ANTIPARKINSONIAN

AGENTS

MA. LENY ALDA G. JUSAYAN, MDDEPARTMENT OF PHARMACOLOGY

NEURODEGENERATIVE DISORDERS

HOW DOES THE BODY MOVES?

THE BRAIN CONTROLS MOVEMENT

CASE 1

F.B., 70 year old male, living in a nursing home was noticed to have episodes of crying spells and labile mood. He also had difficulty in initiating sleep and had night time awakenings. Caregivers noticed also progressive slowing down of movement associated with fine tremors of the hands at rest. Few days PTC there were noticeable rigidity & impairment of body movements.

PARKINSONISM

• Paralysis Agitans• “SHAKING

PALSY”• Tremors are present

even at rest• Rigidity &

impairment of voluntary movements

• Postural tremor, intention tremors

The UK Parkinson's Disease Society Brain Bank Criteria For Clinical Diagnosis:

• Bradykinesia plus one of rigidity, tremor, or postural instability

• At least three of rest tremor, progressive symptoms, unilateral onset, early response to levodopa, revodopa-induced dyskinesia

• No identifiable cause for the parkinsonism.

Motor Symptoms: Tremor:

70% of patients suffer resting tremor pill rolling quality

can affect all of the limbs as well as the face, neck, head and jaw.

Rigidity: increased tone or stiffness in the muscles mask-like face and clog-like release of

muscles. Bradykinesia

difficulty initiating and continuing movement.

Postural InstabilityForward flexion of neck, hips, knees and elbows leads to poor balance.

Gait disorders Shuffling, small steps described as festination, reduced arm swing and sudden freezing spells lead to problems walking

Swallowing (dysphagia) and Speech disorders (dysarthria) Handwriting: Micrographia

Nonmotor Symptoms:

• Depression: – 20-90% major depressive episode, reactive

or endogenous

• Dementia: – 20% of patients will become demented

(have impairments of 3 of the following in the presence of clear consciousness: language, memory, visuospatial skills, emotionality, personality and cognition

Sleep disturbances: Problems with sleep fragmentation, sleep initiation, early morning awakening, excessive daytime somnolence and parasomnias.

Sexual dysfunctionAbility to drive a car Ability to gain employmentConstipation

What causes Parkinson’s Disease?• A viral cause:• In 1918 there was an outbreak of

Encephalitis Lethargica and many sufferers developed postencephalitic Parkinsonism.

• A toxic substance: • For instance, the illegal drug MPTP (1-

methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

• A genetic cause: • Research by the NHGRI (National Human

Genome Research Institute) suggests that a mutated gene, which codes the alpha synuclein protein located on chromosome 4, has a role in familial parkinsonism.

• Other causes: • Head injuries.• Oxidative stress.• Heavy metal ion exposure from

fillings etc.• It is proposed that these factors

cause the neurone's mechanisms for proteolysis to go awry leading to the formation of the characteristic Lewy bodies seen on autopsy of Parkinson’s patients. The cells then fail to function correctly and ultimately die.

PATHOGENESIS:

• Idiopathic

• Genetic (<50 y/o)

• Exposure to unrecognized neurotoxins

• Oxidation reaction with generation of free radicals

• Reduced level of dopamine in the basal ganglia

MOTOR SYMPTOMS:

POSITIVE SYMPTOMS

• Tremor

• Chorea,

• Athetosis

• Ballismus

NEGATIVE SYMPTOMS

• Bradykinesia• Akinesia• Loss of postural

reflexes.

CHOREA

• Irregular, unpredictable involuntary jerks

• Impaired voluntary activity

• ballismus

TICS

• Sudden coordinated abnormal movements

• Repetitive sniffing

• shoulder shrugging

• face & head movement

ATHETOSIS

• Slow & writhing movements

• Abnormal postures (dystonia)

•Extrapyramidal System: •basal ganglia and their cortical connection •basal ganglia are made up of the:

Caudate Nucleus Putamen (Striatum) Globus Pallidus interna (Gpi) Globus Pallidus externa (Gpe) Subthalamic Nucleus Substantia Nigra Main Outputs: Substantia Nigra Globus pallidus interna Both of which feed to the ventrolateral thalamus

The main Pathological feature of Parkinson’s disease is the loss of the dopaminergic nigrostriatal pathway

Dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the striatum are lost

80% of the Dopamine producing cells must be lost before symptoms begin to show

WHAT CAN BE DONE TO HELP PARKINSON’S SUFFERERS?

