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Drugs affecting the Central Nervous SystemDrugs used in the management of Neurodegenerative diseases

Neurodegenerative diseases: neuronal damage in certain brain areas.Causes of neuronal damage:

1. Excessive excitotoxicity(excess glutamate acts on N methyl aspartate receptorsNMDA).

2. Stroke, head trauma.

3. Oxidative stressreactive oxygen species (ROS) free radical as OH..4. Apoptosis(programmed cell death).

Q. why is it difficult to treat neurodegenerative diseases?As CNS neurons CANNOTdivide or regenerateonce they are damaged they cannot be

regenerated so treatment is symptomaticnot alter progression of disease.Examples of neurodegenerative diseases: Parkinsons disease, Alzheimer, Huntington,Multiple sclerosis.

PARKINSON'S DISEASE "Paralysis Agitans" Management

Overview of Parkinsons disease

Definition: It is a progressive neurological disorder of muscle movement, characterized by

the triad: Tremors, Muscular rigidity, Bradykinesia (slowness in initiating & carrying out

voluntary movement). Abnormal posture and gait. It occurs mainly in elderly people over the

age of 65. It was first described by James Parkinson.

Etiology: in the inhibitory dopaminergic (DA) neurons relative to excitatory

cholinergic (Ach) neurons in the basal ganglia (Dopamine is formed in the Substantia

nigra, dopaminergic neurons are connected to the striatum which contains cholinergic

neurons).

Classification:

Primary (Idiopathic) Parkinsons disease (PD):

due to degeneration of > 80% of dopaminergic neurons secreting dopamine in the

substantia nigra

imbalance between the excitatory cholinergic neurons (Ach) & theinhibitory dopaminergic neurons (DA) i.eDA & Ach.

N.B. Oxidative stress formation of free radicals in the substantia nigra degeneration

of dopaminergic neurons.

Secondary Parkinsonism Parkinsons Syndrome:

The imbalance between Ach & DA (DA & Ach) is due to:

Disease-induced viral encephalitis, atherosclerosis

Drug-induced Dopamine blockers (e.g: antipsychotics).

Poisons manganese, carbon monoxide poisoning

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L-dopa Dopa decarboxylase DopamineCNS=Basal ganglia

Peripherally

Required

NOT required

L-dopaDopa decarboxylase

Peripherally

dopamine

L-dopa Dopa decarboxylase dopamine

CarbidopaOr

Benserazide

Inhibited by

DA

Treatment

Treatment goal: restoring the balance between Ach. & DA.DA & Ach.

Treatment leads to temporary relief of symptoms and slow but not prevent progression of

disease (symptomatic treatment).

Anti-Parkinsonian drugs

DA Ach.

1. Dopaminergic drugs e.g. l-dopa.

2. Dopamine receptor agonists.

3. Dopamine releasers.

4. Selective MAOBinhibitors.

- Anticholinergic drugs.

I. Dopaminergic drugs1. Levodopa (l-dopa):MOA:Dopamine itself does not cross the BBB, but its precursor levodopa is readily

transported into the CNS and is converted to dopamine in the brain by the enzyme

dopa decarboxylasethus restoring DA& Ach balance.Number of surviving DA neurons should be adequate for conversion of l-dopa to

DA(80% of the Dopaminergic neurons are degenerated so the remained 20% shouldbe intact to convert l-dopa to DA so that drug gives effect).

Q: Large doses of levodopa (l-dopa) are requiredwhy?Because most of the drug (>90%) is decarboxylated to dopamine in the periphery resulting inperipheral adverse effects.

Peripheral dopa decarboxylase inhibitors: Carbidopa or Benserazide: Selective peripheral (extra-cerebral) dopa decarboxylaseinhibitor that does not

cross the blood-brain barrier.l-dopa + carbidopa or Benserazide

Availability of l-dopa to the CNS.Dose of l-dopa to 1/5.S.Es of the peripheral formed DA.

Levodopa/Carbidopa combination produces good control on disease symptoms butthis effect starts to decline from the 3rdto 5thyear.

