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17 Cards in this Set
- Front
- Back
how nicotinic receptors work
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- 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 |
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how does nicotine work
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- it mimics Ach
- its duration and effect are much longer b/c it’s not metabolized by AChE and it can pass the BBB |
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nictinic receptor structure
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- pentameric ligand-gated ion channels
– SkM receptors are 2 a, and 1 b, g, and d |
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nicotine on peripheral NS
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- 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 |
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nicotine on CNS
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- 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 |
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Nicotine on symp ganglia and adrenal medulla
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- 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 |
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nicotine admin
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– 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 |
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mechanisms of nicotine addiction
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- 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 |
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buproprion
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- ↑ abstinence rates
– mechanism unclear, but effects on dopaminergic NT seem to be involved |
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clonidine
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- A2-agonist
- reduces the severity of alcohol and opiate withdrawal, and has ↑ smoking cessation |
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rimonabant
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- cannabinoid receptor antagonist
- helps stop smoking and is in final FDA stages |
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Prostacyclin (PGI2) pathway
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- 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 |
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epoprostenol
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- 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 |
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endothelin pathway
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- 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 |
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Bosentan
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- is an orally effective antagonist of both ETA and ETB receptors
- may induce hepatic aminotransferase and abnormal liver function |
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NO pathway and PAH
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- 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 |
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sildenafil
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- 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 |