GOALS OF TREATMENT:• Pharmacologic

attempt to restore dopaminergic activity with levodopa and dopamine agonists

• Restore normal balance of cholinergic & dopaminergic influences on the basal ganglia

CASE 2

F.B., was brought to the clinic for evaluation , diagnosed to have Parkinson’s disease.

• What is the goal in the management of this case?

• What is the first line drug that can relieve the signs and symptoms of parkinsonism

REMEDIES FOR STEP 1: DOPAMINE REPLACEMENT

LEVODOPA

• (-) -3-(3-4 dihydroxyphenyl) L- alanine• Immediate metabolic precursor of dopamine• Levorotatory stereoisomer of dopamine• D1 receptors stimulate adenylcyclase, located

in the zona compacta of the substantia nigra• D2 receptors inhibit adenylcylase, located

postsynaptically on striatal neurons &presynaptically in the substantia nigra

PHARMACOKINETICS:

• Rapidly absorbed from the SI

• Food delays absorption

• Amino acids in food compete with drug

• Peak plasma concentration: 1-2 hrs

• Plasma t ½ : 1-3 hrs

• HVA, DOPAC (dihydroxyphenylacetic acid) are main metabolites

• 1-3% enters the brain

CLINICAL USE:

• Responsiveness may be lost secondary to disappearance of dopaminergic nigostriatal nerve terminals

• Early use lowers mortality rate• Combined with Carbidopa & Benseraside• Sinemet – dopa preparation containing

levodopa in fixed proportion (1:10 or 1:4)• Sinemet 25/100 TID• 30 -60 minutes before meals

ADVERSE EFFECTS:

• Fluctuations in response

• Misc: mydriasis, blood dyscrasias, hot flushes, gout, brownish discoloration of the urine, abnormal smell, priapism, transient elevations of transaminases & BUN

ADVERSE EFFECTS:• GIT effects: vomiting (CTZ)

–Reduced by carbidopa

–Phenothiazenes are contraindicated

• Cardiovascular: tachycardia, ventricular extrasystoles, atrial fibrillation

• Dyskinesias–Common in patients

receiving carbidopa• Behavioral effects:

–Common in patients receiving levodopa

–controlled by clozapine, olanzapine, resperidone

DRUG INTERACTIONS:• Vitamin B6 enhance

extracerebral metabolism of levodopa

–Prevented by decarboxylase inhibitors

• MAO – A inhibitors

–Hypertensive crisis

CONTRAINDICATIONS:

• Psychoses

• Angle closure glaucoma

• Cardiac dysrhythmia– Less incidence in combination with

carbidopa

• PUD

• Melanoma or suspicious undiagnosed skin lesions

CASE 3

• F.B. Was maintained on low dose of Levodopa and was titrated until given the highest dose where he started to had palpitations and chest pain.

• What is next step in your management?

PERIPHERAL DOPAMINE DECARBOXYLASE INHIBITORS (PDI)

• Carbidopa, Benseraside• Does not penetrate the BBB• Reduce the peripheral metabolism of levodopa• Increase plasma levels of levodopa• Prolongs the plasma half life of levodopa• Increase available amounts of dopa for entry into

the brain• Reduce the daily requirement of levodopa by

75%

CASE 4

• F.B. After 1 year of taking Levodopa develop rigidity and bradykinesia with worsening of the tremors.

• What treatment option should F.B. receive?

DOPAMINE AGONISTS

• Do not require enzymatic conversion for an active metabolite

• No potential toxic metabolites

• Do not compete with other substances for an active transport

• First line in parkinsonism

• End of dose akinesia to levodopa

• On & off phenomenon refractory to levodopa

ERGOT ALKALOIDS:

• BROMOCRIPTINE (Parlodel)

– D2 agonists

– Endocrinologic disorders (hyperprolactinemia)

– Absorbed variably in GIT

– Peak plasma levels: 1-2 hrs

ERGOT ALKALOID:

• PERGOLIDE

– Stimulates both D1 and D2

– More effective than bromocriptine

– Associated with clinical or subclinical valvular heart disease

CLINICAL USE:

BROMOCRIPTINE:– 7.5 mg & 30 mg– 1. 25 mg BID after meals X 2-3

months and increase 2.5 mg q 2 wks

PERGOLIDE:- 3 mg daily

- 0.05 mg starter dose

NON-ERGOT DOPAMINE AGONISTS:PRAMIPEXOLE

Preferential affinity to D3Monotherapy is effectiveNeuroprotective (H scavenger)Enhance neurotrophic activityRapidly absorbedPeak plasma concentration: 2 hrs0.125 mg TID then doubled after 1 wkIncrements of 0.75 mg at weekly

intervals

NON-ERGOT ALKALOIDS:• ROPINIROLE

– Pure D2 receptor agonists– 0.25 mg TID then total daily dose is

increased by 0.75 mg at weekly intervals until the 4th wk & increased by 1.5 mg thereafter

