Anti Parkinsonian Drugs

Anti- parkinsonian Drugs

— You should be able to list major symptoms of Parkinson's disease (PD)

— Explain the relationship between dopamine and acetylcholine in the basal ganglia

— Describe the action of the drug that increase the dopamine level or decrease acetylcholine levels in the basal ganglia

— Discuss the action and adverse effect of different types of antiparkinsonian drugs

— Facts

— First describe by James Parkinson in 1817

— Affects about 1 in 200 of the elderly population

— Caused by degeneration of the substantia nigra in the midbrain,

— consequent loss of dopamine-containing neurones in the nigrostriatal pathway --------- characterized by disturbance of movement

— Also know as disorder of the extrapyramidal system (a complex neuronal network that helps regulate movement

— Parkinsonism (PD)

— Extrapyramidal motor function disorder characterized by

— Tremor

— Rigidity

— Hypokinesia/Bradykinesia

— Impairment of postural balancing – falling

— Psychological disturbances including

— Dementia

— Depression and

— Impaired memory

— Aim of therapy of parkinsonism

— Relief of rigidity, tremor and akinesia

— Correction of mood changes and control of psychotic symptoms

— Treatment of other symptoms

— Treatment of cause, when possible

— Non pharmacological measures

— Education

— Support

— Physiotherapeutic exercise and nutrition

— Objective of therapy

1.  Enhancement of dopaminergic activity by drugs which may

a)  Replenish neuronal dopamine by supplying Levodopa, which is its natural precursor; administration of dopamine itself is ineffective as it dose not cross the BBB

b) Act as dopaminergic agoinst e.g. Bromocriptine, Pregolide, Cabergoline,  Apomorphine

c)   Prolong the action of dopam

ine through selective inhibition of its metabolism e.g. Selegiline

d) Release dopamine from stores and inhibit reuptake e.g. Amantadine

2.  Reduction of cholinergic activity by antimuscarinic e.g. Biperiden

— Classification
 

     I.            Drug affecting brain dopaminergic system

                              i.            Dopamine precursor: Levodopa

                           ii.            Drugs that inhibits dopamine metabolism

                                                  a)            MAO-B inhibitors: Selegiline

                                                 b)            COMT inhibitors: Entacapone, Tolcapone

                        iii.            Dopamine facilitator: Amantadine

                        iv.            Dopaminergic agonist: Bromocriptine, Ropinirole, Pramipexole

                           v.            Drugs affecting brain cholinergic system

                        vi.            Central anticholinergic: Trihexyphenidyl (Benzhexol), Procyclinedine, Biperiden

                     vii.            Antihistaminics: Orphenadrine, Promethazine

                  viii.            Point to remember

— Current drug

— Temporary relief from the symptoms of disorder

— But do not arrest or reverse the neuronal degeneration caused by the disease.

— Levodopa

— Single most effecting agent in PD

— Metabolic precursor – L-amino acid transpoters – decarboxylation to dopamine

— Increase level of dopamine

— Lessening of Parkinsonian symptoms and significant improvement in physical morbidity

— 95% is decarboxylated to dopamine in gut and liver

— 1-2% crosses BBB, taken up by neurons and DA is formed

— Why PD is treated by Levodopa but not dopamine?

— Cannot crosses the BBB (Even IV adminstratered dopamine cannot be use as it is insufficient to penetrate the CNS)

— Shorter half life (Metabolized in the gut, blood and liver by monoamine oxidase and catchol-O-methyyltransferase)

— Pharmacokinetic

— Administered orally

— Rapid absorption and food delays absorption by slowing gastric emptying

— High protein diet reduces the therapeutic effect

— Small fraction 1-3% of the total drug crosses the BBB

— Decarboxylase inhibitor such as Carbidopa

— Excreted through urine as unchanged drug and its metabolites

— Pharmacological actions

— CNS Action

— Bradykinesia/Akinesia responds first followed by rigidity and tremor

— Reduction in tremor effect with continued therapy

— Improves mood, memory and makes the patients more alert and interested in themselves and surroundings

— Newly diagnosed patients ------not responded to 1.2 g of Levodopa daily ---------three months --------do not have PD

— Drug induced parkinsonism, however does not response to Levodopa

— Cardiovascular action

— Tachycardia and ventricular extra systoles result from dopaminergic action on the heart.

