Neurodegenerative diseases Hiwa K. Saaed, PhD Department of Pharmacology & Toxicology College of Pharmacy University of Sulaimani Hiwa.saaed@univsul.edu.iq 2018-19 Neurodegenerative diseases of the CNS Progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorder of movement, cognition, or both. Include: Alzheimer disease: dementia and disordered cognitive function. Parkinson s disease: a disabling motor impairment disorder. Huntington disease: excessive and abnormal movement. Amyotrophic lateral sclerosis (ALS): progressive weakness and muscle atrophy. Multiple Sclerosis: is an autoimmune inflammatory demyelinating disease of the CNS. 2 1
State of DA/ACH imbalance 3 PARKINSON S DISEASE Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals. Degeneration of neurones within nigrostriatal pathway resulting in loss of dopaminergic activity cause an extrapyramidal motor disorder https://www.youtube.com/watch?v=rimbxfvh9h4 4 2
PATHOPHYSIOLOGY Imbalance of dopaminergic & cholinergic activity within the extrapyramidal system reduced dopaminergic OR Increased cholinergic activity 5 RAFT Characterized by: RAFT; rigidity, akinesia, flat facies, tremor (1) Rigidity of skeletal muscles, (2) Akinesia (or bradykinesia, or hypokinesia; slowness in initiating and carrying out voluntary movements, (3) Flat facies (mask like face), (4) Tremor at rest With secondary manifestations like postural and gait abnormalities with a tendency to fall backwards or forwards. https://www.youtube.com/watch?v=4qdd4ny34cc Handwriting of a person affected by PD 6 3
PARKINSON S DISEASE ETIOLOGY: Primary; unknown cause Secondary (Drug-induced Parkinsonism): Reversible (also called pseudoparkinsonism): Haloperidol, phenothiazine, reserpine (at high dose) Irreversible: MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) Treatment with MAOB Inhibitors protects against MPTP neurotoxicity in animals. 7 STRATEGY OF TREATMENT is to re-establish the balance between dopamine and Ach. This can be accomplished by either 1. increasing dopamine activity in the NG, 2. decreasing muscarinic cholinergic activity in the striatum, 3. or both. Through: 1. Drug affecting brain dopaminergic system 2. Drug affecting brain cholinergic system 8 4
PHARMACOLOGIC TREATMENT OPTIONS: I. Drug affecting brain dopaminergic sys. -Dopamine precursor: levodopa -Peripheral decarboxylase inhibitors: carbidopa, benserazide -Dopaminergic agonists: Ergot derivatives: bromocriptine Non ergot derivatives: ropinirole, pramipexole, rotigotine, -MAO-B inhibitors: selegiline, rasagiline -COMT inhibitors: entacapone, tolcapone -Dopamine facilitator: amantadine 9 PHARMACOLOGIC TREATMENT OPTIONS: II. Drugs affecting brain cholinergic system 1. Central anticholinergics: trihexyphenidyl (benzhexol), procyclidine, benztropine, biperidine 2. Antihistaminics: diphenhydramine, promethazine. Q. Can these drugs cure? No! Pharmacologic treatments can only offer temporary relief; they neither reverse nor arrest the disease process Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body. 10 5
1. LEVODOPA High therapeutic index-drug of choice for symptom control especially in elderly. Mechanism of action Dopamine itself has low bioavailability and does not readily cross the BBB, its precursor, Levodopa, is readily transported into the CNS, and is converted to dopamine in the brain by the enzyme DOPA decarboxylase, which is present in many body tissues. Q. The effects of levodopa on the CNS can be greatly enhanced by carbidopa? carbidopa, a drug that does not cross the BBB but inhibits DOPA decarboxylase in peripheral tissues. 11 levodopa carbidopa Without carbidopa, much of the drug is decarboxylated to dopamine in the periphery, resulting in nausea, vomiting, cardiac arrhythmias, and hypotension. The addition of carbidopa lowers the dose of levodopa needed by four- to fivefold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine. Therapeutic uses: Is an efficacious drug regimen. It decreases rigidity, tremors, and other symptoms. Substantially reduces the severity of symptoms for the first few years of treatment in approximately 2/3rds of patients. Patients typically experience a decline in response during the 3rd to 5th year of therapy. 12 6
