Antiparkinsonian drug

Antiparkinsonian drug
Classification
 
 
1. Drug affecting brain dopaminergic system
  • Dopamine precursor: Levodopa  (I-dopa)
  • Peripheral decarboxylase inhibitors: Carbidopa, Benserazide
  • Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole
  • MAO-B inhibitors: Selegiline, Rasagiline
  • COMT inhibitors: Entacapone, Tolcapone
  • Glutamate (NMDA receptor) antagonist (Dopamine facilitator): Amantadine 
2. Drugs affecting brain cholinergic system
  • Central anticholinergics: trihexyphenidyl (Benzhexol), Procyclidine
  • Antihistaminics: Orphenadrine, Promethazine
 
 Levodopa
 
Pharmacological action
 
1. CNS
  • Do not produce any effect in normal individuals or in patients with other neurological diseases
  • Marked symptomatic improvement occurs in parkinsonian patients
  • Hypokinesia and rigidity resolve first, later tremors as well
  • Secondary symptoms of posture, gait, handwriting, speech, facial expression, mood, self care and interest of life are gradually normalized
  • General alerting response. In some patients, this progress to excitement- frank psychosis may occur in some individual
  • Used to produce a non specific awakening in hepatic coma
  • A single dose of levodopa is well tolerated and when given in combination with physiotherapy, enhances motor recovery in patients with hemiplegia. (1)
  • Levodopa lowers central nervous system S-adenosymethionine concentrations in humans. (2)
  • When used in combination with carbidopa and benserazide, central nervous system actions and side effects depends on the daily dose of levodopa regardless of the different ratios of decarboxylase inhibitors to levodopa. (3)
  • Levodopa signifiantly lowersthe blood pressure and heart rate at rest and enhanced orthostatic hypotension. Heart rate variability, skin perfusion and temperature increased after administration of levodopa. (4)
  • Levodopa/Dopa decarboxylase inhibitor (DDCI) and entacapone is well tolerated, with notable adverse events including worsening dyskinesia, nausea and diarrhea. Patients experiencing re emergence of symptoms due to wearing off may benefit from optimized levodopa therapy with levodopa/carbidopa/entocapone. (5)
  • Clinical data suggests levodopa either slows the progression of parkinson's disease or has a prolonged effect on the symptoms of disease. The neuroimaging data suggest that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals. Its pharmacological effects modify the dopamine transporter. (6)
  • Levodopa is still used for treatment of Parkinson's disease but the drug delivery is a critical factor for the drug's propensity to induce motor complications. (7)
  • Extended release carbidopa-levodopa might be useful treatment for patients with Parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency. (8)
  • Levodopa remains the most effective and best tolerated Parkinson's drug to date and should have an important role in all therpeutic strategies, both as monotherapy in early Parkinson's disease and as part of combination therapy in advanced disease. (9)
  • The main therapeutic strategies to treat levodopa induced dyskineisa includes prevention by early use of dopamine agonist rugs and reduce levodopa dose intake; symptomatic treatment with putative antidyskinetic interventions; reverting dyskinesia by continous dopaminergic stimulation. (10)
  • The long term treatment of levodopa results in increase in homocysteine levels. The treatment of this includes vitamin (folic acid) supplementation and levodopa application in combination with a strong, centrally acting inhibitor of catechol-O-methyltransferase (COMT), which prolongs half life and increase the brain delivery of levodopa. (11)
  • Both levodopa and pramipexole can be used for the treatment of Parkinson's disease but with different efficacy and adverse effect profiles. Pramipexole results in lower incidences of dyskinesias and wearing off. Levodopa results in lower incidence of freezing, somnolence and edema and provides a better symptomatic control. (12)
  • Levodopa used in the treatment of Parkinson's disease causes significant orthostatic hypotension. (13)
  • The risk of occlusion amblyopia increase with the use of levodopa that might affect the plasticity of the visual cortex. (14)
  • Levodopa/ carbidopa intestinal gel infusion is efefctive for the long term treatment of advanced parkinson's disease patients and exerts a positive and clinically significant effect on motor complications with a relatively low dropout rate. (15)
2. CVS
  • Cause tachycardia by acting on β adrenergic receptors
  • Postural hypotension is quite common, rise in BP is not seen
3. CTZ
  • DA formed peripherally gains access to the CTZ without hindrance- elicits nausea and vomiting
 
