PARKINSONISM

CHARACTERIZATION: It is a chronic progressive disease occurring in older age groups.
It is characterized by:
Tremors at rest (rhythmic oscillatory movements around a joint).
Rigidity of muscles (lead pipe or cogwheel type).
Bradykinesia (slowness in initiating and carrying out voluntary movements.
Characteristic flexed posture and shuffling gait.

ETIOLOGY: The disease is correlated with a reduction in the activity of inhibitory dopaminergic neurons in substantia nigra and corpus striatum parts of basal ganglia system of brain that are responsible for motor control.
Genetic and environmental factors may have a little influence in etiology of the disease.

SUBSTANTIA NIGRA: It is the part of extrapyramidal system and is the source of dopaminergic neurons that terminate in the striatum.
Each dopaminergic neuron makes thousand of connections in striatum and therefore modulates the activity of a large number of cells.
These dopaminergic projections fire tonically rather than in response to specific muscular movements or sensory input.
STRIATUM: Normally striatum is connected to substantia nigra by GABA inhibitory neurons and in turn, substantia nigra sends back inhibitory dopaminergic neurons.
Nerve fibers from cerebral cortex and thalamus secrete acetylcholine in the striatum causing excitatory effects that initiate and regulate gross intentional movements of body.
In Parkinsonism, destruction of cells occurs in substantia nigra, which results in degeneration of neurons responsible for secretion of dopamine in striatum.
Thus, the normal modulating inhibitory influence of dopamine on neostriatum is significantly diminished resulting in tremors.

MAIN CAUSES OF PARKINSONISM:
Idiopathic nigrostriatal degeneration
Post encephalitic (viral infection).
Atherosclerotic, Cerebrovascular diseases.
Drug Induced:
Drugs that block dopamine receptors e.g. Phenothiazines and Antipsychotics.
Drugs that deplete striatal dopamine e.g. Reserpine, Methyldopa.
Poisoning due to carbon monoxide (CO), manganese (Mn), Mercury (Hg), Copper (Cu), etc, etc.


*Etiology:
1. Study of causes: the philosophical investigation of causes and origins.
2. Medical specialty: the branch of medicine that investigates the causes and origins of disease.
3. Cause of a disease: the set of factors that contributes to the occurrence of a disease.


STRATEGY OF TREATMENT:
In addition to an abundance of inhibitory dopaminergic neurons, the striatum is also rich in excitatory acetylcholine neurons that oppose the action of dopamine.
Many of the symptoms of Parkinsonism show an imbalance between excitatory cholinergic neurons and greatly reduced number of inhibitory dopaminergic neurons.
The therapy is aimed at restoring dopamine in basal ganglia and blocking acetylcholine actions thus re-establishing the correct dopamine/ acetylcholine balance.

CLASSIFICATION OF ANTIPARKINSONISM DRUGS:
Currently available drugs offer temporary relief from symptoms of disorder but do not reverse the neuronal degeneration caused by the disease.

DOPAMINERGIC DRUGS:
Levodopa
Peripheral Decarboxylase Inhibitors e.g. Carbidopa, Benserazide
Ergolines e.g. Bromocriptine, Lergotrile
Aporphines e.g. Apomorphine, N-Propylnoraporphine.
MAO (Monoamine Oxidase) Inhibitors e.g. Deprenyl
Dopamine releasing Drugs e.g. Amantadine
Dopamine b-hydroxylase Inhibitors e.g. Furaric Acid.

ANTICHOLINERGIC DRUGS:
Natural Belladonna Alkaloids e.g. Atropine, Hyoscine.
Synthetic Anticholinergics e.g. Benzhexol, Benztropine, Biperiden, Procyclidine.
Antihistamines e.g. Diphenhydramine HCl, Orphenadrine.
Phenothiazines with Anticholinergic activity e.g. Ethopropazine HCl.


LEVODOPA:

CHEMISTRY:
Levodopa is a metabolic precursor of dopamine call dihydroxyphenylalanine.
PHARMACOKINETICS:
Levodopa is absorbed rapidly from small intestine but dopamine does not.
Levodopa can penetrate BBB (Blood Brain Barrier) but dopamine does not.
Levodopa undergoes extensive peripheral decarboxylation and during first pass metabolism. Thus, almost 1% Levodopa is able to penetrate BBB (Blood Brain Barrier).
To reduce this effect peripheral decarboxylase inhibitors (Carbidopa) are co-administered with Levodopa thus enhancing its CNS bioavailability.
Metabolites of Levodopa are excreted mainly in urine.
MECHANISM OF ACTION:
Levodopa is readily transported into CNS and is converted to dopamine in the brain to replenish the dopamine stores in substantia nigra.
Therefore, dopamine is effective as long as there are adequate numbers of dopaminergic neurons in degenerated substantia nigra, which can change Levodopa to dopamine. However, unfortunately with the passage of time the no. of healthy neurons decreases and effects of Levodopa may fluctuate. There are two types of dopaminergic neurons in CNS i.e. D1 & D2. D1 stimulate adenyl cyclase to produce more cAMP. D2 receptors inhibit adenyl cyclase thus lowering cAMP level.
Beneficial antiparkinsonism effects of Levodopa are due to stimulation of D2.

