ANTIPARKINSONIAN AGENTS MA. LENY ALDA G. JUSAYAN, MD DEPARTMENT OF PHARMACOLOGY
HOW DOES THE BODY MOVES?
THE BRAIN CONTROLS MOVEMENT
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 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: 70% of patients suffer resting tremor can affect all of the limbs as well as the face, neck, head and jaw. increased tone or stiffness in the muscles mask-like face and clog-like release of muscles.
difficulty initiating and continuing movement.
Forward flexion of neck, hips, knees and elbows leads to poor balance . Shuffling, small steps described as festination, reduced arm swing and sudden freezing spells lead to problems walking Swallowing (dysphagia) and Speech disorders (dysarthria)
Nonmotor Symptoms: 20-90% major depressive episode, reactive or endogenous
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
Problems with sleep fragmentation, sleep initiation, early morning awakening, excessive daytime somnolence and parasomnias .
Ability to gain employment
What causes Parkinson’s Disease? In 1918 there was an outbreak of Encephalitis Lethargica and many sufferers developed postencephalitic Parkinsonism. For instance, the illegal drug MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). 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. 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: Exposure to unrecognized neurotoxins Oxidation reaction with generation of free radicals
Reduced level of dopamine in the basal ganglia
Loss of postural reflexes .
CHOREA Irregular, unpredictable involuntary jerks
Impaired voluntary activity
Sudden coordinated abnormal movements
ATHETOSIS Slow & writhing movements
Abnormal postures (dystonia)
begins in the primary motor cortex descends through the corticospinal and corticobulbar tracts
affects the lower motor neurons in the brain stem and spinal cord .
basal ganglia and their cortical connection basal ganglia are made up of the: Globus Pallidus interna (Gpi) Globus Pallidus externa (Gpe)
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
PATHOPHYSIOLOGIC BASIS OF TREATMENT:
Dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum are lost
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 Amino acids in food compete with drug Peak plasma concentration: 1-2 hrs
HVA, DOPAC (dihydroxyphenylacetic acid) are main metabolites
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)
30 -60 minutes before meals
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) Phenothiazenes are contraindicated
Cardiovascular: tachycardia, ventricular extrasystoles, atrial fibrillation
Common in patients receiving carbidopa Common in patients receiving levodopa
controlled by clozapine, olanzapine, resperidone
DRUG INTERACTIONS: Vitamin B6 enhance extracerebral metabolism of levodopa
Prevented by decarboxylase inhibitors
CONTRAINDICATIONS: Less incidence in combination with carbidopa
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) 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: Endocrinologic disorders (hyperprolactinemia)
Peak plasma levels: 1-2 hrs
ERGOT ALKALOID: Stimulates both D1 and D2 More effective than bromocriptine
Associated with clinical or subclinical valvular heart disease
1. 25 mg BID after meals X 2-3 months and increase 2.5 mg q 2 wks
NON-ERGOT DOPAMINE AGONISTS: Preferential affinity to D3 Neuroprotective (H scavenger) Enhance neurotrophic activity Peak plasma concentration: 2 hrs 0.125 mg TID then doubled after 1 wk
Increments of 0.75 mg at weekly intervals
NON-ERGOT ALKALOIDS: Pure D2 receptor agonists
0.25 mg TID then total daily dose is increased by 0.75 mg at weekly intervals until the 4 th wk & increased by 1.5 mg thereafter
ADVERSE EFFECTS: GIT: anorexia, nausea, vomiting, bleeding PUD, reflux esophagitis
Cardiovascular: postural hypotension, painless digital vasospasm
CONTRAINDICATIONS: History of psychotic illness Recent myocardial infarction
Peripheral vascular disease
APOMORPHINE 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 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
Stupor, rigidity, agitation, and hyperthermia - MEPERIDINE
RASAGILINE 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 Prolongs the duration of levodopa by decreasing its peripheral metabolism
Helpful in patients receiving levodopa who have fluctuations
STALEVO Combination of levodopa with both carbidopa and entacapone
Requires consumption of a lesser number of tablets
AMANTADINE Potentiates dopaminergic function by influencing the synthesis, release, reuptake of dopamine
peak plasma concentration: 1-4 hrs after oral dose
CLINICAL USE: Less potent than levodopa and benefits are short-lived Restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations & confusion
Livedo reticularis – clears within a month after drug withdrawal
ACETYLCHOLINE BLOCKING AGENTS:
Improve tremor & rigidity of parkinsonism but have little effect in bradykinesia
ADVERSE EFFECTS: Mydriasis, urinary retention, constipation, tachycardia, tachypnea, increase IOP, palpitations, cardiac arrythmias
Acute suppurative parotitis
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 Environmental chemicals may contribute to neurodegenerative disorders Can occur with excessive glutamate and kainic acids
Results from sustained rise in intracellular Ca
Cell is systematically dismantled & shrunken remnants are removed by macrophages without causing inflammation
Result of excessive production of oxygen and hydroxyl free radicals and hydrogen peroxide
ISCHAEMIC BRAIN DAMAGE Interruption of blood supply to the brain Cerebral edema & inflammation Calcium & Na channel blockers NMDA receptor antagonists
Selfotel, eliprodil, dexrtromethorphan
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
β AMYLOID PROTEIN – by product of neuronal death
tangles = severity of cognitive impairment
DRUGS FOR ALZHEIMER’S DISEASE
CHOLINESTERASE INHIBITORS: TACRINE- central inhibitor DONEZEPIL(Aricept) – not hepatotoxic, selective inhibitor
For mild to moderate Alzheimer’s disease
TACRINE Tetrahydroaminoacridine, THA Long acting anticholinesterase & muscarinic modulator 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 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: 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
THANK YOU !!!
POST –TEST: NMDA glutamate receptor inhibitor
Neuronal Nicotinic Receptors