4. Endocrine
  • DA acts on pituitary mammotropes to inhibit prolactin release and on somatotropes to increase GH release
 
Pharmacokinetics
 
  • Levodopa  is rapidly absorbed from the small intestine by utilizing the active transport process
  • Bioavailability of levodopa  is affected by:
  • Gastric emptying
  • Amino acid present in food compete for the same carrier for absortion
  • Levodopa  undergoes high first pass metabolism in gi mucosa and liver
  • About 1% of administered levodopa  that enters brain, aided by amino acid carrier mediated active transport across brain capillaries, also undergoes the same transformation
  • The plasma t ½ of levodopa  is 1-2 hours
  • Pyridoxal is a cofactor for the enzyme dopa- decarboxylase
  • The metabolites are excreted in urine mostly after conjugation

Adverse effects                              

  • At the initiation of therapy
  • Nausea and vomiting
  • Postural hypotension
  • Cardiac arrhythmias
  • Exacerbation of angina
  • Alteration in taste sensation
  • After prolonged therapy
  • Abnormal movements (dyskinesia)
  • Behavioral effects: mild anxiety, nightmares, severe depression, mania, hallucinations, mental confusion or frank psychosis
  • Fluctuation in motor performance
  • Cautious use of levodopa  is needed in the elderly, patients with ischemic heart disease, cerebrovascular, psychiatric, hepatic and renal disease; peptic ulcer; glaucoma and gout. 
 
Interactions:
  • Pyridoxine: abolishes the effect of levodopa
  • Phenothiazines, butyrophenones, metoclopramide reverse the therapeutic effect of levodopa
  • Nonselective MAO inhibitors prevent degradation of DA and NA that is synthesized in excess from the administered levodopa at peripheral sites
  • Antihypertensive drugs: postural hypotension is accentuated in patients receiving antihypertensive drugs
  • Atropine and antiparkinsonian anticholinergic drugs have additive therapeutic action with low doses of levodopa but retard its absorption- efficacy of levodopa is reduced

 

