• chlorpheniramine
• diphenhydramine
• dimenhydrinate

loratidine

fexofenadine

cimetidine

ranitidine

famotidine

• compounds released and act locally periphery
• ex
  • histamine
  • PG's
  • leukotriens
  • kinins
  • serotonin

• GI- ECL cells in stomach fundus
• CNS- NT: cell bodies in ventral posterior hypothalamus
• periphery
  • widespread, esp. lungs, skin
  • syn/stored in mast cells and basophils

• decarboxylate L histidine via histidine decarboxylase with cofacter pyridoxal phosphate

• stored bnound to heparin in stored granules in mast cells, basophils

• exposure of sensitized subject to Ag trigger mast degranulation and histamine release in TYPE 1 hypersensitivity
• degranulation releases other chemicals
• however, histamine can modulate its own release from many mast cells via H2 receptors via negative feedback

• physical or chem injury to skin or mucosal surface cause immediate release of histamine from mast cells

• morphine
• Ach
• tubocurarine
• radiocontrast media
• plasma expanders

methylxanthines

beta agonists

PG's

• distribution
  • smooth muscle
  • endothelium
  • brain
• postreceptor resonse (Gq)
  • increase IP3
  • increase DAG
  • increase NO
  • increase Ca

• distribution
  • gastric mucosa
  • cardiac muscle
  • mast cells
  • brain
• post R response
  • increase cAMP, increase Ca (Gs)

• presynaptic: brain, symp. NS, myenteric plexus

• stimulate nerve endings for pain and itch via H1 and H3 (part of injury, inflam. response)

• cell bodies of ventral post. hypothal.
• regulate wakefulness, drinking, appetite, body temp. bp via post syn. H1, H2
• H3 are presyn.
  • inhibits release of neurotransmitter
  • metabolic balance (no H3 leads to increase food intake, insulin resistance, decrease energy output, obesity)

• stimulate gastric acid secretion via H2 receptors on parietal cells
• also stimulate secretion in intestines
• stimulate contraction of intestinal smooth muscle

• vasodilation of arterioles via relax precapillary sphincters (decrease bp)
  • most via H1, some H2; release of NO from endothelium
• increase heart rate and contractility due to reflex tachycardia
  • at higher doses, directly stimulates heart (H2)
• increase capillary permeability in post capillary venules (H1)
  • contribute to edema w/inflammation

• localized red spot
  • vasodilation
• edema/wheal
  • increase vascular endothelium permeability leading to fluid leak
• spreading flush or flare
  • stimulate free nerve endings and axon reflex

seasonal

perennial

• allergen avoidance
• hyposensitization (to desensitize for specific allergens)
• pharmacotherapy
  • accute and anaphylaxis: beta agonists also corticosteroids
  • subacute and preventative
    • inhaled steroids
    • inhaled leukotrine antagonists
  • mast cell stabilizers
    • inhibit mast cell degranulation
    • need 3-4 tims daily dose, not additive with steroid inhales

• fluticasone
• momestasone

• montelukast
• zafirlukast

Role of histamine released by allergic response or injury

• triple response
• sensory nerve action (pain, itch)
• leakage of:
  • complement
  • C reactive protein
  • other mediators
• chemoattraction for inflam. cells (mediated by H4)
• inhibit T and B lymphocyte functions (mediated by H4)

1. IgE antibodies bound to Fce receptors on mast cells crosslinked by antigen
2. triggers calcium influx, decrease cAMP, increase cGMP
3. storage granules fuse with membrane and release contents

• anaphylaxis- severe and rapid systemic response
  • insect stings
  • drug previously sensitized too
• local reactions
  • urticaria (hives
  • eczematous dermitis
  • some forms of asthma
  • allergic rhinitis- marked conjuection following exposure of nasal mucosa to airborne allergens

antipsyc.

antidepressants

• competitive antagonists at H1
• most 1st generations can block other receptors
  • muscarinic
  • alpha 1
  • serotonin (5-HT)
  • local anesthetic receptors

• rapidly absorbed (peak 1-2 hrs) and widely distributied
• 1st gen. penetrate BBB and 2nd gen. dont
  • thus, sedative
• many extensively metabolized, some produce active metabolites
• some second generation drugs use CYP3A4
  • subject to drug interactions
• first generation drugs have duration 4-6 hrs
• second generation last longer

• drug of choice for prevention or treatment of symtpoms
• for continued use, minimizing sedation valuable
• some find diminshed response over time, may need to switch to different AH

• common response to most first generation antihistamines
  • second gen. dont penetrate BBB
• can limit daytime use
  • enhanced by alcohol use
  • little evidence of abuse (different mechanism that traditional sedative hypnotics)
• some children experience CNS excitation
  • toxic doses produce stimulation, agitation, even convulsions
• several sold OTC as sleep aids

• antimotion sickness
  • best prophylactically
  • several first generation drugs effective
    • diphenhydramine
    • promethazine
    • piperazines (cyclizine, meclizine, hydroxyzine) also effective, but less sedative (contraindicated in pregnancy)
    • all more effective when combined with stimulant
• antiemetic
  • promethazine
  • doxylamine used to treat morning sickness before withdrawn in 1983 (assoc. w/teratogenic effects)

• prominent w/several 1st gen.
• dry mouth
• blurred vision
• urinary retention
• anti-parkinson's activity
• contribute to symptom releif in common cold by inhibiting nasal secretion

• some 1st gen. blcok sodium chnnales in same manner as procain and lidocaine
• diphenhydramine and promethazine used when patients allergic to standard local anesthetics

• cetirizine- inhibit mast cell release of histamine
• cyproheptadine- block serotonin (anti migraine)
• promethazine (block alpha1 receptors to treat orthostatic hypotension)

• specific, reversible, competitive inh.

• supprese histamine stimulated acid secretion
• supress parietal response to gastrin and ACh
• best effects on nocturnal acid sec.
• modest effect on meal stimulated acid secretion

• act on H receptors in parietal cells
• histamine released by ECL cells in stomach fundus
  • increase cAMP, inhibit H/K ATPase (proton pump)
    • omeprazole (PPI) act on ATPase directly
  • gastrin, Ach do same, but via increased intracellular Ca

• GERD (prior to meals)
• duodenal and gastric ulcer
  • promote healing
  • prophylactic to inhibit recurrence
  • declined use due to role of H pylori in ulcers
• hyper-secretory states
  • Zollinger Ellison- gastrin secreting tumor
  • use blocker prior to surgery

• safe drugs with high therapeutic index
• few incidence of:
  • diarrhea
  • headach
  • constipation
  • fatigue
  • myalgia
• if used IV, possible mental status change in elderly

• increase prolactin, inhibit E2 met. inh. DHT receptor binding
• leads to male gynecomastia and impotence
• lead to female galactorrhea

• 1st pass metabolism with 50% bioavailability
• half life of 1-4 hrs, but duration of 4-8 hrs
• dose reduction needed with renal and hepatic insufficiency
• ranitidine can suppress first pass metabolism of ethanol
• significant drug interaction with cimetidine leading to inh. of many CYP isoforms