ADVERSE EFFECTS:

• GIT: anorexia, nausea, vomiting, bleeding PUD, reflux esophagitis

• Cardiovascular: postural hypotension, painless digital vasospasm

• Dyskinesias• Mental disturbances• Misc: erythromelalgia

CONTRAINDICATIONS:

• History of psychotic illness

• Recent myocardial infarction

• Peripheral vascular disease

• Peptic ulceration

APOMORPHINE

• Apokyn• Potent dopamine agonist• Temporary relief of off-periods of

akinesia • Rapidly taken by blood and brain (10

minutes) and persists for 2 hours• Nausea – trimethobenzamide• Dyskinesias, drowsiness, sweating,

hypotension, bruising at injection site

MONOAMINE OXIDASE INHIBITORS

MAO – A: metabolizes NE & serotonin

MAO – B: metabolizes dopamine

SELEGILINE (Deprenyl)

• Selective irreversible inhibitor of

MAO-B (normal doses)

• Inhibits MAO-A (higher doses)

• Retards breakdown of dopamine

• Prolongs & enhances the effect of levodopa

• Adjunct in fluctuating response to levodopa

SELEGELINE

• 5 mg with breakfast & lunch

• Cause insomnia when taken later during the day

• Not to be taken with meperidine, TCAs, SSRIs

• Increase adverse effects of levodopa

• METABOLITES: amphetamine & metamphetamine

DRUG INTERACTION:

• Stupor, rigidity, agitation, and hyperthermia - MEPERIDINE

RASAGILINE

• MAO-B inhibitor

• Potent than selegiline in preventing MAO-B toxins induced parkinsonism (MPTP)

• Combination with levodopa – HPN crisis

CATHECO-O-METHYLTRANSFERASE INHIBITORS:

• Compensatory activation pathways of levodopa metabolism after dopa decarboxylase inhibition

• Increase 3-O-methyldopa (3OMD) poor therapeutic response to levodopa– Competes with levodopa for an active carrier

mechanism in the intestinal mucosa & BBB

CATHECOL-O-METHYLTRANSFERASE INHIBITORS: (SELECTIVE)

• TOLCAPONE- central & peripheral metabolism

• ENTACAPONE– peripheral metabolism– Prolongs the duration of levodopa by

decreasing its peripheral metabolism– Helpful in patients receiving levodopa

who have fluctuations– t ½ = 2 hrs

STALEVO

• Combination of levodopa with both carbidopa and entacapone

• Simplifies drug regimen

• Requires consumption of a lesser number of tablets

SIDE EFFECTS:

• Postural hypotension• Fatigue• Somnolence• Peripheral edema• Nausea• Constipation• Dyskinesias• Confusion

AMANTADINE

• Antiviral agent

• Potentiates dopaminergic function by influencing the synthesis, release, reuptake of dopamine

PHARMACOKINETICS:peak plasma concentration: 1-4 hrs

after oral dosePlasma t ½ = 2-4 hrs

CLINICAL USE:

• Less potent than levodopa and benefits are short-lived

• 100 mg BID-TID

ADVERSE REACTIONS:Restlessness, depression, irritability,

insomnia, agitation, excitement, hallucinations & confusion

Livedo reticularis – clears within a month after drug withdrawal

CONTRAINDICATIONS:

• History of seizures

• Heart failure

ACETYLCHOLINE BLOCKING AGENTS:• Improve tremor & rigidity of

parkinsonism but have little effect in bradykinesia

• Benztropine mesylate

• Biperiden

• Orphenadrine

• Procyclidine

• Trihexyphenidyl

ADVERSE EFFECTS:

• CNS

• Mydriasis, urinary retention, constipation, tachycardia, tachypnea, increase IOP, palpitations, cardiac arrythmias

• Acute suppurative parotitis

• Dryness of the mouth

CONTRAINDICATIONS:

• Prostatic hyperplasia

• Obstructive GI diseases

• Angle closure glaucoma

The net result of all of these medications is the balancing out of the acetylcholine/dopamine balance and an improvement in movement

SURGICAL PROCEDURES:

Thalamotomy – conspicous tremor

Posteroventral pallidotomy or deep-brain stimulation

NEURONAL DEATH

EXCITOTOXICITY

• Environmental chemicals may contribute to neurodegenerative disorders

• Can occur with excessive glutamate and kainic acids

• Results from sustained rise in intracellular Ca

NEURONAL DEATH

APOPTOSIS

• Cell is systematically dismantled & shrunken remnants are removed by macrophages without causing inflammation

NEURONAL DEATH

OXIDATIVE STRESS

• Result of excessive production of oxygen and hydroxyl free radicals and hydrogen peroxide

CLINICAL SCENARIO

• A.D. 70 year old female living in a nursing home, has gradual onset of difficulty in recalling what time she has taken her snack but easily recalls the first ball she had in high school.

