Anti Parkinson’s Drugs

8/3/2019 Anti Parkinson’s Drugs

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Anti Parkinson’s Drugs



Introduction



Pathophysiology

• The dopaminergic deficit in PD arises from a

loss of the neurons in the substantia nigra pars

compacta that provide innervation to the

striatum (caudate and putamen)



Dopamine Receptors • At least 5 different types D1 to D5

• All G protein coupled receptors

• D1 D5 – Increase CAMP

•D2D3D4-Decrese CAMP ,Modulate Ca+ K+current

Location

• D1D2- Striatum• D3- Nucleus Accumbence, Olfactory Tuberclw

• D4D5-Extrastriatal



Neuronal Circuits

Normal Physiology Parkinson’s Disease



Effect of Loss of Dopaminergic

Neurons • Decreased activity of D1 dependent direct

pathway

• Increased activity of D2 Dependant Indirect

pathway

• Effective increase in inhibitory impulses to

Thalamus Leading to Decesed excitation of

cortex trough thalamus

• Ultimate loss of Upper motor neuron inhibition



Classification of Drugs

• Dopamine Agonists- Ropinirole , Pramipexole

• Levodopa carbidopa-

• COMT Inhibitors-Entacapone, Tolcapone

• MAO Inhibitors-Selegiline,Rasagiline

• Anticholinergics- Trihexyphenidyl , Benztropine

mesylate, Diphenhydramine hydrochloride

• Disease Modifying Agents & Potential therapeutic

Targets-Rasagiline, CoenzymeQ10



Levodopa • the metabolic precursor of DA, is the single most effective agent in the

treatment of PD

• administered orally, levodopa is absorbed rapidly from the small bowel bythe transport system for aromatic amino acids

• The t1/2 in plasma is short (1-3 hours)

•

ompetition for absorption sites in the small bowel from dietary amino acidsalso may have a marked effect on the absorption of levodopa

• . Entry of the drug into the CNS across the blood-brain barrier also ismediated by a membrane transporter for aromatic amino acids

• In the brain, levodopa is converted to DA by decarboxylation primarilywithin the presynaptic terminals of dopaminergic neurons in the stratium.

The DA produced is responsible for the therapeutic effectiveness of thedrug in PD; after release, it is either transported back into dopaminergicterminals by the presynaptic uptake mechanism or metabolized by theactions of MAO and catechol-O- methyltransferase



Inhibitors of aromatic L-amino

acid decarboxylase • Carbidopa , Benserazide

• If levodopa is administered alone, the drug is largely decarboxylated byenzymes in the intestinal mucosa and other peripheral sites so that relativelylittle unchanged drug reaches the cerebral circulation and probably <1%penetrates the CNS. In addition, DA release into the circulation byperipheral conversion of levodopa produces undesirable effects, particularlynausea. Inhibition of peripheral decarboxylase markedly increases thefraction of administered levodopa that remains unmetabolized andavailable to cross the blood-brain barrier and reduces the incidence of GIside effects.





Dopamine Receptor Agonists • Ropinirole,Pramipexoe(selectiv D2D3 noD1)

• Pergolide(Cardiac Valve fibrosis), Bromocriptine

•Advantages:

• Activity do not depend on the functionalcapacities of the nigrostriatal neurons.

• Longer duration of action(8-24 )

• Less motor fluctuation• Might retard progression

• Ropinirole is also available in a once-dailysustained release formulation



• Side Effects:

• Hallucinosis or confusion

•

Nausea and orthostatic hypotension• Fatigue and somnolence

• Sudden attacks of irresistible sleepiness





Apomorphine • A dopaminergic agonist that can be administered by subcutaneous injection

• It has high affinity for D4 receptors

• approved as a "rescue therapy" for the acute intermittent treatment of "off"

episodes in patients with a fluctuating response to dopaminergic therapy

• highly emetogenic , QT prolongation, injection-site reactions

• hypotension and loss of consciousness have occurred when apomorphinewas administered with ondansetron; hence, the concomitant use ofapomorphine with antiemetic drugs of the 5-HT3 antagonist class iscontraindicated

• appropriate only when other measures, such as oral DA agonists or COMTinhibitors, have failed to control the "off" episodes

