Neurodegenerative Disorders PDF

J. Parkinson Antiparkinsonian drugs By Harshika Patel KeMU NRSG 232 Pharmacology 2 Date : 28/09/2020  Parkinson’s disease (PD) is a progressive neurodegenerative disorder. It is...

J. Parkinson Antiparkinsonian drugs By Harshika Patel KeMU NRSG 232 Pharmacology 2 Date : 28/09/2020  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 nigrostriatal neurons and DA depletion The symptomatic triad includes bradykinesia, rigidity and tremor with secondary manifestations like defective posture and gait, mask-like face and sialorrhea; dementia may accompany Parkinsonism Clinical ClinicalPharmacology Pharmacology––99thEd. th Ed.(2003) (2003)  High concentration of DA in the basal ganglia of the brain is reduced in PD. Normal balance of cholinergic and dopaminergic influences on the basal ganglia. Pathophysiologic 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 cholinergic 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 Causative factors of PD The degeneration of nigrostrial neurons is not precisely clear  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 glutathione 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. – Genetic 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. 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).   Grippe Essential EssentialofofMedical Medical Pharmacology Pharmacology–– 55ststEd. Ed.(2003) (2003) Factors contributing to degeneration of nigrostrial DA-ergic neurones causing PD Objectives of antiparkinsonian pharmacotherapy The dopaminergic/cholinergic balance may be restored 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 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.  Central DA-ergic Drugs Levodopa Levodopa Dopamine (-) Selegiline MAO-B (-) Amantadine Reuptake Amantadine (+) Bromocriptine (+) Pergolide D2-receptors LEVODOPA (DOPA – DihydroOxy- PhenylAlanine t1/2 1.5 hrs a natural amino acid precursor of DA. The major disadvantage is the extensive decarboxylation of levodopa to DA in peripheral tissues. So that only 1–3% of an oral dose reaches the brain. Basic Basic&&Clinical ClinicalPharmacology Pharmacology––10 10thEd. th Ed.(2007) (2007)  Thus large quantities of levodopa would have to be given. Adverse reactions: Levodopa and its metabolites cause peripheral actions: like nausea, arrhythmia, postural hypotension. ( reduced by decarboxylase inhibitors: benserazide, carbidopa)* – 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. – Example : – Co-careldopa (carbidopa and levodopa in proportions 12.5/50 mg, 25/100 mg, 50/250 mg) – Sinemet®. – Co-beneldopa (benserazide and levodopa in proportions 12.5/50 mg, 25/100 mg, 50/200 mg) – Madopar®. Basic Basic&&Clinical ClinicalPharmacology Pharmacology––10 10thEd. th Ed.(2007) (2007)  BROMOCRIPTINE t1/2 5 hrs a derivative of ergot alkaloids Ergot de savle, Secale cornutum). MOA: – It is a D2-receptor agonist, but also a weak alpha-adrenoceptor antagonist. Bromocriptine is commonly used with levodopa. Dosage: – initial dose should be very low: 1–1.25 mg p.o. at night, inc’ the dose at weekly interval according to clinical response. Uses : – 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) prolonged use may cause – pleural effusion and retroperitoneal fibrosis. CABERGOLINE (an ergot derivative) has 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 parkinsonian patients due to lack of levodopa. PRAMIPEXOLE is a non-ergot D2-receptor agonist it is more effective against tremor than the others. ROPINIROLE 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- MethylTranspherase), 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 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 only MAO-B selectively and irreversibly 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. AMANTADINE: Antivirus drug used for influenza to a parkinsonian patient (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. Adverse effects: not caused any severe effects – ankle edema (probably a local effect on blood vessels) – orthostatic hypotension – insomnia, – hallucinations, rarely – fits.  Central antimuscarinic drugs Atropa belladonna L. (Deadly night shade) Radix Belladonna: (cura bulgara) – atropine Belladonna roots have been empirically used for treatment of PD in 1920s in Bulgaria by healer Ivan Raev (Sopot: 1876–1938). BIPERIDEN, TRIHEXYPHENIDYL, TRIPERIDEN Trihexyphenidyl They 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, muscular stiffness and leg cramp, but little in bradykinesia, which is the most disabling symptom PD.  Adverse effects dry mouth (xerostomia), blurred vision, constipation, urine retention, glaucoma, hallucinations, memory defects, toxic confusion states psychoses (which should be distinguish from presenile dementia). Pharmacotherapy of PD 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 – 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. 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.  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 confusion state and hallucinations. As these symptoms are often aggravated by medication, it is preferable gradually to reduce the antiparkinsonian treatment.  Antimuscarinic drugs are suitable only for younger patients predominantly troubled with tremor and rigidity. They do not benefit bradykinesia, the main disability symptom. The ARs of acute angle glaucoma, retention of urine, constipation and psychiatric disturbance 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 Anti- Alzheimer’s drugs Alzheimer’s Disease and it’s Treatment  What is Alzheimer’s ?  Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia.  This incurable, degenerative, terminal disease was first described by a German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him.  