ALZHEIMER’S DISEASE

• Loss of intellectual ability with age• Dementia that does not have

antecedent cause• Associated with brain shrinkage,

localized loss of neurons in the hippocampus & basal forebrain

• Amyloid plaques, neurofibrillary tangles in the hippocampus

• Loss of cholinergic neurons

MOLECULAR MODEL FOR THE DEVELOPMENT OF ALZHEIMERS DISEASE

PATHOPHYSIOLOGY:

• Decrease in ACETYLCHOLINE• CHOLINERGIC DEFICIENCY

SYNDROME• Decrease in markers of cholinergic

neuron activity• Changes in brain glutamate, dopamine,

norepinephrine, serotonin and somatostatin activity

• Cholinergic and other neurons die or are destroyed

PATHOPHYSIOLOGY:

• Abnormal neuronal lipoprotein processing

• Familial form is associated with abnormal lipoprotein - APOLIPOPROTEIN E4

AMYLOID PLAQUES

• β AMYLOID PROTEIN – by product of neuronal death

NEUROFIBRILLARY TANGLES:

• More abundant in AD

• tangles = severity of cognitive impairment

DRUGS FOR ALZHEIMER’S DISEASE

CHOLINESTERASE INHIBITOR:

CHOLINESTERASE INHIBITORS:

• TACRINE- central inhibitor

• DONEZEPIL(Aricept) – not hepatotoxic, selective inhibitor

• RIVASTIGMINE (Excelon)

• GALANTHAMINE (Reminyl)

• For mild to moderate Alzheimer’s disease

TACRINE

• Tetrahydroaminoacridine, THA

• Long acting anticholinesterase & muscarinic modulator

• Orally active

• Duration of action: 6-8 hrs

• Blocks both acetylcholinesterase & butyrylcholinesterase

• Inhibitory effects on M1, M2 & muscarinic cholinoceptors

• Increases the release of acetylcholine from cholinergic nerve endings

• Inhibit MAO

• Decrease the release of GABA

• Increase the release of NE, dopamine, serotonin from nerve endings

DONAZEPIL, RIVASTIGMINE, GALANTAMINE• Newer cholinesterase inhibitors with

adequate penetration to the CNS

• Indirect cholinomimetic effects than tacrine

ADVERSE EFFECTS:

• Nausea and vomiting

• Hepatotoxicity is increased with tacrine

• Should be used with caution: ketoconazole, quinidine

NEURONAL NICOTINIC RECEPTORS (NNRs)

TARGACEPT

• Neuronal nicotinic receptors (NNRs), serve as key regulators of nervous system function.

• When the natural neurotransmitter acetylcholine, or a drug that mimics acetylcholine, binds to an NNR, the NNR normalizes chemical signaling, allowing neurons to communicate properly (neuromodulation)

• ."

• results in increased signaling when the nervous system is understimulated and decreased signaling when the nervous system is overstimulated

• nervous system's "volume knob

NMDA GLUTAMATE RECEPTOR INHIBITORS

MEMANTINE (Ebixa)

• Binds to NMDA receptor channels

• Produces a noncompetitive blockade

• Prevents the effect of excess glutamate leaking out from the damaged brain cells

• Treatment of moderate to severe form of Alzheimer’s disease

TREATMENT:

INHIBITING NEURODEGENERATION

• Anti-inflammatory drugs– Ibuprofen, indomethacin

• Metal chelating agent– Clioquinol

POST –TEST:

1. Tacrine

2. Targacept

3. Rivastigmine

4. Memantadine

5. Donazepil

A. NMDA glutamate receptor inhibitor

B. Neuronal Nicotinic Receptors

C. Cholinesterase inhbitor

6. SELEGILINE

7. TOLCAPONE

8. ROPINOROLE

9. BENSERASIDE

10. BIPERIDEN

A. MAOI

B. COMT INHIBITOR

C. DOPAMINE AGONIST

D. ACH BLOCKING AGENT

E. DOPA DECARB INHIBITOR