Histamine/PG Flashcards
Autocoids
endogenous substances in the body (histamine, serotonin, peptides, prostaglandins, leukotrienes)
- short duration of action, act near site of synthesis/release
- high levels cause inflammation, pain, bronchospasm, anaphylactic shock
Histamine
- Synthesized from L-histidine
- Delivered by degranulation of basophils and mast cells at sites of injury (via IgE cross linking0
- Acts in brain as NT
- Enterochromaffin like cells in stomach which activate acid production (H2 receptor)
Immunologic histamine release
- Crosslinked IgE causes degranulation releasing histamine
- Causing Type 1 allergic reactions- hay fever, urticaria and inflammation and immune modulation (blood vessel dilation, complement activation, cytokine, T and B cell modulation
Chemical induced histamine release
-morphine, tubocurarine, cpd 48/80, mast cell injury
first two lead to release of histamine
Cromolyn
Inhibits histamine release
Also nedocromil
H1 receptor mediated response
-urticarial response, respiratory neuron singaling, vasodilation via NO release (reflex tachycardia), edema, bronchoconstriction, contraction of intestinal smooth muscle
First gen antihistamines
Carbinoxamine, dimenhydrinate, diphenhydramine (more sedative effect), hydroxyzine, cyclizine, meclizine, brompheniramine, chlorpheniramine, promethazine, cyproheptadine
anti cholinergic activity causes sedation, anti-motion sickness activity, and some anti emesis (promethazine)
4-6 hrs duration of action
Second gen antihistamine
Fexofenadine, loratidine (long acting), cetirizine, azelastine, desloratidine
12-24 hr duration of action
Use of H1 receptor antagonist
- allergic reactions- hay fever, urticaria, not utilized for bronchial asthma
- motion sickness- prevention
- local anesthetic (diphenhydramine and promethazine more potent than procaine)
-antiparkinsonian, anticholinergic, adrenergic blocking, serotonin blocking
Toxicity and drug interactions of H1 receptor antagonist
sedation, anti muscarinic (urinary retention), blurred vision
-interacts with cyp450 (inhibition),
H2 receptor mediated responses
- secretory in parietal cells (gastric acid secretion)
- CV system: high doses of histamine- cAMP dep vasodilation and direct stimulation (inc contractility and pacemaker), antagonists have little effect on cardiac function
H2 receptor antagonists
reduce gastric acid secretion- peptic ulcer, gerd, hypersecretory diseases
(do not impact intestinal secretion or oher peripheral H2 receptor mediated effects like HR)
cimetidine, famotidine, nizatidine, ranitidine
H3 receptor mediated response
Nervous system- presynaptic receptor modulates NT release
Metabolic effects
thioperamide (also H4 blocker), chlobenpropit, iodophenpropit
Eicosanoids
- Family of oxygenation products of polyunsaturated LCFA
- wide spectrum of biologic activity
Arachidonic acid
most abundant eicosanoid
- liberated by phospholipase a2 from glycophospholipids
- oxidated by COX, LOX (to form leukotrienes), CYP450, and nonezmatic (free radicals)
COX
Convert AA to prostaglandins
COX1
constitutively expressed, widely distributed, houskeeping
COX2
inducible, production of inflammatory molecules
expressed in vascular endothelium (prostacyclin- PGI2)
-renal cox2 essential for normal fxn
PGH2
Thromboxanes, prostaglandins, prostacyclins are derived from PGH2 (which is derived from AA)
Eicosanoid receptors
G protein coupled, with cAMP or Ca++ being second messengers
PG effect on vasculature
TXA2 and PGF2a- vasoconstriction
PGE2 and PGI2-vasodilation (inc cAMP, dec Ca)
PG effect on GI tract
longitudinal muscle contraction and relaxation of circular muscles. cause colicky cramps
PGE2
PG effect on Airway
PGE2 and PGI2- relaxation
PDG2, TXA2, PGF2a- contraction
Platelets and PGs
TXA2 enhances platelet aggregation
PGs on Kidney
Medulla and cortex synthesize PGs- PGE2 and PGI2
Maintain bp and renal fxn via vasodilation
Regulation of water and electrolyte secretion via COX1 and COX2 products:
- COX1- promote salt excretion in collecting ducts
- COX2- increase medullary blood flow and inhibit tubular sodium reabsorption
Loop diuretics have effects in part due to inc cox activity (inhibitors can reduce effect)
PGs male reproductive
found in semen
PG levels correlate with fertility and enhanced by testosterone
PGE1- enhances penile erection by relaxing smooth muscles in corpus cavernosum
PGs- female reproductive
PGF2a and low PGE2 promotes uterine contraction
High PGE2 concentration–> relaxation
Misoprostol
1st and 2nd trimester abortion
oral PGE1
tx of NSAID induced ulcer
Dinoprostone
PGE2
vaginally for abortion by stimulating contraction of uterus
inducing labor
Carboprost
PGF2a
contract uterus to control post partum hemorrhage
AE of PG on female repro
vomiting, fever, diarrhea, bronchoconstriction, altered bp, flushing
PG inflammation and immunity
PGE2 and PGI2- inc edema and vascular permeability
PGD2 released from mast cells to recruit eosinophils
Alprostadil
relaxes smooth muscle
PDA, erectile dysfunction, impotence
PGE1
Latanoprost
PGF1a- topical
tx of open angle glaucoma
Dysmenorrhea
inc endometrial synthesis of PGE2 and PGF2a
Prostacyclin
PGI2- inhibits platelets and is a vasodilator
used for pulmonary hypertension because dec pulmonary, peripheral and coronary resistance
Tx of pulmonary htn
Prostacyclin
Epoprostenol (flushing, headache, hypotension, nausea, diarrhea)-requires continuous IV infusion
Iloprost- inhaled 6-9 times per day
Treprostinil- sc injxn of iv because half life 4 hrs
NSAIDs
Salicylates- aspirin, salicylic acid
Other- ibuprofen, indomethacin, ketorolac, naproxen, oxaprozin, piroxicam, sulindac
COX2 inh- celecoxib
analgesic antipyretic and antiinflammatory
Leukotriene biosynthesis
LTC4 and LTD4- potent bronchoconstrictors cause asthma and anaphylaxis
Formed via LOX from AA
Leukotrienes in inflammation
chemoattractants of eosinophils and monocytes
Proinflammatory mediators of asthma and IBD
LTs in heart and smooth muscle
cause cardiac depression by reducing myocardial contractility and reducing coronary blood flow
GI- IBD by recruitment of PMNs
Airways- bronchoconstrictors which inc microvascular permeabilit, mucus secretion, chemotaxis of eosinophils
Zileuton
5-LOX enzyme inhibitor
inhibits leukotriene biosynthesis
Leukotriene receptor antagonist
Montelukast
given for asthma
