AntiparkinsonianAntiparkinsoniandrugsdrugs(Abstract)(Abstract)

Assoc. Prof. Iv. LambevE-mail: itlambev@mail.bgwww.medpharm-sofia.eu

J. Parkinson

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. It is caused by degeneration of substantia nigra in themidbrain, and consequent loss of DA-containing neurons in thenigrostrial pathway. Two balanced systems are important in theextrapyramidal control of motor activity at the level of the corpus striatum and substantia nigra; in the first the neurotransmitter isACh, in the second – DA. The symptoms of PD are connected with loss of nigrostrialneurons and DA depletion. The symptomatic triad includesbradykinesia, rigidity and tremor with secondary manifestationslike defective posture and gait, mask-like face and sialorrhoea;dementia may accompany.

ParkinsonismParkinsonism

Clinical Pharmacology – 9th Ed. (2003)Clinical Pharmacology – 9th Ed. (2003)

Rang et al. Pharmacology – 5st Ed. (2003)Rang et al. Pharmacology – 5st Ed. (2003)

Distribution and characteristics of DA receptors in the central nervous system

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006) Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

The normally high concentration of DA in the basal ganglia of thebrain is reduced in PD, and pharmacologic attempts to restore DA-ergic activity with levodopa and DA agonists have beensuccessful in alleviating many of the clinical features of the disorder.An alternative but complementary approach has been to restore thenormal balance of cholinergic and dopaminergic influences on thebasal ganglia with antimuscarinic drugs. The pathophysiologic basisfor this therapy is that in idiopathic parkinsonism, dopaminergicneurons in the substantia nigra that normally inhibit the output ofGABA-ergic cells in the corpus striatum are lost.In contrast, Huntington's chorea involves the loss of some cholin-ergic neurons and an even greater loss of the GABA-ergic cells thatexit the corpus striatum. Drugs that induce parkinsonian syndromesare DA receptor antagonists (e.g., antipsychotic agents) which lead to the destruction of the DA-ergic nigrostriatal neurons.

The cause of selective degeneration of nigrostrial neurones in PDis not precisely known. It appears to be multifactorial. Oxidation ofDA by MAO-B and aldehyde dehydrogenase generate hydroxylfree radicals (˙OH) in the presence of ferrous iron (basal gangliaare rich in iron). Normally these radicals are quenched by gluta-thione and other endogenous antioxidants. Age-related (e.g. inatherosclerosis) and/or otherwise acquired defect in protectiveantioxidant mechanisms allows the free radicals to damage lipidmembranes and DNA resulting in neuronal degenerations. Gene-tic predisposition may contribute to high vulnerability of substantianigra neurons. Environmental toxins or some infections (grippe)may accentuate these defects. A synthetic toxin N-methyl-4-phenyltetrahydropyridine (MPTP), which occurs as a contaminant ofsome illicit drugs, produces nigrostrial degenerations similar to PD.Neuroleptics and other DA blockers may cause temporary PD too.

Production of free radical by the metabolism of dopamine (DA).DA is converted by MAO and aldehyde dehydrogenase (AD) in 3,4-dihydroxyphenylacetic acid (DOPAC), producing hydrogenperoxide (H2O2). In the presence of ferrous ion hydrogen per-oxide undergoes spontaneous conversion, forming a hydroxylfree radical (The Fenton reaction).

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006) Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

Factors contributing to degeneration ofFactors contributing to degeneration of nigrostrial DA-ergic neurones causing PDnigrostrial DA-ergic neurones causing PD

Grippe

Essential of MedicalPharmacology – 5st Ed. (2003)

Essential of MedicalPharmacology – 5st Ed. (2003)

The key steps in the synthesis and degradation of dopamineand the sites of action of various psychoactive substances at the

dopaminergic synapse

Objectives of antiparkinsonian pharmacotherapyThe dopaminergic/cholinergic balance may berestored by two mechanisms.

1. Enhancement of DA-ergic activity by drugs which may:(a) replenish neuronal DA by supplying levodopa, which is its natural precursor; administration of DA itself isineffective as it does not cross the BBB;(b) act as DA agonists (bromocriptine, pergolide, cabergoline, etc.);(c) prolong the action of DA through selective inhibition of itsmetabolism (selegiline);(d) release DA from stores and inhibit reuptake (amantadine).2. Reduction of cholinergic activity by antimuscarinicdrugs; this approach is most effective against tremor and rigidity,and less effective in the treatment of bradykinesia.