ACTIONS OF LEVODOPA:

CNS:
Improves hypokinesia and rigidity more rapidly than tremors.
Improvements in posture, gait, facial expressions, speech and mood of patient.
CTZ (chemoreceptor trigger zone) is stimulated to cause nausea and vomiting.
CVS:
Stimulation of a and b–adrenoceptors.
Tachycardia and cardiac arrhythmias.
Cause postural hypotension.
All these effects are due to increased dopamine blood concentration resulting from peripheral decarboxylation of Levodopa.
ENDOCRINE EFFECTS:
Prolactin secretion is inhibited.
Growth Hormone secretion occurs in normal subjects but no Growth Hormone secretion in Parkinsonism subjects.
EYE:
Mydriasis due to adrenergic activity.
Intraocular pressure may increase precipitating Glaucoma.


THERAPEUTIC USES:
1. Combination of Levodopa and Carbidopa is the drug of choice in the treatment of Parkinsonism. It is useful for 2-3 years of treatment after which its effects may decline.
2. Treatment of galactorrhoea as it inhibits prolactin secretion.
3. Treating comatose patients due to hepatic encephalopathy because of its non-specific CNS arousal effect.

ADVERSE EFFECTS:
Side effects of Levodopa are generally dose-dependant and reversible.
GIT:
Nausea and vomiting is the common side effect of Levodopa therapy and may be reduced by administering the drug with food. With continuous therapy, tolerance develops and GIT side effects tend to disappear.
Anorexia is also common.
Perforation & bleeding of peptic ulcer.
CVS:
Cardiac arrhythmias especially in older age people suffering already from cardiac disturbances. It is due to stimulation of b-receptors of heart.
Postural hypotension (unknown mechanism).
MOVEMENTS: (DYSKINESIA)
These develop on long-term therapy and include faciolingual tics, grimacing, head bobbing and various oscillatory and rocking movements of arms, legs and trunk.
Tolerance does not develop regarding to these effects.
BEHAVIORAL DISTURBANCES:
Hallucinations, paranoia, mania, insomnia, anxiety, nightmares and emotional disturbances.
Requiring withdrawal of drug treatment.
MISCELLANEOUS: Dark sweat and urine, headache, sweating, tachypnoea.

DRUG INTERACTIONS:
1st. Pyridoxine (Vitamin B6) reverses the effects of Levodopa by enhancing peripheral decarboxylation.
2nd. Reserpine antagonizes therapeutic effects of Levodopa by depleting stores of central dopamine.
3rd. Phenothiazines and Butyrophenones may antagonize Levodopa by blocking dopamine receptors.
4th. Non-specific MAO (Mono Amine Oxidase) Inhibitors interfere with inactivation of dopamine and noradrenalin and may enhance their actions.
5th. Anticholinergics drugs are given with Levodopa to reduce tremors, they may cause slowing of gastric emptying and thus may cause decreased Levodopa absorption and hence its action is reduced.

PRECAUTIONS:
Great care should be exercised when using Levodopa in endocrine, renal, hepatic, pulmonary or cardiovascular disease, skin melanoma, diabetes mellitus and peptic ulcer.
Levodopa is not indicated for drug-induced Parkinsonism but may be used after surgery.

CONTRAINDICATIONS: Levodopa is contraindicated in
a) Closed-Angle Glaucoma
b) Psychosis
c) Pregnancy
d) Severe Psychoneuroses

PRODUCT NAMES:
I. LARODOPA
II. DOPAR

PERIPHERAL DECARBOXYLASE INHIBITORS:
Since about 95% of orally administered Levodopa is rapidly decarboxylated in the periphery to dopamine which cannot penetrate BBB (Blood Brain Barrier).
So large doses of Levodopa must be taken to allow sufficient accumulation of Levodopa in the brain to be converted to dopamine and this may lead to severe adverse effects.
In order to decrease the incidence of adverse effects, Levodopa is used along with a Peripheral Decarboxylase Inhibitor i.e. Carbidopa or Benserazide.

Levodopa + Carbidopa = SINEMET
Levodopa + Benserazide = MADOPA

MECHANISM OF ACTION:
i. Peripheral Decarboxylase Inhibitors block dopamine formation from Levodopa outside the brain.
ii. They themselves do not cross BBB (Blood Brain Barrier) and thus do not inhibit conversion of Levodopa to dopamine in the brain.
iii. Smaller dose of Levodopa is required for treatment of Parkinsonism when given along with Carbidopa or Benserazide.

