Drugs for Neurodegenerative Diseases Kaukab Azim, MBBS, PhD

Drug List Drugs for Parkinson’s Disease Drugs that increase brain dopamine levels Dopamine receptor agonists M receptor antagonists Levodopa Carbidopa Selegiline Entacapone Amantadine Bromocriptine Pramipexole Benztropine Drugs for Huntington’s DiseaseDrugs for Alzheimer’s Disease Haloperidol* Diazepam* Donepezil

Learning Outcomes By the end of the course the students will be able to  Explain the mechanism of action of each drug in each group  Describe the main effects of each drug on different organ systems  Describe the absorption, distribution and metabolism of levodopa and carbidopa  Describe the administration routes of each drug in each class  Describe the main adverse effects of each drug in each class  Explain the on/off effect and wearing-off effect of levodopa / carbidopa  Explain the therapeutic value of combining levodopa with carbidopa in Parkinson’s disease  Explain the use of dopamine agonists and antimuscarinic drugs in Parkinson’s disease  Explain the use of neuroleptic and benzodiazepines in Huntington’s disease  Explain the use of central cholinesterase inhibitors in Alzheimer’s disease

Levodopa Chemistry The amino acid levodopa is the biosynthetic precursor of dopamine. Mechanism of action In the brain levodopa is taken up by dopaminergic terminals in the striatum and is converted to dopamine by levo- aromatic amino acid decarboxylase (LAAD) (dopamine as such cannot be used since it does not enter the brain). Levodopa itself is largely inert. Its effects depend on the increased synthesis of dopamine in the brain and are mostly related to activation of D2 receptors.

Medulla Glucocorticoid +

Levodopa Pharmacological effects The peripheral effects of levodopa are related to the plasma concentration of dopamine. Pharmacokinetics Oral bioavailability: 5% (the firs-pass effect is very large; 95% is metabolized in the gut wall and in the liver) Additional amounts are converted into dopamine and therefore only 1% enter the brain.

Levodopa Adverse effects CNS Anxiety, agitation, insomnia or sleepiness, nightmares, euphoria or depression, confusion, delusions, hallucinations, personality changes. [clozapine is the best drug to treat these effects] Dyskinesias[A gr of Involantary movement] (up to 80% of patients treated for more than 3 years): choreoathetosis[Jerky Involantary movement] of the face and the extremities, tics[a repeated & largely Involantary movement], myoc lonus[a sudden spasm of the Muscle], tremor. [therapy is unsatisfactory. A drug holiday can help] Gastrointestinal system Anorexia, nausea and vomiting (up to 80% of patients), weight loss. Tolerance to these effects can occur after several months. Cardiovascular system Palpitations, cardiac arrhythmias (about 10% of patients) Postural hypotension (about 25% of patients). Tolerance can develop in a few months. Other systems Leukopenia, agranulocytosis, hemolytic anemia.

Levodopa Drug interactions High doses of pyridoxine (vit B6) enhances the extracerebral metabolism of levodopa. Nonselective MAO inhibitors inhibit dopamine metabolism (an hypertensive crisis may ensue) Neuroleptics that block D2 receptors reduce the efficacy of levodopa and can exacerbate motor dysfunctions. Contraindications and Precautions Melanoma (levodopa is a precursor of melanin and can activate malignant melanoma) Cardiac disease Psychosis Depression with suicidal ideation Treatment with nonselective MAO inhibitors

Levodopa Therapeutic Uses  Levodopa ameliorates all signs of parkinsonism. Bradykinesia is the most sensitive to improvement.  The drug however does not cure the disease and responsiveness fluctuates and decreases with time.  Two main types of fluctuations occur over time: 1. The wearing-off effect (also called end-of-dose akinesia{loss of muscular tonicity OR responsiveness}): each dose improves mobility for 1-2 hours but akinesia rapidly returns. 2. The on-off effect: ‘off’ periods of marked akinesia alternate with ‘on’ periods of improved mobility.  Levodopa therapy must not discontinued abruptly (a malignant syndrome can result)

Carbidopa  Carbidopa is a DOPA decarboxylase inhibitor that does not cross the blood-brain barrier.  When given with levodopa, the peripheral metabolism of levodopa is reduced with the following consequences: 1. The half-life of levodopa is increased. 2. More levodopa is available for entering the brain (this reduces by about 75% the daily requirement) 3. Gastrointestinal and cardiovascular effects of levodopa are substantially reduced. 4. CNS adverse effects are increased. Levodopa is usually given in combination with carbidopa.

Other drugs that increase dopamine levels Selegiline  Selegiline is a selective inhibitor of MAO B (the enzyme that metabolizes dopamine) so preventing the metabolism ( oxidation ) of dopamine.  This increases brain dopamine levels and prevents the formation of hydroxide radicals, that may play a role in the degeneration of nigrostriatal neurons.  Selegiline may reduce the ‘wearing-off’ and the ‘on-off’ effects.  Adverse effects are related to increased levels of dopamine both centrally (insomnia, mood changes, dyskinesias) and peripherally (nausea, hypotension).  It is used as a single agent in mild Parkinson’s disease or, more often, as an adjunct to levodopa, so allowing a reduction of levodopa dose.

