Trimethaphan and Long Term Smoking

kwakster928 said:

Hello,

I have a case presenation this week but i cannot seem to get a grasp on this question.

Pt was admitted to ER with a diagnosis of acute dissecting aortic anuerysm. physican ordered trimethaphan infusion. pt also has been smoking heavily for last 30 years. would his past smoking habit alter the effect of trimethaphan?

trimethaphan is ganglionic blocker used for hypertension emergencies. i think prolonged stimulation of nicotinic receptors due to smoking causes some desensitization. but i am really not sure what the effect will be in presence of antagonist. any help will be greatly appreciated.

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Trimethaphan is a direct arterial vasodilator and an alpha-adrenoceptor antagonist
T Harioka, Y Hatano, K Mori and N Toda


In helically cut strips of dog cerebral, mesenteric, and femoral arteries contracted with prostaglandin(PG)F2 alpha, trimethaphan (10(- 5)-10(-3)M) caused a dose-related relaxation that was not influenced by atropine, propranolol, diphenhydramine, cimetidine, aminophylline, or indomethacin. Trimethaphan-induced relaxation was greater in extracerebral than in cerebral arteries. The relaxation was greater in phenylephrine-contracted arteries than in PGF2 alpha-contracted arteries. On the other hand, hexamethonium did not relax the arteries. Trimethaphan (10(-4)-10(-3)M) shifted the dose-response curve for norepinephrine in mesenteric arteries to the right, but failed to influence the contractile response to 25 mM KCl. Treatment with trimethaphan (10(-4)-10(-3)M) protected alpha-adrenergic receptors from persistent blockade by phenoxybenzamine. Trimethaphan (10(-7)-3 X 10(- 6)M) and hexamethonium (3 X 10(-8)-10(-6)M) significantly attenuated the contractile response of mesenteric arteries to nicotine in a dose- dependent manner, but did not alter the response to transmural electrical stimulation. The antinicotinic potency of trimethaphan was approximately one-fourth that of hexamethonium. It is concluded that, unlike hexamethonium, trimethaphan acts directly on vascular smooth muscle to induce vasodilation, more prominently in extracerebral arteries than in cerebral arteries. In high concentrations, trimethaphan appears to possess an alpha-adrenergic blocking action.

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Effects of central and peripheral nicotinic blockade on human nicotine discrimination.

Perkins KA, Sanders M, Fonte C, Wilson AS, White W, Stiller R, McNamara D.

Department of Psychiatry, University of Pittsburgh, PA 15213, USA. [email protected]

Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg p.o.), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10-40 microg/kg per min i.v.), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 microg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 microg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects.

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Plasma concentrations of nicotine decline in a biphasic manner. Most of the drug is metabolized in the liver by oxidation to cotinine and nicotine-1'-oxide. The initial half-life of nicotine is 2—3 minutes and the terminal half-life is 30—120 minutes, with considerable variation among individuals. However, with the transdermal patch, the elimination half-life is 3—4 hours due to continued absorption from skin depot. Cotinine has a plasma half-life of about 10—40 hours. Nicotine and its metabolites are excreted by the kidneys; roughly 10—20% of nicotine is eliminated unchanged in the urine.

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kwakster928 said:

.

Pt was admitted to ER with a diagnosis of acute dissecting aortic anuerysm. physican ordered trimethaphan infusion.

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spyderdoc said:

😕 Why?

From Tintinalli:

Aortic Dissection

Patients with suspected aortic dissection commonly will require antihypertensive treatment, which must be provided without increasing the shear force on the intimal flap of the aorta. Therefore, medications with negative inotropic effects must be given initially. β-blockers (e.g., esmolol, metoprolol, or propranolol) are used commonly for this purpose.

Vasodilators (such as nitroprusside) may be added for further antihypertensive treatment after successful administration of a negative inotrope. Nitroprusside may be infused at an initial dose of 0.3 ug/kg per min IV. Patients should have clear evidence of adequate β-receptor or calcium channel blockade prior to starting a vasodilator. Close monitoring of the pulse rate is required because this is a convenient indicator of blockade in most patients. Aortic dissections may cause hypotension, which requires fluid or blood product resuscitation.

Don't see trimethaphan mentioned....

Edit: added Tintinalli reference.....