Levodopa Levodopa

Dopamine

MAO-BSelegiline

Amantadine Reuptake Amantadine

BromocriptinePergolide

D2-receptors

(-)

(-)

(+)

(+)

Central DA-ergic DrugsCentral DA-ergic Drugs

The Principles of MedicalPharmacology (1994)

The Principles of MedicalPharmacology (1994)

▼LEVODOPA (DOPA – DihydroOxy-PhenylAlanine; (t1/2 1,5 h) is a natural amino acidprecursor of DA. The major disadvantageis the extensive decarboxylation of levodopa to DA inperiferal tissues. So thatonly 1–3% of an oral dosereaches the brain.

Basic & Clinical Pharmacology – 10th Ed. (2007) Basic & Clinical Pharmacology – 10th Ed. (2007)

Thus large quantities of levodopa would have to be given. Levodopa and its metabolites cause significant adverse reactions(ARs) by peripheral actions, notably nausea, arrhythmia, posturalhypotension. This problem has been largely circumvented bydecarboxylase inhibitors (benserazide, carbidopa), which do not enter the CNS; they prevent only the extracerebral metabolismof levodopa. The inhibitors are given in combination withlevodopa; but in this case only 25% of the dose of levodopa isrequired and ARs diminish significantly. Levodopa alone and incombination is introduced gradually and titrated according toclinical response; the dose being altered every two weeks.• Co-careldopa (carbidopa and levodopa in proportions 12.5/50 mg, 25/100 mg, 25/250 mg) – Sinemet®.• Co-beneldopa (benserazide and levodopa in proportions 12.5/50 mg, 25/100 mg, 50/200 mg) – Madopar®.

Basic & Clinical Pharmacology – 10th Ed. (2007) Basic & Clinical Pharmacology – 10th Ed. (2007)

▼BROMOCRIPTINE (t1/2 5 h) – a derivative of ergot (Ergot de savle, Secale cornutum).It is a D2-receptor agonist, but also a weak alpha-adrenoceptor anatagonist. Bromocriptine is com-monly used with levodopa. It should be started at very low doses (1–1,25 mg p.o. at night), increasing at weekly interval and according to clinical response. It is also used for treatmentof prolactin-secreting adenomas, amenorrhea/galactorrhea tohyperprolactinemia, to stop lactation, acromegaly.ADRs: Nausea and vomiting, which may be prevented withdomperidone; postural hypotension (may cause dizziness orsyncope); after prolonged use – pleural effusion andretroperitoneal fibrosis.

▼CABERGOLINE, also an ergot derivative, has a t1/2 >80 h. This allows it to be used in a single daily (or even twice weekly) dose. Cabergoline alleviates night-time problems in parkinso-nian patients due to lack of levodopa. ▼PRAMIPEXOLE is a non-ergot D2-receptor agonist; it is more effective against tremor than the others. ▼ROPINIROLE (Requip®) is a new non-ergot direct D2-receptor agonist. There are insufficient data to allow an informed choice between pramipexole and ropinirole. ▼ENTACAPONE inhibits COMT (catechol-O-methyltrans-pherase), one of the main enzymes responsible for the metabolism of DA; the action of levodopa is thus prolonged.Entacapone is most effective for patients with early end-of-dose deterioration.

▼SELEGILINE. The problem with nonselective MAO inhibitors isthat they prevent degradation of dietary adrenomimetic amines, especially tyramine, by MAO-A inhibition which causeshypertensive “cheese reaction”.Selegiline does not cause the cheese reaction, because MAO-A is still presented in the liver to metabolize tyramine.MAO-A also metabolizes tyramine in the sympathetic nerveendings in periphery. Selegiline inhibits selectively only MAO-Bin the CNS and protects DA from intraneuronal degradation.It is used as an adjunct drug in PD if levodopa/carbidopa orlevodopa/benserazide therapy is deteriorating.