 
Peripheral Decarboxylase inhibitors
 
  • Carbidopa and benserazide are extracerebral dopa decarboxylase inhibitors
  • They do not penetrate blood brain barrier and do not inhibit the conversion of levodopa to DA in the brain
  • Administered along with levodopa, they increase its t ½ in the periphery and make more of it available to cross blood brain barrier and reach its site of action
  • The benefits of combination are:
  • Plasma t ½ of levodopa is prolonged and its dose os reduced to approximately ¼th
  • Systemic concentration of DA is reduced, nausea and vomiting are not prominent- therapeutic doses of levodopa can be attained quickly
  • Cardiac complications are minimized
  • Pyridoxine reversal of levodopa effect does not occur
  • On-off effect is minimized since cerebral DA levels are more sustained
  • Degree of improvement is higher
  • Problems not resolved or accentuated are:
  • Involuntary movements
  • Behavioral abnormalities
  • Excessive day time sleepiness in some patients
  • Postural hypotension 
  • The continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson;s disease with motor complications. (16)
  • Extended release carbidopa-levodopa might be useful treatment for patients with parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency. (17)
  • Levodopa/ carbidopa/ entacapone 200/50/200 mg provides improvements in symptomatic control and convenience and that switching to this dose was not associated with safety concerns. (18)
  • Acute overdosage and intoxication with carbidopa/ levodopa can be detected in the subacute stage by measurement of 3-o-methyldopa. (19)
  • Carbidopa by increasing bone formation and compensating BMD loss in parkinson's disease patients may lead to reduce osteoporotic symptoms. (20)
  • Carbidopa enhances the sensitivity of 18F-DOPA PET for adrenal phaechromocytomas and extraadrenal abdominal paragangliomas by increasing the tumor-to-background ratio of tracer uptake. The sensitivity of 18F-DOPA PET for metastasis of paraganglioma appears to be limited. (21)
  • Premedication with carbidopa masks positive finding of insulinoma and beta cell hyperplasua in [18F]-Dihydroxy-Phenyl-Alanine Positron emission Tomography. (22)
  • Although carbidopa/levodopa may be useful in the treatment of individual cases of attention deficit disorder with hyperactivity, the general use of the drug is not recommended. (23)
  • Carbidopa is effective in reucing the damage caused by reactive oxygen intermediates on human catecholaminergic cells either alone or in combination with L-Dopa. (24)
  • The benserazide dose response data suggests that even at very high doses extracerebral decarboxylase is not yet completely inhibited. (25)
  • The combination of carbidopa and benserazide is useful in patients with parkinson's disease. (26)
  • Seperate, frequent small doses of levodopa and benserazide give better control of brittle parkinsonism. (27)
  • The catecholics benserazide, catechol, 3-methoxycatechol, pyrogallol, taxifolin and fenoldopam display agonistic activity against GPR35. (28)
  • Levodpa/benserazide loaded microspheres could be used to ameliorate the expression of levodopa induced dyskinesia by reducing the expression of pGIuR1S831 and pGluR1S845 as well as Arc and Penk. (29)
  • The administration of benserazide decrease both total plasma clearance and apparent volume of distribution of levodopa, but did not change the rate constant of the terminal phase of the plasma levodopa decay curve. Thus it does not alter the plasma half life of levodopa. (30)
  • Benserazide does not alter the growth hormone values either in normal subjects or in acromegalic patients. A significant increase occurs in prolactin level in both normal and acromegalic patientsand increase in thyroid stimulating hormone (TSH) levels only in acromegalic patients. (31)  
  • Levodopa methyl ester (LDME)/ benserazide loaded nanoparticles can be used to reduce the expression of dyskinesia in dyskinetic rats. (32)
  • Benserazide used in the treatment of parkinson's disease can induce diarrhea as a side effect. (33)
  • Levodopa/benserazide combination therapy can be used in elderly patients with parkinsonism. The combination was well tolerated and side effects are not troublesome. (34)
  • Levodopa plus bensearzide combination can be used for treatment of restless legs syndrome. (35)
Dopaminergic agonists
 
  • DA agonist act on striatal DA receptors. They are longer acting, can exert subtype selective activation of DA receptors involved in parkinsonism.
Bromocriptine
  • Ergot derivative which acts as potent on D2 but partial agonist or antagonist on D1 receptors
  • Improvement in parkinsonism symptoms occur within ½-1 hr after oral dose of bromocriptine and last for 6-10 hours
  • Side effects include vomiting, hallucinations, hypotension, nasal stuffiness, conjunctival injection
  • Marked fall in BP has occurred in some patients with first dose
  • Bromocriptine is a sympatholytic D2-dopamine agonist approved for the treatment of type 2 diabetes. It also reduces fasting and post meal free fatty acid (FFA) and triglycerides levels. (36)
  • Bromocriptine act on the circadian neuronal activities in the hypothalamus, to reset an abnormally hypothalamic drive for increased plasma glucose, free fatty acids and triglycerides in insulin resistant patients. The novem mechanism of action, good side effect profile, and its effects to reduce cardiovascular events makes it attractive option for the treatment of type 2 diabetes. (37)
  • Bromocriptine therapy may noe be the treatment of choice for hyperprolactinaemic men with large tumours. (38)
  • The estradiol-induced breakdown in B-cell tolerance can be abrogated by bromocriptine, which induces anergy in the high affinity DNA reactive B cells. (39)
  • Bromocriptine mesylate may prove to be a revolution in treatment of type-2 diabetes. It restes the circadian rhythm, can be used with other antdiabetic agents, ease of single morning dose, lowers the incidence of MI stroke and vascular events. (40)
  • Bromocriptine inhibits catecholamine release in the peripheral nerves. (41)
  • A single 1 mg dose of cabergoline is atleast as effective as bromocriptine 2.5 mg twice daily for 14 days in preventing puerperal lactation. (42)
  • Bromocriptine reduces growth hormone in acromegaly. (43)
  • Bromocriptine with clomiphene is effective for infertility in women with galactorrhea and normal prolactin levels. (44)
  • Bromocriptine should be used with caution during pregnancy as it increases uterine contractions. Oxyocin should be used with caution during delivery of females pretreated with bromocriptine. (45)
  • Bromocriptine in combination with levodopa is effective in patients with Parkinson's disease. (46)
  • Bromocriptine is a promising therapy for diabestes patients and demonstrates modest improvements in glycemic control. (47)
  • Mania is exacerbated with the use of bromocriptine. (48)
Ropinirole and Pramipexole
 