Centrally

COMTinhibitors: Entacapone & Tolcapone: l-dopa undergoes O-methylation by COMT to inactive metabolite (3-O-methyldopa);

minor pathway for levodopa metabolism. However, when peripheral dopaminedecarboxylase is inhibited by carbidopa, a significant concentration of 3-O-methyldopais formed that competes with l-dopa for active transport into the CNS.

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A peripheral COMT inhibitor is given together with l-dopa to protect it fromdestruction by COMT.

l-dopa + Entacapone or Tolcaponedegradation of l-dopaside effectsdoses required.availability of l-dopa to the CNS.

Pharmacokinetics:

1. Short t(1-2 hrs)fluctuations in plasma concentration.

Fluctuations in plasma concentration "on-off phenomenon" due to short half life of

l-dopa Motor fluctuations.

a. ON no symptoms of parkinsons i.e parkinsons free period.

b. OFFparkinsons symptoms appearHow to overcome the on-off phenomenon?1- Giving more frequent dose of levodopa or a sustained-release preparation2- Combined treatment with a direct dopamine receptor agonist.

Wear-off phenomenon End of dosemeans patients do not respond totreatment, because all dopaminergic neurons are degeneratedi.e. complete degeneration of dopaminergic neurons 100%.

Food (high protein diet)Absorption of l-dopa from small intestinesotake 30 minutes before a meal. l-dopa is transported & absorbed from GIT as

aminoacids, so if protein is taken compete with l-dopa absorption of l-dopa.

Adverse effects of l-dopa: DA centrally & peripherally1. Central side effects

a. Dyskinesia: Excessive abnormal involuntary movements develop usually within 2 yearsof starting l-dopa therapy.

b. DA in the mesolimbicDelusions, Hallucinations & psychosis, vivid dreams,confusion, mood changes, anxiety & depression (CI in psychosis).

2. Peripheral side effects

1. dopamine in CTZin medulla nausea, vomiting & anorexia.

2. 1tachycardia and arrthymia.3. Postural hypotensiondue to

a. -ve feedback of NA releaseNA releaseb. Dopamine is a venodilator.c. V.D. of renal blood vessels (D1 receptor)RBFReninAldosterone.

4. Catecholamine oxidation melanin pigment Brown saliva and urine.

5. Mydriasis stimulate -receptor on radial muscle in high doses only (CI in acuteangle closure glaucoma).

Treatment= l-dopa + Carbidopa + Entacapone

Carbidopa: peripheral dopa decarboxylase inhibitor.

Entacapone: peripheral COMT inhibitor

Availability of l-dopa in CNSGreater more l-dopa crosses the BBBMore constant (sustained) Dopaminergic

stimulation in the brainsymptoms of the disease.

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Drug interactions:1. Vit B6(pyridoxine)peripheral decarboxylation of l-dopa to dopamineefficacy

of l-dopa.

2. Levodopa + Phenelzine (MAO inhibitor)catecholamine accumulation BP(hypertensive crisis).

3. Anti-psychotics (D2-blockers)cause parkinsonian syndrome so CI in PD patients.4. Cardiac patients should be monitored because of risk of cardiac arrhythmias.

Drug holiday: transient withdrawal of levodopa may improve the complications of its chronicuse.

II. Dopamine receptor agonists

Dopamine receptor agonists are used as initial therapy in patients who have mild PD and ayounger age of onset or as adjuncts to levodopadopa decarboxylase inhibitor combinationsin patients with severe motor fluctuations (onoff phenomena). They decrease the dose of l-dopa in advanced PD.

Adverse effects: Similar to l-dopa1-dopamine in CTZ in medulla nausea, vomiting.2- Confusion, psychomotor excitation, hallucination (N.B. Neuropsychiatric disorders aremore frequent than with levodopa monotherapy).3- Orthostatic hypotension

1. Bromocriptine (Ergotamine derivative)Drugdisease interactions:

1. Worsening of patient with peripheral vascular disease (due to vasoconstriction as itis ergotamine derivative)2. Serious cardiac problems in patients with history of myocardial infarction.3. In psychiatric illness, bromocriptine and l-dopa may cause mental condition toworsen.

2. Non ergot drugs: Apomorphine, Pramipexole, Ropinirole.RotigotineApomorphine as s.c injectionis used for acute management of off periods, but it causes

severe nausea must be preceded by antiemetic.