Alzheimer's disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception.  Many scientists believe that Alzheimer's disease results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death.  Causes of Alzheimer’s Disease Not fully understood, but it is clear that it develops because of…. a complex series of events that take place in the brain over a long period of time. It is likely that the causes include genetic, environmental, and lifestyle factors.  Some drug therapies propose that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid leading to generalized neuroinflammation.  Contd’… Alzheimer's disease is characterized by a build- up of proteins in the brain  Though this cannot be measured in a living person, extensive autopsy studies have revealed this phenomenon. The build-up manifests in two ways:  Plaques– deposits of the protein beta- amyloid that accumulate in the spaces between nerve cells  Tangles – deposits of the protein tau that accumulate inside of nerve cells  PHARMACOLOGICAL AGENTS AND TEHIR EFFECTS 1. Donepezil – Used to delay or slow the symptoms of AD – Loses its effect over time – Used for mild, moderate and severe AD – Does not prevent or cure AD 2. Citalopram – Used to reduce depression and anxiety – May take 4 to 6 weeks to work – Sometimes used to help people get to sleep 3. Sodium Valproate – Used to treat severe aggression – Also used to treat depression and anxiety  Contd’…. 4. Rivastigmine Used to delay or slow the symptoms of AD – Loses its effect over time – Used for mild to moderate AD – Can get in pill form or as a skin patch – Does not prevent or cure AD 5. Namenda: Used to delay or slow the symptoms of AD – Loses its effect over time – Used for moderate to severe AD – Sometimes given with other anti-alzeimer’s agents – Does not prevent or cure AD 6. Galantamine: Used to prevent or slow the symptoms of AD – Loses its effect over time – Used for mild to moderate AD – Can get in pill form or as a skin patch – Does not prevent or cure AD  Contd’…. 7. Sertraline: Used to reduce depression and anxiety – May take 4 to 6 weeks to work – Sometimes used to help people get to sleep 8. Oxcarbazepine & Carbamazepine : Used to treat severe aggression – Also used to treat depression and anxiety 9. Mirtazapine : Used to reduce depression and anxiety – May take 4 to 6 weeks to work – Sometimes used to help people get to sleep  Treatment  Although there is currently no way to cure Alzheimer's disease or stop its progression, researchers are making encouraging advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management.  Mild/Moderate AD: Cholinesterase inhibitors: Increase the levels of acetylcholine in the brain, which plays a key role in memory and learning.  This kind of drug postpones the worsening of symptoms for 6 to 12 months in about half of the people who take it.  The drugs for mild to moderate Alzheimer's disease include  Aricept (donezepil HCL),  Exelon (rivastigmine), and  Razadyne (galantamine). Drugs for Alzheimer’s Galantamine HBr It is FDA-approved for mild and moderate stages of the disease. a cholinesterase inhibitor that prevents the breakdown of acetylcholine in the brain. Acetylcholine plays a key role in memory and learning; higher levels in the brain help nerve cells communicate more efficiently. Also stimulates nicotinic receptors to release more acetylcholine in the brain.  Continued  Razadyne/galantamine delays the worsening of Alzheimer's symptoms for 6 to 12 months in about half of the people who take it.  Razadyne is available in tablet and capsule form, and is commonly started at 4 mg twice a day. If it's well tolerated after 4 weeks, the dosage may be increased to 8 mg twice a day.  Razadyne also comes in an extended release, once-a-day tablet.  Razadyne is available in generic form (galantamine HBr).  Continued Rivastigmine (Exelon )  FDA approved for mild and moderate stages of the disease; it is also approved for the treatment of mild to moderate dementia due to Parkinson's disease.  is available as a capsule, liquid, and patch.  Continued A cholinesterase inhibitor that prevents the breakdown of acetylcholine and butyrylcholine in the brain by blocking the activity of two different enzymes. Acetylcholine and butyrylcholine play a key role in memory and learning. When given orally, bioavailability is about 40% in the 3 mg dose. The compound can cross the blood-brain barrier.  Continued Donepizel (Aricept) One of the most widely used drugs to treat the symptoms of Alzheimer's disease. FDA-approved for mild, moderate, and severe stages of the disease. Available in tablet form or an orally disintegrating tablet form, and is commonly started at 5 mg a day. Can cross the blood-brain barrier.  Continued Memantine (Namenda) an N-methyl D-aspartate (NMDA) antagonist that regulates the activity of glutamate in the brain. Glutamate plays a key role in memory and learning, but excess glutamate can lead to the disruption of nerve cell communication or nerve cell death.  Continued Namenda (memantine) regulates glutamate in the brain, which plays a key role in processing information. This drug is used to treat moderate to severe Alzheimer's disease and may delay the worsening of symptoms in some people. It may allow patients to maintain certain daily functions a little longer than they would without the medication.  Continued Studies involving Namenda have shown that the drug can slow the rate of decline in thinking and the ability to perform daily activities in individuals who have moderate to severe Alzheimer's disease A dysfunction of glutamatergic neurotransmission is thought to be involved in the etiology of AD. It is available in generic form (memantine HCL). Thank You ?