  • Selective D2/D3 receptor agonists with negligible affinity for D1 and nondopaminergic receptors
  • Pramiprexole has greater affinity for D3 receptors
  • Lower incidence of dyskinesia and motor fluctuations in patients treated wit these drugs
  • Ropinirole is well absorbed orally, 40% plasma protein bound, extensively metabolized mainly by hepatic CYP1A2, to inactive metabolites and eliminated with terminal t ½ of 6 hours  
  • Side effects are nausea, dizziness, hallucination and postural hypotension
  • Ropinirole is FDA approved for use in restless leg syndrome. 
  • Ropinirole is found to be safe and effective in treating the motor symptoms of restless leg syndrome and improves the sleep quality. (49)
  • Ropinirole improves the symptoms of restless legs syndrome with benefits apparent by week 1. It is generally well tolerated. (50)
  • Ropinirole is a dopamine agonist, approved for use to treat symptoms of early and advanced Parkinson's disease, available in a 24 hour formulation in addition to the immediate release version. (51)
  • Once-daily ropinirole release improves nocturnal symptoms in patients with advanced parkinson's disease not optimally controlled with levodopa who suffer troublesome nocturnal disturbance. (52)
  • Othello syndrome is reported secondary to the use of ropinirole. (53)
  • Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for Parkinson's disease patients with motor fluctuations. (54)
  • The neuroprotective activity of ropinirole is due to the blockade of the Ca2+ triggered permeability transition. (55)
  • Pramipexole does not have a disease modifying effect in patients with Parkinson's disease. (56)
  • Pregabalin reduces the symptoms of anxiety while pramipexole has a positive effect on depression in patients with resless legs syndrome. (57)
  • Pramipexole extended release is safe and effective in early and advanced Parkinson's disease. Adverse events are typical fordopaminergic medications and Unified Parkinson's Disease Rating Scale (UPDRS) scores suggested sustained symptomatic benefit. (58)
  • Pramipexole is shown to be effective in patients with Parkinson's disease. (59)
  • Pramipexole treatment has antidepressant effects in depressive Parkinson's disease patients and also ameliorates HAM-D score in nondepressive parkinson's disease petients in addition to motor function. (60)
  • There is a risk of heart failure with the use of pramipexole in patients with Parkinson's disease. (61)
  • Once daily formulation of pramipexole posesa significant potential advantage for patuents and is reflected by a relatively stable plasma levels. There is an opportunity to provide a continuous drug delivery in a fashion that could help minimize dyskinesia if the drug is used early in the disease course. (62)
  • As monotherapy for early parkinson's disease, pramipexole ER (extended release) is noninferior to pramipexole IR (immediate release) and is significantly more effective. Tolerability and safety did not differ between the formulations. (63)
  • In patients with fibromyalgia, treatment with pramipexole improves the scores on assessments of pain, fatigue, funtion and global status and is safe and well tolerated. (64)
  • Pramipexole is an important therapeutic option for treatment resistant bipolar and unipolar depression. (65)
  • Pramipexole improves depressive symptoms in patients with Parkinson's disease maily through direct antidepressant effect. This effect should be considered in the clinical management of patients withParkinson's disease. (66)
  • Pramipexole is a promising agent in the treatment of treatment resistant depression (TRD) and tardive dyskinesia (TD). (67) 
  • Pramipexole use in healthy volunteers reduces alertness, causes pupil dilatation, increase heart rate, reduce prolactin and thyroid stimulating hormone, increases growth hormone level. Pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus. (68)
  • Pramipexole provides long lasting protection against cognitive impairment known to occur when very young animals are exposed to anesthesia during peak of brain development. (69)
  • Pramipexole is used in the treatment of unipolar and bipolar depression. (70)
MAO-B inhibitors
 
