Monoamine oxidase inhibitors levodopa

The dopaminergic drug are contraindicated in patients with known hypersensitivity to the drugs. Levodopa is contraindicated in patients with narrow-angle glaucoma, those receiving a monoamine oxidase inhibitor (see... 

Levodopa interacts with many different drugs. When levodopa is used with phenytoin, reserpine, and papaverine, there is a decrease in response to levodopa The risk of a hypertensive crisis increases when levodopa is used with the monoamine oxidase inhibitors (see Chap. 31). Foods high in pyridoxine (vitamin B6) or vitamin B6 preparations reverse the effect of levodopa However, when carbidopa is used with levodopa, pyridoxine has no effect on the action of levodopa hi fact, when levodopa and carbidopa are given together, pyridoxine may be prescribed to decrease the adverse effects associated with levodopa... 

Bromocriptine is a dopamine agonist acting by direct stimulation of the dopamine receptors. In Parkinson s disease, it is reserved for use in patients who are intolerant to levodopa or in whom levodopa alone is not sufficient. Orphenadrine is an antimuscarinic indicated in Parkinson s disease. Antimuscarinics tend to be more effective than levodopa in targeting tremor rather than rigidity and bradykinesia. Moclobemide is an antidepressant referred to as a reversible monoamine oxidase inhibitor (RIAAA) type A. 

A growing number of drugs are used that affect the many neurotransmitters in the brain benzodiazepines and others act on GABAergic transmission antidepressants, such as monoamine oxidase inhibitors and tricyclic antidepressants, are thought to increase the concentration of transmitter amines in the brain and so elevate mood—these will also act at peripheral nerve terminals, so interactions with them are a combination of peripheral and central actions. Levodopa (L-dopa) increases central as well as peripheral dopamine, and the newer class of psychoactive drugs, the selective serotonin reuptake inhibitors (SSRIs) of which the ubiquitous fluoxetine (Prozac) is best known, act in a similar way on serotonergic pathways. 

Postural hypotension is common and often asymptomatic, and tends to diminish with continuing treatment. Hypertension may also occur, especially in the presence of nonselective monoamine oxidase inhibitors or sympathomimetics or when massive doses of levodopa are being taken. 

Interactions. With nonselective monoamine oxidase inhibitors (MAOI), the monoamine dopamine formed from levodopa is protected from destruction it accumulates and also follows the normal path of conversion to noradrenaline (norepinephrine), by dopamine (J-hydroxylase severe hypertension results. The interaction with the selective MAO-B inhibitor, selegiline, is possibly therapeutic (see below). Tricyclic antidepressants are safe. Levodopa antagonises the effects of antipsychotics (dopamine receptor blockers). Some antihypertensives enhance hypotensive effects of levodopa. Metabolites of dopamine in the urine interfere with some tests for phaeochromocytoma, and in such patients it is best to measure the plasma catecholamines directly. 

The combination of a monoamine oxidase inhibitor with levodopa causes hypertension, sometimes with very high pressures (59,60). 

Metoclopramide increases gastric transit time, enhancing the absorption of substances absorbed in the small intestine (e.g., ethanol, cyclosporin) and decreasing the absorption of substances absorbed in the stomach (e.g., cimetidine, digoxin). Anticholinergic drugs and dopamine-function-enhancing substances such as levodopa reduce the effectiveness of metoclopramide. Because metoclopramide releases catecholamine, it should be used cautiously with monoamine oxidase inhibitors such as tranylcypromine. Because metoclopramide inhibits plasma cholinesterase, it increases the effectiveness of succinylcholine, a skeletal muscle relaxant. 

Those who are taking medications such as monoamine oxidase inhibitors, neuroleptics, or medications containing levodopa... 

Many other infrequent symptoms and abnormal laboratory findings have been associated with levodopa treatment. Metabolites cause the urine to turn reddish and then black. Many drug interactions are possible few are confirmed, but this possibility should be watched. Some monoamine oxidase inhibitors reported effective in Parkinson s disease caused hypertensive reactions in combination with levodopa, but tricyclic antidepressants... 

Therapy in the deficiencies of TH, AADC and DpR is aimed at correcting the neurotransmitter abnormalities. Bypassing the metabolic block using levodopa/carbidopa together with dopamine agonists has led to improvement in TH deficiency [10]. Monoamine oxidase inhibitors, in conjunction with dopamine agonists and vitamin B6 (cofactor for AADC) ameliorated symptoms in AADC deficiency [3] and dihydroxyphenylserine (DOPS - decarboxylated to form norepinephrine) has corrected the norepinephrine deficiency in DpH deficiency [8]. Currently a therapy for MAO-A deficiency has not been described. 