L-DOPA HONEYMOON In early disease (lasts 5-6 years typically), the number of residual dopaminergic neurons in the substantia nigra (typically about 20% of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients, the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects wear off. Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of converting exogenously administered levodopa to dopamine. Consequently, motor control fluctuation develops. 13 ABSORPTION AND METABOLISM The drug is absorbed rapidly from the small intestine. levodopa should be taken on an empty stomach, typically 30 minutes before a meal. Because, Ingestion of large, neutral amino acids leucine and isoleucine compete with levodopa for absorption from the gut and for transport across the BBB. It has an extremely short half-life (1-2 hrs.), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response on-off phenomenon. Withdrawal from the drug must be gradual. 14 7
TOXICITY Peripheral effects: (due to stimulation of dopamine receptor): GIT: anorexia, nausea, and emesis. Tolerance to EMETIC action of levodopa usually occurs after several months. CVS: Tachycardia and ventricular extrasystoles. postural hypotension is common, especially in the early stage of treatment. In some individuals, blood dyscrasias and a positive reaction to the Coombs test are seen. Saliva and urine are a brownish color because of the melanin pigment produced from catecholamine oxidation. CNS: Visual and auditory hallucinations and abnormal involuntary movements: (Dyskinesias choreoathetosis) of the face and distal extremities occurs frequently. chorea (the ceaseless occurrence of rapid, jerky involuntary movements). ballismus (Jerky or shaking movements of the arms or legs), myoclonus. tics (an involuntary, compulsive, rapid, repetitive, stereotyped movement or vocalization. Also called habit spasm.). tremor. Behavioural effects: Levodopa can also cause mood changes, depression, psychosis, and anxiety. 15 DRUG INTERACTIONS & CONTRAINDICATIONS Antipsychotic drugs, because these block dopamine receptors and produce a parkinsonian syndrome themselves. The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness. Non selective MAOI, such as phenelzine, which could lead to a life threatening hypertensive crises caused by enhanced catecholamine production. In patient with a history of psychosis, Levodopa exacerbates symptoms, possibly through the build up of central amines. In patients with glaucoma, the drug can cause an increase in intraocular pressure. Q. delay L-dopa use especially in younger patients?? Answer: Neurotoxicity of L-dopa-DOPA metabolism results in neurotoxic breakdown products results in the progression of Parkinson s. 16 8
2. MAO B INHIBITORS; Selegiline and rasagiline Selegiline, selectively inhibits MAO B (which metabolizes dopamine, but does not inhibit MAO A (which metabolizes norepinephrine and serotonin). Therefore, it enhances the actions of levodopa, selegiline substantially reduces the required dose of levodopa. Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than mid-afternoon. Rasagiline, an irreversible and selective inhibitor of brain MAO type B, has five times the potency of selegiline. Unlike selegiline, rasagiline is not metabolized to an amphetamine-like substance. Cheese reaction: at recommended doses has little potential for causing hypertensive crisis (Does not cause cheese reaction ). However, if selegiline is administered at high doses, the selectivity of the drug is lost, and the patient is at risk for severe hypertensive. 17 3. CATECHOL-O -METHYLTRANSFERASE (COMT) INHIBITORS Entacapone and tolcapone are nitrocatechol derivatives that selectively and reversibly inhibit COMT. Normally, the methylation of levodopa by COMT to 3-Omethyldopa is a minor pathway for levodopa metabolism. However when peripheral DDC activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport. Adverse effects: Diarrhoea, postural hypotension, nausea, anorexia, dyskinesia, hallucinations, and sleep disorders. Fulminating hepatic necrosis is associated with tolcapone. Entacapone does not exhibit this toxicity and has largely replaced tolcapone. 18 9
