Download Free Medical Antiparkinsonian drugs PowerPoint Presentation

Antiparkinsonian drugs PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical presentation on Pharmacology, which is titled "Antiparkinsonian drugs", to know about antiparkinsonian drugs.

Tags : Pharmacology, Antiparkinsonian drugs

Published on : Jul 18, 2021 | Views : 3825 | Downloads : 4

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Antiparkinsonian drugs (Abstract) Assoc. Prof. Iv. Lambev E-mail: itlambev@mail.bg www.medpharm-sofia.eu J. Parkinson
Slide 2-

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. It is caused by degeneration of substantia nigra in the midbrain, and consequent loss of DA-containing neurons in the nigrostrial pathway. Two balanced systems are important in the extrapyramidal control of motor activity at the level of the corpus striatum and substantia nigra; in the first the neurotransmitter is ACh, in the second – DA. The symptoms of PD are connected with loss of nigrostrial neurons and DA depletion. The symptomatic triad includes bradykinesia, rigidity and tremor with secondary manifestations like defective posture and gait, mask-like face and sialorrhoea; dementia may accompany.
Slide 3-

ppt slide no 3 content not found
Slide 4-

Parkinsonism
Slide 5-

Clinical Pharmacology – 9th Ed. (2003)
Slide 6-

Rang et al. Pharmacology – 5st Ed. (2003)
Slide 7-

Distribution and characteristics of DA receptors in the central nervous system Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
Slide 8-

The normally high concentration of DA in the basal ganglia of the brain is reduced in PD, and pharmacologic attempts to restore DA-ergic activity with levodopa and DA agonists have been successful in alleviating many of the clinical features of the disorder. An alternative but complementary approach has been to restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs. The pathophysiologic basis for this therapy is that in idiopathic parkinsonism, dopaminergic neurons in the substantia nigra that normally inhibit the output of GABA-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 that exit the corpus striatum. Drugs that induce parkinsonian syndromes are DA receptor antagonists (e.g., antipsychotic agents) which lead to the destruction of the DA-ergic nigrostriatal neurons.
Slide 9-

The cause of selective degeneration of nigrostrial neurones in PD is not precisely known. It appears to be multifactorial. Oxidation of DA by MAO-B and aldehyde dehydrogenase generate hydroxyl free radicals (˙OH) in the presence of ferrous iron (basal ganglia are rich in iron). Normally these radicals are quenched by gluta- thione and other endogenous antioxidants. Age-related (e.g. in atherosclerosis) and/or otherwise acquired defect in protective antioxidant mechanisms allows the free radicals to damage lipid membranes and DNA resulting in neuronal degenerations. Gene- tic predisposition may contribute to high vulnerability of substantia nigra neurons. Environmental toxins or some infections (grippe) may accentuate these defects. A synthetic toxin N-methyl-4-phenyl tetrahydropyridine (MPTP), which occurs as a contaminant of some illicit drugs, produces nigrostrial degenerations similar to PD. Neuroleptics and other DA blockers may cause temporary PD too.
Slide 10-

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 hydrogen peroxide (H2O2). In the presence of ferrous ion hydrogen per- oxide undergoes spontaneous conversion, forming a hydroxyl free radical (The Fenton reaction). Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
Slide 11-

Factors contributing to degeneration of nigrostrial DA-ergic neurones causing PD  Grippe Essential of Medical Pharmacology – 5st Ed. (2003)
Slide 12-

The key steps in the synthesis and degradation of dopamine and the sites of action of various psychoactive substances at the dopaminergic synapse
Slide 13-

Objectives of antiparkinsonian pharmacotherapy The dopaminergic/cholinergic balance may be restored by two mechanisms. 1. Enhancement of DA-ergic activity by drugs which may: replenish neuronal DA by supplying levodopa, which is its natural precursor; administration of DA itself is ineffective 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 its metabolism (selegiline); (d) release DA from stores and inhibit reuptake (amantadine). 2. Reduction of cholinergic activity by antimuscarinic drugs; this approach is most effective against tremor and rigidity, and less effective in the treatment of bradykinesia.
Slide 14-

Levodopa Levodopa Dopamine MAO-B Selegiline Amantadine Reuptake Amantadine Bromocriptine Pergolide D2-receptors (-) (-) (+) (+) Central DA-ergic Drugs The Principles of Medical Pharmacology (1994)
Slide 15-

▼LEVODOPA (DOPA – DihydroOxy- PhenylAlanine; (t1/2 1,5 h) is a natural amino acid precursor of DA. The major disadvantage is the extensive decarboxylation of levodopa to DA in periferal tissues. So that only 1–3% of an oral dose reaches the brain.
Slide 16-

