Sympathetic depressants

The chief use of reserpine is in the treatment of mild to moderate hypertension. As with other sympathetic depressant drugs, tolerance to the antihypertensive effects of reserpine can occur, owing to a compensatory increase in blood volume that frequently accompanies decreased peripheral vascular resistance. Reserpine, therefore, should be used in conjunction with a diuretic. 

An important aspect of a-methyldopa s hemodynamic effects is that renal blood flow and glomerular filtration rate are not reduced. As occurs with most sympathetic depressant drugs and vasodilators, long-term therapy with a-methyldopa leads to fluid retention, edema formation, and plasma volume expansion. While data conflict somewhat, it is generally thought that a-methyldopa suppresses plasma renin activity. 

The most commonly encountered side effects of a-methyldopa are sedation and drowsiness. These CNS effects are probably the result of reductions in brain catecholamine levels. Other side effects, also typical of sympathetic depression, are dry mouth, nasal congestion, orthostatic hypertension, and impotence. 

III. Clinical presentation. Manifestations of intoxication result from generalized sympathetic depression and include pupillary constriction, lethargy, coma, apnea, bradycardia, hypotension, and hypothermia. Paradoxic hypertension, caused by stimulation of peripheral alpha-1 receptors, may occur with clonidine, oxymetazoline, and tetrahydrozoline (and possibly guanabenz) and is usually transient. The onset of symptoms is usually within 30-60 minutes, although peak effects may occur more than 6-12 hours after ingestion. Full recovery is usual within 24 hours. In an unusual massive overdose, a 28-year-old man who accidentally ingested 100 mg of clonidine powder had a three-phase intoxication over 4 days initial hypertension, followed by hypotension, and then a withdrawal reaction with hypertension. 

Nitrous oxide produces respiratory depression (38,39). It has been shown to produce a direct myocardial depressant effect in dogs (40) and in humans breathing a 40% N2O/60% oxygen mixture (41) however, this may be offset by the activation of the sympathetic nervous system (42). The combination of nitrous oxide and opioids can produce decreases in myocardial contractiHty, heart rate, and blood pressure (43). 

General types of physiological functions attributed to quaternary ammonium compounds are curare action, muscarinic—nicotinic action, and ganglia blocking action. The active substance of curare is a quaternary that can produce muscular paralysis without affecting the central nervous system or the heart. Muscarinic action is the stimulation of smooth-muscle tissue. Nicotinic action is primary transient stimulation and secondary persistent depression of sympathetic and parasympathetic ganglia. 

As of the mid-1990s, use of MAOIs for the treatment of depression is severely restricted because of potential side effects, the most serious of which is hypertensive crisis, which results primarily from the presence of dietary tyramine. Tyramine, a naturally occurring amine present in cheese, beer, wine, and other foods, is an indirecdy acting sympathomimetic, that is, it potently causes the release of norepinephrine from sympathetic neurons. The norepinephrine that is released interacts with adrenoceptors and, by interacting with a-adrenoceptors, causes a marked increase in blood pressure the resultant hypertension may be so severe as to cause death. 

In contrast, iproniazid, introduced in 1951 for treatment of tuberculosis, induced euphoria and was described as a psychic energiser . In fact, these patients, when given iproniazid, could become quite disruptive and this action was regarded as an undesirable side-effect However, its beneficial effects in depression were soon recognised and it was regarded as the first effective antidepressant drug. Studies of peripheral sympathetic neurons, later extended to noradrenergic neurons in the brain, showed that iproniazid irreversibly inhibits the catalytic enzyme, monoamine oxidase (MAO). Because only cytoplasmic monoamines are accessible to MAO, inhibition of this enzyme first increases the concentration of the pool of soluble transmitter but this leads to a secondary increase in the stores of vesicle-bound transmitter i.e. the pool available for impulse-evoked release (Fillenz and Stanford 1981). 

Psychogenic dysfunction occurs if a patient does not respond to psychic arousal. It occurs in up to 30% of all cases of ED. Common causes include performance anxiety, strained relationships, lack of sexual arousability, and overt psychiatric disorders such as depression and schizophrenia.5 It is postulated that the anxious or nervous man will have excessive stimulation of the sympathetic system, leading to smooth muscle contraction of arterioles and vascular spaces within erectile tissue.6 O Many patients may initially have organic dysfunction, but develop a psychogenic component as they try to cope with their inability to achieve an erection. It has been estimated that up to 80% of ED cases have an organic cause, with many having a psychogenic component as well.1... 

Veith, R. C., Lewis, N., Linares, O. A. etal. (1994). Sympathetic nervous system activity in major depression. Arch. Gen. Psychiatry, 51,411-22. 

Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake indicated for depression and painful diabetic neuropathy, is expected to become first-line therapy for SUI. Duloxetine is thought to facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase. 

Madden, K.S. et al., Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and in vitro following chemical sympathectomy, Brain Behav. Immun., 3, 72, 1989. 

The main limitation to the clinical use of the MAOIs is due to their interaction with amine-containing foods such as cheeses, red wine, beers (including non-alcoholic beers), fermented and processed meat products, yeast products, soya and some vegetables. Some proprietary medicines such as cold cures contain phenylpropanolamine, ephedrine, etc. and will also interact with MAOIs. Such an interaction (termed the "cheese effect"), is attributed to the dramatic rise in blood pressure due to the sudden release of noradrenaline from peripheral sympathetic terminals, an event due to the displacement of noradrenaline from its mtraneuronal vesicles by the primary amine (usually tyramine). Under normal circumstances, any dietary amines would be metabolized by MAO in the wall of the gastrointestinal tract, in the liver, platelets, etc. The occurrence of hypertensive crises, and occasionally strokes, therefore limited the use of the MAOIs, despite their proven clinical efficacy, to the treatment of atypical depression and occasionally panic disorder. 

Adverse effects. Cardiovascular crises are a possible risk emotional stress of the patient may cause sympathoadrenal activation with epinephrine release. The resulting rise in blood pressure can be all the more marked because persistent depression of sympathetic nerve activity induces supersen-sitivily of effector organs to circulating catecholamines. 

Cardiac failure Sympathetic stimulation is a vital component supporting circulatory function in CHF, and -blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

Clonidine is an agonist at a - and o 2-adreno-ceptor subtypes. It reduce the sympathetic tonus and is thereby a useful antihypertensive drug. Clonidine can induce sedation, depression and peripheral side effects like a dry mouth. Unspecific a-adrenoceptor blocking agents like tricyclic antidepressants can reduce the antihypertensice effect of clonidine. 

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