BROMOCRIPTINE:

Bromocriptine is ergotamine derivative with dopamine agonist activity.

MECHANISM OF ACTION:
Bromocriptine is partial agonist at presynaptic D2 receptors.

PHARMACOLOGICAL ACTIONS:
Bromocriptine stimulates D2 receptors in corpus striatum.
Inhibits synthesis and release of Prolactin.
Lowers elevated secretions of Growth Hormone in patients with acromegaly.
Stimulates CTZ (chemoreceptor trigger zone).
Non-specific arousal of CNS.

CLINICAL USES:
As an alternative to Levodopa in Parkinson’s disease.
Dopaminergic therapy may be initiated with a low dose of Carbidopa plus Levodopa and then increased by the addition of Bromocriptine.
For the treatment of hyperprolactinaemia.
Treatment of acromegaly.
Suppression of lactation.

ADVERSE EFFECTS:

CNS: Dyskinesia, mental disturbance (confusion, hallucinations, delusions and other psychiatric reactions), headache.
CVS: Arrhythmias, orthostatic hypotension, painless digital vasospasm.
GIT: Anorexia, nausea, vomiting, constipation, dyspepsia, reflux esophagitis, bleeding form peptic ulcer.
RESPIRATORY TRACT: Nasal congestion.
ERYTHROMELALGIA: Consisting of red, painful swollen feet & hands associated with arthralgia.

CONTRAINDICATIONS:
Patients with recent myocardial infarction.
Patients with a history of psychotic illness.
Peptic ulcer.
Peripheral Vascular Disease.

PRODUCT NAMES:
BROTIN, CEROTIN, CRIPTON, PARLODEL.

AMANTADINE:

Amantadine is an antiviral drug effective in the treatment of influenza.
It was discovered accidentally that Amantadine has antiparkinsonism activity.

MECHANISM OF ACTION:
It releases dopamine from remaining intact neurons, delays re-uptake into these neurons and exerts an anticholinergic action.
If dopamine release is already at maximum then Amantadine has no effect.

PHARMACOLOGICAL ACTIONS:
Exerts an antiparkinsonism effect.
Acts prophylactically against H2 Influenza virus.
Amantadine is less efficacious than Levodopa.
The drug has little effect on tremors but is more effective against rigidity and bradykinesia.

ADVERSE EFFECTS:
a) Restlessness, agitation, confusion, hallucinations.
b) Acute toxic psychosis, orthostatic hypotension.
c) Urinary retention, peripheral edema, dry mouth.

PRODUCT NAMES:
PK-MERZ, SYMMETREL

MAO-B (MONO AMINE OXIDASE-B) INHIBITORS:

Deprenyl (SELEGILINE):
Deprenyl selectively inhibits MAO-B (Mono Amine Oxidase-B) Inhibitors, which metabolizes dopamine but does not inhibit MAO-A which metabolizes noradrenalin and serotonin.
Thus by decreasing the metabolism of dopamine, Deprenyl increases dopamine level in brain.

ACTIONS:
It enhances actions of Levodopa and when these drugs are co-administered, Deprenyl reduces dose of Levodopa.

CLINICAL USES:
As antiparkinsonism drug.

ADVERSE EFFECTS:
Hypotensive crisis, nausea, vomiting, confusion, agitation.

PRODUCT NAMES:
EKLIN, JUMEX

CENTRALLY ACTING ANTICHOLINERGIC DRUGS:

Examples: Benzhexol (Trihexyphenidyl), Benztropine, Biperidine, Procyclidine, Orphenadrine.

MECHANISM OF ACTION:
They block the central cholinergic receptors and reduce excessive cholinergic stimulation in basal ganglia.
Blockage of cholinergic transmission produces effects similar to augmentation of dopaminergic transmission because of the creation of an imbalance in the dopamine/acetylcholine ratio.

CLINICAL USES:
Used in Parkinsonism where it improves tremors and rigidity.

ADVERSE EFFECTS:
CNS: Drowsiness, mental slowness, inattention, restlessness, confusion, agitation, delusions, hallucinations, mood changes, dyskinesia.
CVS: Tachycardia, cardiac arrhythmias.
GIT: Xerostomia (dry mouth), nausea, vomiting, constipation.
EYE: Blurred vision, mydriasis, increased intraocular pressure,
RESPIRATION: Tachypnoea.
RENAL: Urinary retention.

CONTRAINDICATIONS:
Prostatic hypertrophy.
Pyloric stenosis
Paralytic ileus
Closed-Angle Glaucoma

PRODUCT NAMES:

Benzhexol PACITANE

Procyclidine KEMADRIN