Basic & Clinical Pharmacology – 10th Ed. (2007)
Slide 17-

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, postural hypotension. This problem has been largely circumvented by decarboxylase inhibitors (benserazide, carbidopa), which do not enter the CNS; they prevent only the extracerebral metabolism of levodopa. The inhibitors are given in combination with levodopa; but in this case only 25% of the dose of levodopa is required and ARs diminish significantly. Levodopa alone and in combination is introduced gradually and titrated according to clinical 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®.
Slide 18-

Basic & Clinical Pharmacology – 10th Ed. (2007)
Slide 19-

▼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 treatment of prolactin-secreting adenomas, amenorrhea/galactorrhea to hyperprolactinemia, to stop lactation, acromegaly. ADRs: Nausea and vomiting, which may be prevented with domperidone; postural hypotension (may cause dizziness or syncope); after prolonged use – pleural effusion and retroperitoneal fibrosis.
Slide 20-

▼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-Ortho-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.
Slide 21-

▼SELEGILINE. The problem with nonselective MAO inhibitors is that they prevent degradation of dietary adrenomimetic amines, especially tyramine, by MAO-A inhibition which causes hypertensive “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 nerve endings in periphery. Selegiline inhibits selectively and irreversibly only MAO-B in the CNS and protects DA from intraneuronal degradation. It is used as an adjunct drug in PD if levodopa/carbidopa or levodopa/benserazide therapy is deteriorating. In a transdermal patch selegiline is used as a treatment for major depression.
Slide 22-

▼AMANTADINE is an antivirus drug which, given for influenza to a parkinsonian patient, was noted to be beneficial. Antiviral and antiparkinsonian effects of amantadine are probably unrelated. Antiparkinsonian effect is due to increase synthesis and release of DA, and diminish neuronal reuptake too. Amantadine also has slight antimuscarinic effect. It is used for oral adjunct treatment of PD and influenza A virus 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.
Slide 23-

Atropa belladonna L. (Deadly night shade) Radix Belladonnae: (cura bulgara) – atropine Belladonna roots have been empirically used for treatment of PD in 1920s in Bulgaria by healer Ivan Raev (Sopot: 1876–1938). Central antimuscarinic drugs
Slide 24-

▼BIPERIDEN, TRIHEXYPHENIDYL, TRIPERIDEN are synthetic compounds (central M-cholinolytics). They benefit parkinsonism by blocking ACh receptors in the CNS, thereby partially redressing the imbalance created by decreased DA-ergic activity. They also produce modest improvement in tremor, rigidity, sialorrhoea (hypersalivation), muscular stiffness and leg cramp, but little in bradykinesia, which is the most disabling symptom of Parkinson’s disease. ARs of antimuscarinic drugs include dry mouth (xerostomia), blurred vision, constipation, urine retention, glaucoma, hallucinations, memory defects, toxic confusional states and psychoses (which should be distinguish from presenile dementia). Trihexyphenidyl
Slide 25-

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 in symptom relief, but it does not alter the progressive course of PD. Treatment should begin only when it is judged necessary in each individual case. Two conflicting objectives have to be balanced: the desire for satisfactory relief of current symptoms and the avoidance of ARs as a result of long-continued treatment. There is a debate as to whether the treatment should commence with levodopa or a synthetic DA agonist. Levodopa provides the biggest improvement in motor activity but its use is associated with the development of dyskinesia (involuntary movement of the face and limbs) after 5–10 years, and sometimes sooner.
Slide 26-

DA agonists have a much less powerful motor effect but are less likely to produce dyskinesias. The treatment usually begins with levodopa in low doses to get a good motor response and adds a DA agonist when the initial benefit begins to wane. A typical course is that for about 2–4 years on treatment with levodopa or DA agonist, the patient’s disability and motor performance remains near normal despite progression of the underlying disease. After some 5 years about 50% of patients exhibit problems of long-term treatment, namely, dyskinesia and end-of-dose deterioration with the “on-off” phenomenon. After 10 years virtually 100% of patients are affected.
Slide 27-

End-of-dose deterioration is managed by increasing the frequency of dosing with levodopa (e.g. to 2 or 3-hourly), but this tends to worsen the dyskinesia. The motor response then becomes more brittle with abrupt swings between hyper- and hypomobility (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 deterioration without causing dyskinesia. Some 20% of the patients with Parkinson’s disease, notably the Elderly ones, develop impairment of memory and speech with a fluctuating confusional state and hallucinations. As these symptoms are often aggravated by medication, it is preferable gradually to reduce the antiparkinsonian treatment.
Slide 28-

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 piperazine phenothiazines (e.g. trifluoperazine) and butyrophenones (e.g. haloperidol) often cause Parkinsonism because they block D2-receptors.
Slide 29-

Treatment approaches to newly diagnosed idiopathic PD
Slide 30-

Comparison of levodopa + benserazide, levodopa + benserazide + selegiline and bromocriptine on progression of PD symptoms
Slide 31-

ppt slide no 31 content not found
Slide 32-

ppt slide no 32 content not found