MECHANISM OF ACTIONS Inhibition of COMT by entacapone or tolcapone leads to decreased plasma concentration of 3-Omethyldopa, increased central uptake of levodopa, and increased concentrations of brain dopamine. Both reduce the symptoms of wearing-off phenomena seen in patients on levodopacarbidopa. Tolcapone penetrates the BBB and inhibits COMT in the CNS and it has a relatively longer duration of action compared to entacapone. 19 4. DOPAMINE RECEPTOR AGONISTS Ergot derivatives Bromocriptine (D2) Pergolide (D1 and D2): discontinued due to the potential for heart valve damage. Non ergot derivatives Pramipexol (oral) Ropinirole (oral) Rotigotine (transdermal delivery systems) Apomorphine (injectable) These agents have durations of action longer than that of levodopa, thus have been effective in patients exhibiting fluctuations in their response to levodopa. These agents alleviate the motor deficits in patients who have never taken levodopa and also in patients with advanced Parkinson s disease who are treated with levodopa. Dopamine agonists may delay the need to use levodopa in early Parkinson s disease and may decrease the dose of levodopa in advanced Parkinson s disease. Not neurotoxic? neuroprotective 20 10
Ergot derivatives BROMOCRIPTINE Bromocriptine, in addition to being used to treat Parkinson s disease, it is the drug of choice to treat cases of hyperprolactinemia. Side effects severely limit the utility of dopamine agonists. The actions of the ergot derivative bromocriptine are similar to those of levodopa, except that hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more common, whereas dyskinesia is less prominent. In psychiatric illness, bromocriptine may cause the mental condition to worsen. It should be used with caution in patients with a history of myocardial infarction or peripheral vascular disease. In patients with peptic ulcer, there is a worsening of the ulcer. Because bromocriptine is an ergot derivative, it has the potential to cause pulmonary and retroperitoneal fibrosis. 21 Non ergot derivatives PRAMIPEXOLE, ROPINIROLE, APOMORPHINE & ROTIGOTINE Apomorphine is used for acute management of the hypomobility off phenomenon in advanced Parkinson s disease. Rotigotine is administered as a once-daily transdermal patch that provides even drug levels over 24 hours. Unlike the ergotamine derivatives, these agents do not exacerbate peripheral vascular disorders or cause fibrosis. ADVERSE EFFECTS Nausea, hallucinations, insomnia, dizziness, constipation, and orthostatic hypotension. Dyskinesia less frequent than with levodopa. DRUG INTERACTION Cimetidine, which inhibits renal tubular secretion of organic bases, increases the half-life of pramipexole by 40%. Fluoroquinolone antibiotics inhibit the metabolism of ropinirole, and enhance the AUC by 80%. 22 11
AMANTADINE Increase the release of dopamine Blockading cholinergic receptors Act on NMDA receptors NB: if dopamine release is already at a maximum, amantadine has no effect. Compared to L-dopa, Amantadine is less efficacious, tolerance develops more rapidly and has fewer side effects. Compared to anticholinergic, Amantadine has little effect on tremor, but is more effective against rigidity and bradykinesia. Side effects Restlessness, agitation, confusion, and hallucinations. at HIGH DOSES, it may induce acute toxic psychosis, orthostatic hypotension, urinary retention, peripheral edema, and dry mouth. 23 ANTIMUSCARINIC AGENTS: benztropine, Trihexphenidyl, and biperiden They are much less efficacious than levodopa and play only an adjuvant role in Parkinsonism therapy. SE: Mood changes, xerostomia and visual problems 24 12
