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17 Cards in this Set

  • Front
  • Back
how nicotinic receptors work
- two agonists bind to two a’s to open the channel, which is permable to Na and K
– they open briefly b/c they go to a desensitized state
– low []’s can make them desensitized w/out opening
how does nicotine work
- it mimics Ach
- its duration and effect are much longer b/c it’s not metabolized by AChE and it can pass the BBB
nictinic receptor structure
- pentameric ligand-gated ion channels
– SkM receptors are 2 a, and 1 b, g, and d
nicotine on peripheral NS
- unpredictable, ranging from activation to paralysis of SNS or PNS
– a small dose evokes discharge of EPI from the adrenal medulla
– higher []’s desensitize NRs on chromaffin cells -> loss of response to splanchnic nerve stimulation
– can get tachy or brady depending on the effect
– a brief stimulation at NMJ is followed by neuromuscular blockade
nicotine on CNS
- stimulates!
– causes weak analgesia at low doses and to tremors and convulsions at toxic doses
– induces vomiting via central (chemoreceptor trigger zone in the medulla) and peripheral actions
– Most brain R’s are prejunctional, and the stimulatory and pleasure-reward action is from the effects on release of other NTs, like aa’s and dopamine
Nicotine on symp ganglia and adrenal medulla
- vasoconstriction and tachy
– there is ↑ tone and motor activity of GI
– NandV, and diarrhea often w/ 1st exposure
– stimulation of salivary and bronchial secretions followed by inhibition
nicotine admin
– 1 cigarette has 6-11 mg, 1-3 of which enter blood
– the blood enters L heart then cerebral circulation w/out dilution in systemic circulation
– CNS effects in 7 seconds
- ½ life is 2 hours
– metabolized in the liver creating the metabolite, cotinine, via C-oxidation
– the principal P450 enzyme appears to be CYP2A6
mechanisms of nicotine addiction
- unknown, but B2 appears to be the rewarding subunit, as does A4
– the midbrain ventral tegmental area (VTA) is involved
– All addictive drugs elicit dopamine release, apparently via the B2 receptor in VTA
- ↑ abstinence rates
– mechanism unclear, but effects on dopaminergic NT seem to be involved
- A2-agonist
- reduces the severity of alcohol and opiate withdrawal, and has ↑ smoking cessation
- cannabinoid receptor antagonist
- helps stop smoking and is in final FDA stages
Prostacyclin (PGI2) pathway
- Many EC stimuli promote Ca2+-dependent activation of PL-A2 in the endothelium
– -> release of aa
– PGI2 formed form aa
- acts on VSM cells to activate adenylyl cyclase, ↑ cAMP, and promote vasodilation
– it is also a powerful inhibitor of platelet aggregation
- like a prostaglandin
- treats PAH (dont know why)
- only available IV due to a short half-life (3 min) and instability at a low pH
– can give longterm via a portable infusion pump
– it ↓ mortality associated with PAH, but only modestly improves hemodynamic fcn
endothelin pathway
- a potent vasoconstrictor and proinflamm mediator
– promotes SM hypertrophy, hyperplasia, and fibrosis
– Plasma levels are elevated in pts w/ PAH
– ETA R causes sustained vasoconstriction and proliferation of VSM cells
- ETB causes clearance of pulmonary endothelin-1 and NO and prostacyclin production
- is an orally effective antagonist of both ETA and ETB receptors
- may induce hepatic aminotransferase and abnormal liver function
NO pathway and PAH
- many signaling molecules cause vasodilation by activating NO synthase in endothelial cells
– NO activates guanylyl cyclase and promotes formation of cGMP, which causes powerful relaxation of SM
– PAH has been associated with defective production of NO
- a selective inhibitor of phosphodiesterase type 5
– a cGMP-specific isoform exhibits a limited tissue distribution, and goes to PAs
– it ↑ cGMP levels in PA cells -? vasodilation
– it is as effective as bosentan in improving symptoms in PAH patients