▼AMANTADINE is an antivirus drug which, given for influenzato a parkinsonian patient, was noted to be beneficial. Antiviraland antiparkinsonian effects of amantadine are probablyunrelated. Antiparkinsonian effect is due to increase synthesis and release of DA, and diminish neuronal reuptake too. Amantadine also has slightantimuscarinic effect.It is used for oral adjunct treatment of PD and influenza Avirus infection. Amantadine is relatively free from ARs, which, however, includes ankle edema (probably a local effect on blood vessels), orthostatic hypotension, insomnia, hallucinations, rarely – fits.

Atropa belladonna L.(Deadly night shade)Radix Belladonnae: (cura bulgara) – atropine

Belladonna roots have been empirically used fortreatment of PD in 1920s in Bulgaria by healer

Ivan Raev (Sopot: 1876–1938).

Belladonna roots have been empirically used fortreatment of PD in 1920s in Bulgaria by healer

Ivan Raev (Sopot: 1876–1938).

Central antimuscarinic drugsCentral antimuscarinic drugs

▼BIPERIDEN, TRIHEXYPHENIDYL, TRIPERIDEN are synthetic compounds (central M-cholinolytics). They benefit parkinsonism by blocking ACh receptors in the CNS, therebypartially redressing the imbalance created by decreased DA-ergicactivity. They also produce modest improvement in tremor, rigidity, sialorrhoea (hypersalivation), muscular stiffness and legcramp, but little in bradykinesia, which is the most disablingsymptom of Parkinson’s disease. ARs of antimuscarinic drugsinclude dry mouth (xerostomia), blurred vision, constipation,urine retention, glaucoma, hallucinations,memory defects, toxic confusional statesand psychoses (which should bedistinguish from presenile dementia).

Trihexyphenidyl

Pharmacotherapy of PD(Clinical Pharmacology – 9th Ed., 2003)

The main features that require alleviation are tremor, rigidity and bradykinesia. Drug therapy has the most important role insymptom relief, but it does not alter the progressive course of PD.Treatment should begin only when it is judged necessary ineach individual case. Two conflicting objectives have to be balanced: the desire for satisfactory relief of current symptomsand the avoidance of ARs as a result of long-continued treatment.There is a debate as to whether the treatment should commencewith levodopa or a synthetic DA agonist. Levodopa providesthe biggest improvement in motor activity but its use is associatedwith the development of dyskinesia (involuntary movementof the face and limbs) after 5–10 years, and sometimes sooner.

DA agonists have a much less powerful motor effect but are lesslikely to produce dyskinesias. The treatment usually begins withlevodopa in low doses to get a good motor response and addsa DA agonist when the initial benefit begins to wane.

A typical course is that for about 2–4 years on treatment withlevodopa or DA agonist, the patient’s disability and motorperformance remains near normal despite progression of theunderlying disease. After some 5 years about 50% of patientsexhibit problems of long-term treatment, namely, dyskinesiaand end-of-dose deterioration with the “on-off” phenomenon.After 10 years virtually 100% of patients are affected.

End-of-dose deterioration is managed by increasing thefrequency of dosing with levodopa (e.g. to 2 or 3-hourly), butthis tends to worsen the dyskinesia. The motor response thenbecomes more brittle with abrupt swings between hyper- andhypomobility (the on-off phenomenon). In this case a more effective approach is to use a COMT inhibitor, e.g. entacapone,which can sometimes allay early end-of-dose deteriorationwithout causing dyskinesia.

Some 20% of the patients with Parkinson’s disease, notably the Elderly ones, develop impairment of memory and speech with afluctuating confusional state and hallucinations. As thesesymptoms are often aggravated by medication, it is preferablegradually to reduce the antiparkinsonian treatment.

Antimuscarinic drugs are suitable only for younger patients predo-minantly troubled with tremor and rigidity. They do not benefit bra-dyskinesia, the main disability symptom. The ARs of acute angle glaucoma, retention of urine, constipation and psychiatric distur-bance are general contraindications to their use in the elderly.

Drug-induced Parkinsonism is alleviated by antimuscarinics, but not by levodopa or DA agonist, because antipsychotics block D2-receptors by which these drugs act. The piperazinephenothiazines (e.g. trifluoperazine) and butyrophenones (e.g. haloperidol) often cause Parkinsonism because they blockD2-receptors.

Treatment approaches to newly diagnosed idiopathic PD

Comparison of levodopa + benserazide, levodopa + benserazide + selegiline

and bromocriptine on progression of PD symptoms