Selegiline (Deprenyl)
  • Selective irreversible MAO-B inhibitor
  • Selegiline in low doses does not interfere with peripheral metabolism of dietary amines; accumulation of CAs and hypertensive reaction does not develop, while intracerebral degradation of DA is retarded
  • Higher doses can produce hypertensive interactions with levadopa and indirectly acting sympathomimetic amines
  • Therapy with selegiline and levodopa in combination may be associated with severe orthstatic hypotension not attributable to levodopa alone. Selegiline also has pronounced symptomatic motor effects in advanced Parkinson's disease. (71)
  • Transdermal selegiline for the treatment of major depressive disorder. (72)
  • Selegiline cannot halt the progression of the disease but it can reduce the rate of progression. (73)
  • Selegiline is used in the treatment of attention deficit hyperactivity disorder in adults. It produces dose-dependent changes in monoamine metabolites and DOPA plasma levels. (74)
  • In patients with moderately severe impairment from Alzheimer's disease, treatment witrh selegiline or alpha-tocopherol slows the progression of disease. (75)
  • There is excess mortality in patients taking selegiline under 80 years of age and those with confirmed diagnosis of Parkinson's disease taking selegiline without levodopa. (76)
  • Transdermal selegiline is used for the treatment of depression. (77)
  • Selegiline can prevent the toxicity of clinically used cancer chemotherapeutics through an MAO-B inhibition independent mechanism. It prevents cyclophosphamide induced alopecia. This effect occurs without a concomitant decrease in chemotherapy efficacy at cancer cells. (78)
  • Selegiline hydrochloride can be used to treat anxiety disorders in dogs. (79)
  • Selegiline has a minor therapeutic effect in patients with chronic fatigue syndrome. (80)
  • Selegiline or its desmethyl metabolite has a protective action against glutamate-induced neurotoxicity in cultured retinal neurons. (81)
  • Selegiline seems to be a suitable drug to prevent perphenazine-induced catatonia in rat. (82)
  • Selegiline enhances dopaminergic neural transmission in treatment resistant depression, thus leading to an improvement in depressive symptoms. (83)
  • Adverse effects are:
  • Postural hypotension
  • Nausea
  • Confusion
  • Accentuation of levodopa induced involuntary movements and psychosis
  • Contraindicated in patients with convulsive disorders
  • Interactions 
  • Pethidine
  • Tricyclic antidepressants
  • Selective serotonin reuptake inhibitors 
 