Other drugs that increase dopamine levels Catechol-O-methyltransferase inhibitors  Entacapone and tolcapone are inhibitors of Catechol-O- methyltransferase, the enzyme that transforms methyldopa into 3- Omethyldopa in the gut and the liver.  Since 3-O-methyldopa competes with levodopa for active transport into CNS, this metabolite may contribute to the wearing-off and on- off effects. By inhibiting the enzyme, more levodopa can enter the brain.  Adverse effects are related (in part) to increased levels of dopamine.  Entacapone (which is preferred because it has not been associated with hepatotoxicity) is used as an adjunct to levodopa.

Other drugs that increase dopamine levels Amantadine  The drug is an antiviral agent that probably works by increasing the release and inhibiting the reuptake of dopamine on nigrostriatal neurons.  Adverse effects are related in part to increased levels of dopamine. It can also cause livedo reticularis (a reddish-blue mottling[spot] of the skin with edema)  It is used as a single agent in mild Parkinson’s disease or, more often, as an adjunct to levodopa.

Dopamine Receptor Agonists Drugs Bromocriptine (ergot derivative), pramipexole. Mechanism of action Bromocriptine is a partial agonist at central and peripheral D2- receptors (the activation in mammotroph cells of the pituitary blocks prolactin secretion). Pramipexole is an agonist at D2 and D3 receptors in brain. Pharmacological effects (All are related to activation of central and peripheral D2 receptors) Reduction of plasma prolactin levels (within hours from administration). Stimulation of GH release in normal subjects but blockade (for unknown reasons) of release in acromegalic subjects. Pharmacokinetics and administration Oral bioavailability: bromocriptine. 6 % (extensive first-pass effect) Administration: oral.

Dopamine Receptor Agonists Adverse effects Dopamine-related  Anorexia, nausea and vomiting (up to 50%), stypsis (constipation).  Postural hypotension (common), cardiac arrhythmias.  Dyskinesias (after long-term use of high doses).  Headache, insomnia, nightmares, confusion, delusions[False misbelief about others], hallucinations) Ergot-related  Digital vasospasm (after long-term use)  Erythromelalgia (hot, red, tender, and painful feet or hands) (rare)  Pulmonary or retroperitoneal fibrosis (rare) Contraindications and precautions  Psychotic disorders.  Cerebrovascular disorders

Dopamine Receptor Agonists Therapeutic uses  Prolactin-secreting adenomas (unfortunately expansion of tumor often occurs if the drug is discontinued).  Idiopathic hyperprolactinemia and associated dysfunctions (amenorrhea-galactorrhea syndrome, infertility, hypogonadism).  Parkinson's disease.  Acromegaly  Cocaine detoxification (results are modest, at the best).

Antimuscarinic Drugs in Parkinsonism Drugs  Benztropine and trihexyphenidyl and are centrally acting antimuscarinic drugs used for the treatment of Parkinson’s disease. Mechanism of action  They likely act within the striatum on cholinergic striatal excitatory interneurons.  All subtypes of muscarinic receptors are likely present in the striatum.  The competitive blockade of these receptors decrease the cholinergic tone that is abnormally high in Parkinson’s disease, due to lack of the inhibitory activity of dopamine.

Antimuscarinic Drugs in Parkinsonism Clinical uses  Antimuscarinic drugs may improve sialorrhea[excessive production of saliva] , tremor and rigidity but have little effect on bradykinesia  They are less effective than dopaminergic drugs but may be helpful as adjunct therapy. They can also reduce parkinsonism, acute dystonias and akathisia caused by neuroleptics and other dopamine antagonists (but they can exacerbate tardive dyskinesia). Adverse effects Adverse anticholinergic effects are both: a. Central: drowsiness, restlessness, confusion, agitation, delusions, hallucinations. b. Peripheral; xerostomia, blurring of vision, urinary retention, constipation, tachycardia, increased intraocular pressure. (Elderly people are especially at risk).

Drugs for Huntington’s Disease Drugs used in Huntington’s disease include: 1.Dopamine receptor antagonists Neuroleptics (haloperidol, chlorpromazine) antagonize the excessive dopaminergic activity in basal ganglia and are also helpful to improve motor function and to relieve paranoia[personality disorder] and delusional states that often accompany the disease. 2.Amine depleting drugs Reserpine, which can block the vesicular storage of dopamine (Benzodiazepines which potentiate central GABA activities should help but the results have been somewhat disappointing).

Drugs for Tourette’s Syndrome Drugs used in Tourette’s syndrome include: 1.Neuroleptics (haloperidol, olanzapine, etc.) 2.Clonidine (it is effective in some patients only) 3.Nn blocking drug (mecamylamine)

Drugs for Alzheimer’s Disease The ‘cholinergic hypothesis’ which states that a deficiency of acetylcholine is critical in the genesis of symptoms of AD.  Donepezil, galantamine and tacrine are cholinesterase inhibitors approved for treatment of AD. Donepezil and rivastigmine selectively inhibits cholinesterase in the CNS with less effect on cholinesterases in peripheral tissues.  These drugs can slow the deterioration of cognitive functions, even if they do not affect the underlying neurodegenerative process.  Adverse effects include insomnia, nausea, vomiting and diarrhea.