleepeze-3
H2-histamine receptor antagonists?
Pharm effect of H2-histamine receptor antagonists?
These drugs inhibit:
1. both basal and nocturnal acid secretion

2. secretion of gastric acid induced by food, coffee, insulin, muscarinic agonists, increased vagal nerve activity, histamine agonists (betazole) and gastrin (pentagastrin)

Despite the fact that H2-histamine receptors are found at many sites in the body, H2-receptor antagonists have little effect on phys fxns other than inhibition of gastric acid secretion
Therapeutic uses of H2-histamine receptor antagonists?
1. gastric and duodenal ulcers


3. prophylaxis of stress ulcers (trauma, burns)

4. anaphylaxis

5. viral warts and other skin lesions
Toxicity and S/Es of H2-histamine receptor antagonists?
Pregnancy category B

Cimetidine inhibits hepatic CYP450
1. antiandrogenic effects (may cayse gynecomastia, azoospermia, and decreased libido in males) occur b/c it prevents brkdwn of estrogen by CYP450

2. inhib of CYP450 also increases the half-life of other drugs such as the B-adrenoceptor antagonists, warfarin and diazepam

3. may also produce CNS effects ranging from mental confusion to overt psychosis in older pts, pts w/ prior hx of psychiatric disease and pts receiving large doses for a long period

***Ranitidine and famotidine do not exert these adverse effects

All of these drugs can cause nausea, diarrhea, and skin rash.