Monoamine oxidase exists in two forms, MAOa and MAOb. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like S-phenylethylamine, it is more affected by MAOb. H seems likely that MAOb is the dominant enzyme in human brain and inhibitors of it, such as selegiline, have some value in the treatment of Parkinson s disease by prolonging the action of the remaining endogenous DA as well as that formed from administered levodopa. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Pharmacologic doses of pyridoxine (vitamin B6 ) enhance the extracerebral metabolism of levodopa and may therefore prevent its therapeutic effect unless a peripheral decarboxylase inhibitor is also taken. Levodopa should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their discontinuance because such a combination can lead to hypertensive crises. 

The combined administration of levodopa and an inhibitor of both forms of monoamine oxidase (ie, a nonselective inhibitor) must be avoided, because it may lead to hypertensive crises, probably because of the peripheral accumulation of norepinephrine. 

L-deprenyl (selegiline), a monoamine oxidase B inhibitor, clonidine and guanfacine, a2-adreno-receptor agonists, and levodopa (L-dopa) have been reported to improve cognitive function in some subjects. Zimeldine, citaloprani, and alaproclate — selective serotonin uptake blockers — have no beneficial effects. 

Interactions The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness (Figure 8.6). Concomitant administration of levodopa and monoamine oxidase (MAO) inhibitors, such as phenelzine (see p. 124), can produce a hypertensive crisis caused by enhanced catecholamine production therefore, caution is required when they are used simultaneously. In many psychotic patients, levodopa exacerbates symptoms, possibly through the buildup of central amines. In patients with glaucoma, the drug can cause an increase in intraocular pressure. Cardiac patients should be carefully monitored because of the possible development of cardiac arrhythmias. Antipsychotic drugs are contraindicated in parkinsonian patients, since these block dopamine receptors and produce a parkinsonian syndrome themselves. 

Monoamine-oxidase B inhibitors, such as selegiline and rasagiline, have a use alone in the management of early disease. Early treatment with selegiline alone has been shown to delay the need for levodopa therapy for some months, but other more effective drugs are preferred. Both dmgs can be used in conjunction with levodopa preparations to reduce end-of-dose deterioration in advanced disease. 

Monoamine oxidase type B inhibitors (rasagiline, selegiline) reduce the metabolism of dopamine by MAO-B. They are useful to delay disease progression in the early stages of the disease and as an adjunct to levodopa. 

Selegiline is a relatively selective and irreversible inhibitor of monoamine oxidase type B, which has been used in the treatment of Parkinson s disease. It was originally suggested that selegiline may be neuroprotective. However, in a prospective double-blind study no such action was seen (1). On the other hand, selegiline does delay the start of disability, determined by the need for levodopa and progression of parkinsonian signs and symptoms (2). 

A different approach to Parkinsonism would be the use of inhibitors of monoamine oxidase (MAO), the enzyme that oxidatively deaminates catechol and other monamines, including DA, NE, and EP (see subsequent discussion of metabolism and other uses). Such a drug would tend to preserve brain DA and be effective itself and/or potentiate levodopa. Early attempts at such combinations produced hypertension. Subsequently, with the discovery that two MAO isozymes, A and B, exist (more discussion later), it was realized that the drugs tested were nonselective. It is now understood that MAO B primarily metabolizes DA. Selegiline (Eldepryl) appears to be a specific type B MAO inhibitor, and does extend the duration and increase the efficacy of levodopa. The drug is promising, probably as an adjunct to levodopa or in levodopa refractory patients. 

The dopamine prodrug levodopa remains the treatment option for PD, however, long-term levodopa therapy leads to dyskinesia. Alternatives for early PD therapy include monoamine oxidase B inhibitors, dopamine agonists, catechol-O-methyltransferase (COMT) inhibitors, and amantadine (Hauser and Zesiewicz,... 

FIGURE 20-7 Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AAD, aromatic L-amino acid decarboxylase DA, dopamine DOPAC, 3,4-dihydroxyphenylacetic acid MAO, monoamine oxidase 3MT, 3-methoxyl-tyramine 3-O-MD, 3-O-methyl DOPA. 

Drug therapy is based on the severity of the disease. In the early phases of the disease, a monoamine oxidase B-inhibitor is used that inhibits dopamine degradation and decreases hydrogen peroxide formation. In later stages of the disease, patients are treated with levodopa (L-dopa), a precursor of dopamine. 

Remember that levodopa is a precursor of norepinephrine and epinephrine as well as dopamine and that norepinephrine and epinephrine are metabolized primarily by monoamine oxidase type A. In the presence of nonselective inhibitors of monoamine oxidases, levodopa may cause a hypertensive crisis. Though not contraindicated in Parkinson s disease, tricyclic antidepressants may interfere with the effectiveness of levodopa. The answer is (D). 

---