Parkinson's Disease Lecture 3 PDF

1 Drugs Affecting the Central Nervous System Neurodegenerative diseases ❑ Neurodegenerative diseases: neuronal damage in certain brain areas. ❑ Causes of neuronal damage: 1. Excessive excitotoxicity (excess glutamate → acts on N methyl aspartate receptors NMDA). 2. S...

1 Drugs Affecting the Central Nervous System Neurodegenerative diseases ❑ Neurodegenerative diseases: neuronal damage in certain brain areas. ❑ Causes of neuronal damage: 1. Excessive excitotoxicity (excess glutamate → acts on N methyl aspartate receptors NMDA). 2. Stroke, head trauma. 3. Oxidative stress →  reactive oxygen species (ROS) →  free radical as OH.. 4. Apoptosis (programmed cell death). ❑ Q. Why is it difficult to treat neurodegenerative diseases? As CNS neurons CANNOT divide or regenerate once they are damaged, they cannot be regenerated → so treatment is symptomatic not alter progression of disease. ❑ Examples of neurodegenerative diseases: Parkinson’s disease, Alzheimer, Huntington, Multiple sclerosis. Dopaminergic neurons pathways: ❑ In the CNS, dopamine (DA) is a precursor to NE in noradrenergic pathways and is a neurotransmitter in the following major dopaminergic pathways: 1. Nigrostriatal : The substantia nigra project to the striatum, they release DA, which inhibits GABAergic and cholinergic neurons → regulates kinesis (movement). 2. Mesolimbic-mesocortical : midbrain project to cerebrocortical and limbic structures and release dopamine. Regulates cognitive functions, sensory perception, psychomotor functions. 3. Tuberoinfundibular: Hypothalamus project to anterior pituitary and release dopamine →  prolactin. 4. Chemoreceptor trigger zone (CTZ): in medulla activation of DA receptors →  emesis Dopaminergic neurons pathway The second common neurodegenerative disease after Alzheimer’s disease  7 Parkinson’s Disease (PD) ❑ Definition: Parkinson’s disease is a progressive neurological disorder of muscle movement as a clinical syndrome consisting of 4 cardinal motor features: 1. Bradykinesia (slowness of movement) and, in late stage, a loss of physical movement (akinesia) patient is wheelchair bound or bedridden. 2. Muscular rigidity. 3. Resting tremor. 4. Abnormal gait and posture (shuffling gait) Non motor symptoms: depression, dementia, sleep disturbances. ❑ Occurs mainly in elderly people over the age of 65. ❑ Etiology:  in the inhibitory dopaminergic (DA) neurons relative to excitatory cholinergic (Ach) neurons in the nigrostriatal.  8 Parkinson’s Disease (PD)  10 Classification of PD ❑ Primary (Idiopathic) Parkinson’s disease (PD): degeneration of > 80% of DA neurons →  DA &  Ach. Oxidative stress!!!! Aging ❑ Secondary Parkinsonism “Atypical Parkinsonism”: due to: Vascular Parkinsonism – multiple small strokes affecting parts of the brain related to movement control (small vessel cerebral ischemia). Post-Traumatic Parkinsonism – repeated head trauma, as seen in some athletes. Toxin-Induced Parkinsonism – exposure to certain toxins (e.g., carbon monoxide, manganese, or pesticides). Infectious Parkinsonism – infections like encephalitis that damage the brain's motor regions. Drug-induced → Dopamine blockers (e.g: antipsychotics).  Treatment goal  DA  Ach Anti-Parkinsonian drugs  DA  Ach Dopaminergic drugs Anticholinergic drugs. DA Receptor agonists DA releasers Selective MAOB inhibitors Adv: treat all signs & Adv:  Tremors & symptoms including Rigidity only (adjuvant only) bradykinesia Treatment leads to temporary relief of symptoms and slow but not prevent progression of disease (symptomatic treatment).  12 I. Dopaminergic drugs: Levodopa (L-dopa) ❑ Dopamine itself does not cross the BBB (not lipid soluble) ❑ its precursor levodopa is transported into the CNS and is converted to dopamine in the brain by the enzyme dopa decarboxylase→ restoring DA & Ach balance. ❑ Number of surviving DA neurons in substantia nigra should be adequate for conversion of L-dopa to DA (80% of the Dopaminergic neurons are degenerated so the remained 20% should be intact to convert l- dopa to DA so that drug gives effect). ❑ Q: Large doses of levodopa (L-dopa) are required why? Because most of the drug (>90%) is decarboxylated to dopamine in the periphery (gut, blood, liver) resulting in peripheral adverse effects. I. Dopaminergic drugs: Levodopa (L-dopa) I. Dopaminergic drugs: Levodopa (L-dopa) Carbidopa or  Availability of L-dopa to the CNS. Benserazide  Dose of L-dopa to 1/5. peripheral dopa   S.Es of the peripheral formed DA decarboxylase inhibitor  Availability of L-dopa to the CNS. Entacapone & Tolcapone  doses required COMT inhibitors  degradation of L-dopa  side effects Overcomes short half life l-dopa + Carbidopa + Entacapone N.B. Tolcapone causes hepatotoxicity. I. Dopaminergic drugs: Levodopa (L-dopa) ❑ Adverse effects: ( DA centrally & peripherally) A- Central side effects:  DA in the striatum  Dyskinesia (Excessive abnormal involuntary purposeless movements develop usually within 4-10 years of starting L-dopa therapy ) WHY? Long-term use of levodopa leads to the overstimulation of dopamine receptors (specifically D1 and D2 receptors) in certain parts of the brain, such as the basal ganglia, which controls movement. This overstimulation is linked to the abnormal movements seen in dyskinesia. The supersensitivity of these receptors to levodopa occurs because the brain compensates for the progressive loss of dopamine-producing neurons by becoming more sensitive to the dopamine provided by levodopa. I. Dopaminergic drugs: Levodopa (L-dopa) ❑ Adverse effects: ( DA centrally & peripherally) A- Central side effects:  DA in the mesolimbic and mesocortical pathways Delusions, Hallucinations & psychosis, mood changes, anxiety & depression (CI in psychosis). Low doses of atypical antipsychotics (with weak dopamine antagonism), such as quetiapine are used to treat levodopa induced psychosis. I. Dopaminergic drugs: Levodopa (L-dopa) ❑ Adverse effects: ( DA centrally & peripherally)  CTZ in medulla → nausea, vomiting & anorexia. Most common side effect. How to overcome? D2 blocker that acts only peripherally (Domperidone). Why not metoclopramide? As it crosses BBB. B- Peripheral side effects: β1→ tachycardia and arrythmia. Postural hypotension due to a. Dopamine is a vasodilator. b. V.D. of renal blood vessels (D 1 receptor) increase renal blood flow increase sodium excretion (natriuresis) which can reduce blood volume and lead to lower blood pressure Catecholamine oxidation → melanin pigment homovanellic acid → Brown saliva, sweat (stains clothes), and urine. Mydriasis → stimulate α1-receptor on radial muscle in high doses (CI in acute angle closure glaucoma). ❑ Wear-off phenomenon “End of dose deterioration ” → improvement gained from a dose of levodopa medication gradually fades off and does not last until the time that the next dose of levodopa is due or begins to work, Therefore, patient may want to take the next dose sooner because most dopaminergic neurons are degenerated and fewer cells are capable of converting exogenously administered levodopa to dopamine. ❑ Food (high protein diet; amino acids) →  Absorption of L-dopa from small intestine→ so take 30 minutes before a meal L-dopa is transported from the upper small intestine by active amino acid transport and crosses the blood brain barrier by amino acid transporter that normally transports amino acids into the brain, so if protein is taken  compete with L-dopa → absorption of L-dopa. I. Dopaminergic drugs: Levodopa (L-dopa) Short t½ (1-2 hrs) → fluctuations in plasma concentration. ❑ Fluctuations in plasma & hence brain concentration that rise and fall several times over a day → "on-off phenomenon" due to short half life of L-dopa → Motor fluctuations. a. ON → no symptoms of Parkinson's i.e Parkinson's free period (mobility) b. OFF→ Parkinson's symptoms appear (immobility or freezing) How to overcome the on-off phenomenon? 