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Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration.

Schoedel KA, Sellers EM, Palmour R, Tyndale RF.

Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.

Nicotine metabolism is decreased in smokers compared with nonsmokers, but the mechanism(s) responsible for the slower metabolism are unknown. Nicotine is inactivated to cotinine by CYP2A6 in human liver [nicotine C-oxidation (NCO)]. CYP2B6 also metabolizes nicotine to cotinine but with lower affinity than CYP2A6. To evaluate the effects of long-term nicotine treatment on hepatic levels of CYP2A6 and CYP2B6, and nicotine metabolism, an African green monkey (AGM) model was developed. As in humans, approximately 80 to 90% of in vitro hepatic NCO is mediated by a CYP2A6-like protein (CYP2A6agm) in this species, as determined by inhibition studies. Male AGM (n = 6 per group) were treated for 3 weeks with nicotine (s.c., 0.3 mg/kg, b.i.d.), phenobarbital (oral, 20 mg/kg, as a positive control for P450 induction), and/or saline (s.c., b.i.d.). Immunoblotting demonstrated a 59% decrease (p < 0.05) in hepatic CYP2A6agm protein in nicotine-treated animals. A CYP2B6-like protein (CYP2B6agm) was modestly and insignificantly decreased (14%, p = 0.11). In vitro NCO was decreased by 41% in the nicotine-treated group (p < 0.05), mediated by a decrease in CYP2A6agm, as demonstrated using inhibitory antibodies. CYP2A6agm mRNA (33%, P < or = 0.05) and CYP2B6agm (35%, p < 0.01) mRNA were also significantly decreased in the nicotine-treated group. Phenobarbital-treated animals demonstrated an increase in CYP2B6agm (650%, p < 0.001), but not CYP2A6agm (20%, p = 0.49). NCO was increased in the phenobarbital-treated group (55%, p < 0.05) by an increase in CYP2B6agm-mediated NCO. Consistent with the slower nicotine metabolism observed in smokers, nicotine may decrease its own metabolism in primates by decreasing the expression of the primary nicotine-metabolizing enzyme CYP2A6.

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kwakster928 said:

you are right. i dont know why my pharmacology professor is torturing me with this damn drug dosen't even on the market. do you guys have any idea whether plolonged exposure of nicotine will result in down-regulation, therefore, there will be less number of receptors available for antagonist to act, thus needing more dose of trimethaphan to acheive hypotension effect.

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jdpharmd? said:

Are we in the wrong forum?

Anyway, from what I remember regarding nicotine and smokers; Smokers get to a set nicotine level and then stop increasing the dose. A smoker does not start out at 1 pack/day and end up at 10 packs/day, so my feeble mind would conclude that the (nicotinic) receptors are not down-regulated very much. If they were, the smoker would consistantly need more and more cigs to get the desired effect (which, of course, is death 😉 )

But, FYI

* 4.3 PLACE IN THERAPY
o A. Presently, TRIMETHAPHAN is preferred by many clinicians for emergency control of blood pressure in patients with acute dissecting aortic aneurysm (Anon, 1989; Gilman et al, 1990).
o B. TRIMETHAPHAN is useful in the production of controlled hypotension which helps minimize hemorrhage in the arteriolar beds during surgery. TRIMETHAPHAN may serve as an alternative to sodium NITROPRUSSIDE for patients who are resistant to the latter drug (Gilman et al, 1990). Because it may minimize risk of toxicity from the release of cyanide from NITROPRUSSIDE, TRIMETHAPHAN has received considerable attention for its use in conjunction with NITROPRUSSIDE in a 10:1 mixture for induction of hypotension (Wildsmith et al, 1983; Fahmy, 1985; Miller et al, 1987). The combination enables the use of significantly lower total doses of NITROPRUSSIDE without compromise to the intended hypotensive endpoint.
o C. The ganglionic blocking agents, including TRIMETHAPHAN, were once used in the management of hypertensive cardiovascular disease; however, these agents have been largely replaced by superior agents for the treatment of chronic hypertension.
o D. The drug probably warrants formulary inclusion for emergency control of blood pressure in patients with acute dissecting aortic aneurysm.

(source: Thompson Micromedex Online)

But, I've still never heard of it in class... 😀

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