Rasagiline
  • Newer selective MAO-B inhibitor
  • 5 times more potent, longer acting and not metabolized to amphetamines
  • Once a day in the morning and does not produce excitatory side effects
  • Rasagaline is used in the treatment of Parkinson's disease. It is not associated with cheese effect, is well tolerated. It should be used carefully in patients with hepatic impairment, should not be administered with other MAO inhibitors and co-administration with certain antidepressants and opioids should be avoided. (84)
  • Rasagiline is effective as monotherapy in early Parkinson' disease (PD) patients, reuce off time in more advanced PD patients with motor fluctuations. (85)
  • Rasagiline delays the need for symptomatic antiparkinsonian drugs. (86)
  • Once daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson's disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone. (87)
  • Rasagiline is well tolerated and effective in the treatment of early Parkinson's disease and as adjunctive treatment in levodopa treated patients with Parkinson's disease. It may be associated with clinically significant  neuroprotection. (88)
  • The adjunct rasagiline 1 mg/day is effective in reducing the severity of motor symptoms in the OFF state. (89)
  • The patients treated with rasagiline, 2 and 1 mg/d, for 12 months showed less functional decline than patients whose treatment was delayed for 6 months. (90)
  • Rasagiline used as monotherapy and as adjunctive therapy is effective for reducing tremor severity in patients with Parkinson's disease. (91)
  • Rasagiline treatment is associated with livedo reticularis. (92)
 
COMT inhibitors
 
  • Potent and reversible Entacapone and Tolcapone are introduced as adjuvants to levodopa-carbidopa for advanced Parkinson disease
  • When peripheral decarboxylation of levodopa is blocked by carbidopa/ benserazide, it is mainly metabolized by COMT to 3-O-methyldopa
  • Blockade of this pathway by entacapone/ tolcapone prolongs the t ½ of levodopa and allows a larger fraction of administered dose to cross to brain
  • Entacapone and tolcapone enhance and prolong the therapeutic effect of levodopa-carbidopa in advanced and fluctuating PD
  • They smoothen wearing off, increase on time, decrease off time, improve activities of daily living and allows levodopa dose to be reduced
  • Tolcapone is beneficial in the treatment of patients with Parkinson's disease. It is well tolerated. The adverse effects are levodopa related. Diarrhea is most frequent nondopaminergic adverse event. (93)
  • Administration of tolcapone is associated with significant clinical improvement and benefit in patients with Parkinson's disease involving non-motor features. (94)
  • Tolcapone can induce neurotoxicity in patients with parkinson's disease. (95)
  • Adjunctive therapy with tolcapone significantly reduce the dose of levodopa required. It reduces wearing off and on-off periods in fluctuating patients and improves on time in patients with stable disease. Side effects include headache, nausea, insomnia and diarrhea. (96)
  • Tolcapone additon may improve non motor features in patients with Parkinson's disease. (97)
  • COMT has been confirmed to be first reported modifier gene on polycystic kidney disease (PKD) and tolcapone offers promising drug in treating PKD. (98)
  • The addition of tolcapone to levodopa plus a decarboxylase inhibitor effectively and safely reduces the wearing off phenomenon in parkinsonian patients. (99)
  • Tolcapone prolongs on time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, therby improving the efficacy of long term levodopa therapy. (100)
  • The addition of entacapone results in improvement in motor fluctuations particularly of the wearing off, reduces required levodopa dose, modest improvement in motor and disability scores and in some improvement of health related quality of life scores. (101)
  • Levodopa/carbodopa/entacapone 200/50/200 mg provides improvement in symptomatic control and convenience in patients with parkinson's disease. (102)
  • Adding entacapone to controlled release levodopa preperations provise a useful treatment option in patients with Parkinson's disease with motor fluctuations. (103)
  • Entacapone prove useful in prolonging the duration of the benefit obtained from individual doses of levodopa. (104)
  • Entacapone is an effective COMT inhibitor when combined with either standard levodopa or controlled release levodopa. (105)
  • Carbidopa/levodopa/entacapone is an attractive alternative for patients with nondisabling wearing off or dyskinesia taking carbidopa/levodopa with or without entacapone. It is not recommended for early parkinson;s disease patients as it can induce more dyskinesia. (106)
  • Entacapone should be considered as add-on treatment to levodopa/carbidopa in Parkinson's disease patients with end of dose wearing off effect. (107)
  • Entacapone dissolution is pH dependent showing maximum dissolution at pH 6.8. (108)
  • Tolcapone and entacapone has anti-amyloidogenic action against both α-synuclein and Aβ42 and can be used as anti-amyloidogenic agent. (109)
  • Tolcapone has a longer duration of action and a better brain penetration than entacapone. COMT is inhibited continuously when tolcapone is dosed at 12-h intervals but this is not seen with entacapone. (110)
  • Side effects are:
  • Diarrhea
  • Yellow orange discoloration of urine 
 