1- Giving more frequent dose of levodopa or a sustained release preparation 2- Combined treatment with a direct dopamine receptor agonist 3- COMT inhibitor I. Dopaminergic drugs: Levodopa (L-dopa) ❑ Drug Interactions: Vit B6 (pyridoxine)  peripheral decarboxylation of L-dopa to dopamine  efficacy of L-dopa. Levodopa + nonselective MAO inhibitors (eg Phenelzine, antidepressants) → dopamine formed from levodopa is not destructed and is converted to noradrenaline →  catecholamine accumulation →  BP (hypertensive crisis). Anti-psychotics (D2-blockers) → cause Parkinsonian syndrome (better avoided in PD patients) Cardiac patients should be monitored because of risk of cardiac arrhythmias. Slido.com Lecture3 II. Dopamine receptor agonists ❑ Stimulate D2 receptors in the striatum, act like dopamine ❑ These drugs are ineffective in patients who have not responded to levodopa ❑ Advantage over levodopa: they don’t result in significant motor fluctuations or dyskinesias Why? As they have longer duration of action (t1/2) and they are nor dependent on presynaptic conversion to dopamine by COMT. ❑ Initial therapy in patients who have mild PD and a younger age of onset ❑ Adjuncts to levodopa–dopa decarboxylase inhibitor combinations in patients with severe motor fluctuations (on–off phenomena). ❑ Decrease the dose of L-dopa in advanced PD. Adverse effects: (Similar to L-dopa) 1-  dopamine in CTZ in medulla → nausea, vomiting. 2- Confusion, psychomotor excitation, hallucination (N.B. Neuropsychiatric disorders are more frequent than with levodopa monotherapy). 3- Orthostatic hypotension II. Dopamine receptor agonists 1. Bromocriptine (Ergotamine derivative) Drug–disease interactions: Worsening of patient with peripheral vascular disease (due to V.C, as it is ergotamine derivative which stimulates alpha receptors and serotonin receptors). Serious cardiac problems in patients with history of myocardial infarction due to vasospasm risk. In psychiatric illness, bromocriptine and L-dopa may cause mental condition to worsen. N.B. Prolonged use cause pulmonary fibrosis II. Dopamine receptor agonists 2. Non ergot drugs: Apomorphine, Pramipexole, Ropinirole, Rotigotine Apomorphine is used as s.c injection in OFF period of L-dopa (patients may be stuck or frozen in one position) N.B. causes severe nausea → must be preceded by antiemetic. Pramipexole, Ropinirole taken orally Rotigotine once daily transdermal patch III. Monoamine oxidase B inhibitors MAOB inhibitors 1. Deprenyl (Selegiline) Irreversible selective inhibitor of MAOB → DA in brain Free radical scavenger  ROS ( degeneration) Uses: single drug in early or mild PD, with L-dopa → L-dopa action &  L-dopa required dose, improve motor function in patients who experience wearing off and on-off difficulties with levodopa. S.Es: metabolized into amphetamine & methamphetamine  insomnia, & anxiety if the drug is administered later than midafternoon. Contraindications: Unlike non-selective MAO inhibitors  NO hypertension crisis when combined tyramine-containing food as MAOA in the liver and sympathetic nerve endings can metabolize tyramine. BUT at high doses, inhibit both MAOA & MAOB  hypertensive crisis. III. Monoamine oxidase B inhibitors MAOB inhibitors 2. Rasagiline: ❑ Irreversible selective inhibitor of MAOB ❑ 5 times more potent than selegiline. ❑ Can be used as monotherapy in early stages or combined with L-dopa. ❑ It is not metabolized to an amphetamine like substance. IV. Drugs inducing dopamine release (Amantadine) "Antiviral against influenza A virus" ❑ Mechanism of action: release and  reuptake of dopamine in surviving neurons. Anticholinergic action (block M)  Ach. ❑ It’s less effective than L-dopa, its actions  with time and tolerance develops rapidly to its use. ❑ Used in early disease, especially in younger patients and as an adjunct to L-dopa to reduce dyskinesias.. ❑ S.Es: those of L-dopa +urinary retention & dry mouth (atropine like) + skin discoloration (Levido reticularis; mottled skin due to dilatation of blood vessels; harmless). ❑ About 95% is eliminated by the kidneys and it should not be used in patients with renal failure V. Anticholinergics Benztropine, Trihexyphenidyl, procyclidine, & Biperiden ❑ Pharmacological actions:  Tremors, Rigidity only (but not bradykinesia) so used as adjuvant therapy (effect l-dopa). ❑ Drugs of choice for PD caused by D2 blockers Why?? ❑ Improve sialorrhea ❑ Side effects: Atropine like side effects: mydriasis, blurred vision, urinary retention, xerostomia (dry mouth), decreased GIT motility (constipation) & decreased memory and concentration, confusion with visual hallucination. ❑ Contraindications: glaucoma, prostatic hypertrophy. Slido.com Lecture3 https://www.biogencdn.com/us/identifyalz/2020/alz-mod.mp4