DRUGS FOR ALZHEIMER S Alzheimer s disease; progressive loss of memory and disordered cognitive function. Pathophysiology: Cholinergic transmission decreased in Alzheimer s, Treatment Stratigies: current therapies are aimed at either improving cholinergic transmission within the CNS or preventing the excitotoxicity actions of NMDA glutamate receptors in selected brain areas. I. Acetylcholinesterase inhibitors: e.g., donepezil, rivastigmine, galantamine, tacrine Adverse effects: nausea, diarrhea, abdominal cramps, bradycardia, urine incontinence II. NMDA receptor antagonists: Memantine (dimethyl adamantine derivative related to amantadine) it is an uncompetitive inhibitor of NMDA receptors. 25 HUNTINGTON DISEASE An inherited adult onset neurologic disease due to a single defect on chromosome 4. Pathophysiology: excessive dopaminergic activity and diminished GABA functions in the basal ganglia (caudate and putamen). Characterized by: shuffling gait, stooped posture, resting tremor, speech impediments, movement difficulties, and an eventual slowing of mental processes and dementia Treatment: Dopamine blockers such as haloperidol or tetrabenazine are used to treat this disorder. 26 13
TOURETTE S SYNDROME A neurologic disease of unknown cause Presents with multiple tics associated with snorting, sniffing, and involuntary vocalizations (often absence) Treatment: clonidine, haloperidol 27 Wilson s disease It is a genetic disorder of copper metabolism. Symptoms include: jaundice, vomiting, tremors, muscle weakness, stiff movements, liver failure and dementia. Treatment: a copper chelating agent known as penicillamine Excess copper is deposited in the liver, brain, kidneys, and eyes; 28 14
AMYOTROPHIC LATERAL SCLEROSIS (ALS) Progressive degeneration of motor neurons, resulting in the inability to initiate or control muscle movement. Symptoms: Muscle fasciculation, hypotonia, muscle wasting and paradoxical reflexes. The neurons of sufferers of ALS accumulate glutamate, which may be the cause of the paralysis. Riluzole: an NMDA receptor antagonist, is currently the only drug indicated for the management of ALS. It is believed to act by inhibiting glutamate release and blocking sodium channels. Riluzole may improve survival time and delay the need for ventilator support in patients suffering from ALS. Riluzole is not effective against ALS when the onset of the disease aspects the limbs. 29 AMYOTROPHIC LATERAL SCLEROSIS (ALS) Clinical Considerations Transaminases monitoring at baseline and every month for three months, then every three months, Very rarely, pancreatitis. Riluzole should be taken at least one hour before or two hours after meals. Supportive Therapy: tricyclic antidepressants for depression oxygen therapy for hypoxia from poor respiratory muscle function antimuscarinics to reduce dribbling and salivation baclofen and/or diazepam for spasticity. 30 15
MULTIPLE SCLEROSIS Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the brain and/or spinal cord Onset of MS is at around 20 40 years of age, Affect more women than men. there are four common syndromes of symptoms that reflect the parts of the CNS affected: spinal, brainstem, cerebral and cerebellar syndromes. the most common is the spinal syndrome, which is characterized by muscle weakness, stiffness and slowness, preferentially affecting the limbs. Paraesthesias, pain, muscle spasms and spasticity are also observed. 31 IMMUNOSUPPRESSIVE AGENTS USED IN MS A. Disease-modifying therapies: can reduce the number of relapses and delay the development of new lesions. glatiramer interferon β1a and interferon β1b natalizumab, fingolimod, Teriflunomide and Dimethyl fumarate Mitoxantrone CORTICOSTEROIDS: prednisone or methylprednisolone, can also be effective in acute phases of the disease. Chemotherapeutic agents: such as cyclophosphamide and azathioprine, have also been used. B. Symptomatic Treatments: Many different classes of drugs are used to manage symptoms of MS such as spasticity, constipation, bladder dysfunction, and depression. DALFAMPRIDINE is a potassium channel blocker that readily enters the CNS to interact with demyelinated neurons associated with MS. improves walking speeds in patients with MS. It is the first drug approved for this use. 32 16
https://www.youtube.com/watch?v=3wg9exkwzy4&list=flzdunofczy4eno5r ez_zhjw&index=1[ https://www.youtube.com/watch?v=4qdd4ny34cc 33 Thank You 34 17