Glutamate (NMDA receptor) antagonist
 
Amantadine
 
  • It acts rapidly but has lower efficacy than levodopa
  • Tolerance develops over months and the efficacy is gradually lost
  • Amantadine promotes presynaptic synthesis and release of DA in the brain and has anticholinergic property
  • Used in milder cases in a fixed dose of 100 mg BD, effect after single dose lasts8-12 hours
  • Amantadine administered at a dose of 200 mg/day antagonized the extrapyramidal symptomatology induced by neuroleptic drugs. (111)
  • Amantadine accelerates the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness. (112)
  • Amantadine given as adjuvant to levodopa can markedly improve motor response complications in patient with Parkinson's disease. (113)
  • 300 mg amantadine reduces dyskinesia in Parkinson's disease by approximately 45% but the benefit lasts for less than 8 months. (114)
  • Amantadine toxicity should be considered in the differential diagnosis of altered mental status in patients known to be taking the drug or with conditions commonly treated with amantadine. (115)
  • Amantadine is used in the treatment of Parkinson's disease. The common side effects include insomnia, increased jitterness, abdominal uneasiness, dizziness, depression, confusion and hallucinations. (116)
  • Amantadine should be considered as a potential anti-HCV drug. (117)
  • Although amantadine may improve cognition by acting as a partial agonists at NMDA receptors, it increases the monoaminergic tonus of the amygdala and hippocampus whixh may result in mania switch. (118)
  • Use of amantadine in patients with traumatic brain injury with frontal lobe dysfunction showed improvement in the symptoms. (119)
  • Amantadine might be a powerful antidiabetic tool and could be added to the therapeutic arsenal against type 2 diabetes. (120)
  • Side effects are:
  • Insomnia
  • Restlessness
  • Confusion
  • Nightmares
  • Anticholinergic effects
  • Hallucinations 
 
Central anticholinergics
 
  • These drugs have higher central: peripheral anticholinergic action
  • Trihexyphenidyl is the most commonly used drug. Start with lowest dose in 2-3 ivided portions per day and gradually increase till side effects are tolerated
  • They act by reducing the unbalanced cholinergic activity in the striatum of parkinonian patients
  • Tremor are benefited more than rigidity; hypokinesia is affected least
  • Sialorrhea is controlled by their peripheral action
  • They are the only drug effective in drug (phenothiazine) induced parkinsonism
  • Trihexyphenidyl can cause dependance in patients with Parkinson's disease. (121)
  • Trihexyphenidyl is used in the treatment of dystonia in children with cerebral palsy. (122)
  • Trihexyphenidyl is of no specific value for control of the major features of Parkinson's disease in patients recieving treatment with levodopa. (123)
  • Although trihexyphenidyl may be an effective option in tardive dyskinesia, it may trigger hypomania in patients with bipolar disorders. (124)
  • Trihexyphenidyl is prone for abuse as well as dependence and produces a characteristic withdrawal syndrome. (125)
  • Trihexyphenidyl is useful in the treatment in clozapine-induced nocturnal enuresis and sialorrhea. (126)
  • Trihexyphenidyl shows improvement in dystonia and sialoorhea when used in children with cerebral palsy. (127)
  • Trihexyphenidyl in usual clinical doses may impair total Mini-Mental State Examination (MMSE) and the Cambridge Cognitive Examination (CAMCOG) scores in medicated elderly patients with schizophrenia. (128)
  • Side effects are:
  • Impairment of memory
  • Organic confusional states
  • Blurred vision
  • Urinary retention is common in elderly 
 
 
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