• Apomorphine therapy should be initiated with a 2-mg test dose



COMT Inhibitors • COMT transfers a methyl group from the donor S- adenosyl-L-

methionine, producing the pharmacologically inactive compounds 3-O -methyl DOPA (from levodopa) and 3-methoxytyramine

• The principal therapeutic action of the COMT inhibitors is to block

this peripheral conversion of levodopa to 3-O -methyl DOPA,increasing both the plasma t1/2 of levodopa as well as the fraction ofeach dose that reaches the CNS



• Two COMT inhibitors presently are available forthis use in the United States, tolcapone (TASMAR)and entacapone (COMTAN)

•both agents significantly reduced the "wearingoff" symptoms in patients treated withlevodopa/carbidopa

• The common adverse effects of these agents are

similar to those of levodopa/carbidopa alone andinclude nausea, orthostatic hypotension, vividdreams, confusion, and hallucinations



Entacapone

• Short duration of action

• Administered with L+C

•

Entacapone also is available in fixed-dosecombinations with levodopa/carbidopa

(STALEVO)



Tolcapone

• tolcapone has a relatively long duration of

action, allowing for administration two to three

times a day

• Hepatotoxic



MAO Inhibitors • MAO-A :

• deaminates 5HT, NA

• In Adrenergic nerve endings, IntestinalMucosa,Placenta,Liver

• inhibited by Clorgyline,Moclobemide

• MAO-B:

• deaminates Phenylethylamines

•

Found in Brain ,Platelets,and Liver• Inhibited by Selegiline, Rasagiline

• Nonspescific:

• phenelzine, tranylcypromine, and isocarboxazid



Selective MAO-B Inhibitors

• Selegiline, Rasagiline

• Selectively inactivate MAO-B through

irreversible inhibition of the enzyme

• Inhibition of breakdown of DA in the striatum

• do not substantially inhibit the peripheral

metabolism of catecholamines and can be

taken safely with levodopa

• do not exhibit the "cheese effect"



Selegiline • generally well tolerated in younger patients with early

or mild PD

• In patients with more advanced PD or underlying

cognitive impairment, selegiline may accentuate theadverse motor and cognitive effects of levodopatherapy

•

Metabolites of selegiline include amphetamine whichmay cause anxiety, insomnia, and other adversesymptoms

• available in an orally disintegrating tablet, transdermalpatch



Rasagiline

• Does not give rise to undesirable amphetaminemetabolites

• Rasagiline monotherapy was effective in earlyPD. Adjunctive therapy significantly reducedlevodopa-related "wearing off" symptoms in

advanced PD.

• Neuroprotective effect of rasagiline

I M B



Drug Interactions Of MAO-B

Inhibitors • selegiline can lead to the development of stupor, rigidity,

agitation, and hyperthermia when administered with theanalgesic meperidine

•

selegiline or rasagiline should not be given in combinationwith meperidine.

• Adverse effects have been reported from co-administrationof MAO-B inhibitors with tricyclic antidepressants or with

serotonin-reuptake inhibitors.

• concomitant administration of selegiline or rasagiline withserotonergic drugs should be done with caution



Muscarinic Receptor Antagonists

• The biological basis for the therapeutic actions ofanticholinergics is not completely understood.

• Trihexyphenidyl , Benztropine mesylate,Diphenhydramine hydrochloride

• modest antiparkinsonian activity and are only usedin the treatment of early PD or as an adjunct todopamimetic therapy

• sedation and mental confusion. Other side effectsare constipation, urinary retention, and blurredvision through cycloplegia. All anticholinergicdrugs must be used with caution in patients withnarrow-angle glaucoma



Amantidine • Amantadine an antiviral agent used for the prophylaxis and

treatment of influenza A has antiparkinsonian activity

• alter DA release in the striatum, has anticholinergic

properties, and blocks NMDA glutamate receptors

• It is used as initial therapy of mild PD. It also may be helpfulas an adjunct in patients on levodopa with dose-relatedfluctuations and dyskinesias

• Dizziness, lethargy, anticholinergic effects, and sleepdisturbance, as well as nausea and vomiting

N T



Neuroprotective Treatments for

Parkinson Disease • Rasagiline

• Coenzyme Q10

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Anti Parkinson’s Drugs