III. Drugs inducing dopamine release

Amantadine:"Antiviral against influenza virus"

- release and reuptake of dopaminein surviving neurons.- Anticholinergic action (block M)Ach.

Its less effective than l-dopa, its actionswith time and tolerance develops rapidly to itsuse. Used in early disease, especially in younger patients.S.Es: those of l-dopa + urinary retention & dry mouth.

About 95% is eliminated by the kidneys and it should not be used in patients with renal failure

IV. Monoamine oxidase B inhibitors (MAOB inhibitors)

1. Selegiline (Deprenyl)

- Irreversible selective inhibitor of MAOB DAin brain (No effect on MAOAwhichmetabolizes NE and 5-HT)

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- Uses: combined (adjunct) with l-dopa l-dopa action, l-dopa requireddose, reduce the end-of-dose deterioration in advanced disease.S.Es: Deprenyl is metabolized into amphetamine & methamphetamineinsomnia, & anxiety if the drug is administered later than midafternoon.Contraindications:- Unlike non selective MAO inhibitorsNO hypertensioncrisis when combined

tyramine-containing food. BUTat high doses (six times the therapeutic dose),

selectivity is lost, inhibit both MAOA& MAOBhypertensive crisis.

2. Rasagiline: Irreversible selective inhibitor of MAOB, 5 times more potent thanselegiline. It is not metabolized to an amphetamine like substance.

V. Anticholinergics

e.g. Benztropine, Trihexyphenidyl, Procyclidine, Orphenadrine, & Biperiden- Restore the balance between dopamine and ACh in the Neostriatum.- Pharmacological actions: Tremors, Rigidity only so used as adjuvant therapy

(effectl-dopa). Drug of choice for PD caused by D2blockers Why??

- Side effects: Atropine like side effects: mydriasis, blurred vision, urinary retention,

xerostomia, decreased GIT motility (constipation) & decreased memory andconcentration, confusion with visual hallucination.

- Contraindications: glaucoma, prostatic hypertrophy.

Adverse effects of:levodopa dopamine agonists

DA level or effect in the Striatum Ach level or effect in the StriatumAdv: treat allsigns & symptoms includingbradykinesia

Adv: Tremors & Rigidity only (adjuvantonly)

S.Es: Nausea, Vomiting, AnorexiaTachycardia=arrhythmia.Postural hypotension.Psychosis (centrally).

S.Es: Atropine S.Es

e.g. l-dopa, Bromocriptine, Amantadine,Deprenyl.

e.g. Benztropine, Trihexyphenidyl &Biperiden

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Alzheimers DiseaseAlzheimer's disease is a common age-related dementia.Symptoms: Dementia, loss of intellectual ability & learning deficit.Etiology:

1. Plaques (-amyloid), neurofibrillary tangles mainly in hippocampus.

2. Loss of cholinergic neurons (Ach) in the cortex.Treatment:

No effective therapy is available.

1. Acetylcholinesterase inhibitors: Donepezil, Galantamine, and RivastigmineThey have some selectivity for AChE in the CNS, as compared to the periphery. Used in mildto moderate cases.Rivastigmineis the only agent approved for the management of dementia associatedwith Parkinsons disease and also the only AChE inhibitor available as a transdermalformulation. Ithas no interactions with drugs that alter the activity of CYP450 enzymes. Theother agents are substrates for CYP450 and have a potential for such interactions.Adverse effects: nausea, vomiting, diarrhea, anorexia, tremors, bradycardia, and musclecramps. Treatment of overdose: Atropine

2. NMDA receptor antagonist (used in moderate to severe cases)Stimulation of glutamate receptors in the CNS is critical for memory. However,overstimulation of glutamate receptors, particularly of the NMDA type, assists in the openingof an ion channel that allows Ca2+ to enter the neuron. Excess intracellular Ca2+ results inexcitotoxic effects on neurons, which in turn results in neurodegenerative or apoptotic(programmed cell death) processes.

Memantineis an NMDA receptor antagonist indicated for moderate to severe Alzheimersdisease. It blocks the NMDA receptor and limits Ca2+influx into the neuron. It is often given incombination with an AChE inhibitor.

Adverse effects of ACHE inhibitors