— Hypotension

— CTZ: stimulation- nausea and vomiting – tolerance

— Endocrine actions

— Levodopa may inhibits prolactin secretion and suppress lactation in human

— Increase in GH release

— Adverse effect

— GI

— Nausea vomiting and anorexia occur very commonly

— CVS

— Postural hypotension, palpitation, sinus tachycardia, ventricular arrhythmias (beta adrenergic action)

— Dyskinesia

— Mental changes depression, nightmares, hallucination, agitation and confusion

— Darkening of sweat and urine

— Fluctuations in response

— Occurs after 3-5 years in one-third to one-half of patients.

— Relate to timing of levodopa intake

— Wearing off reaction  or End – of – dose  (on-off phenomenon)

— Off – period ---- marked akinesia

— On – period ---- improve mobility but often marked dyskinesia

— Most likely to occur in patients who responded well to treatment initially-------- mechanism not known

— Injected Apomorphine

— Drug holiday

— Discontinuance of the drug for 3-21 days

— Temporarily improves responsiveness to levodopa

— Reduce toxicity

— A major disadvantage -------levodopa  ------decarboxylated to dopamine in peripheral tissues ------1-5% of an oral dose of levodopa reaches the brain ---------large quantities of levodopa would have to be given.

— Significant adverse effects by peripheral actions, notably nausea, but also cardiac arrhythmia and postural hypotension.

— Decarboxylase inhibitors (DCI)

— Carbidopa and benserazide hydrochloride

— Do not enter the CNS ---No therapeutic effect of its own

— Always used along with Levodopa

— Prevent only the extracerebral metabolism of levodopa

— Concurrent administration of a DCI  enhance the effect of Levodopa

— MOA

— Diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues; thus, it increases the availability of levodopa to the CNS.

— Lowers the dose of levodopa needed by four- to five-fold

— Decreases the severity of the side effects arising from peripherally formed dopamine.

— Advantage of adding DCI to levodopa

— Dose of Levodopa can be reduced by as much as 75%

— Nausea, vomiting and cardiac effects are largely prevented

— Permits more rapid increase in the dose of Levodopa to optimum level

— Pyridoxime does not antagonize the effects of Levodopa

— The control of symptoms is smoother and wide diurnal fluctuations are avoided

— The number of daily doses can be reduced without loss of control

— Dopaminergic agonist

— Bromocriptine, Ropinirole, Pramipexole

— Acts directly on dopamine receptor

— Do not required enzymatic conversion

— Do not competes with other substance for active transport

— Limited adverse drug reaction than levodopa

— Bromocriptine

— Which acts as the potent agonist in D₂

— Less effective then levodopa

— Commonly use along with levodopa in past -----newer dopamine agonist

— Rapidly absorb

— T ½ --- 5 hrs+

— Duration of action is longer then levodopa (8-16 hrs)

— Effective in patients with no/off phenomenon

— ADR

— Nausea, vomiting. Constipation , dyspepsia.

— Postural hypotension,

— Dyskinesia

— Confusion, delusion or hallucination

— To minimize ADR , dose is build up slowly over 2 to 3 months 

— MAO-B inhibitors

— Selegiline

— MOA

— Dopamine is metabolized by an enzyme Monoamine oxidase B

— Selegiline inhibits this enzyme

— As a result concentration of dopamine will be increase and also it prolong the duration of action of dopamine that is formed in the brain

— When combined with levodopa increases and prolongs its duration action

— May reduce mild on /off or wearing off phenomena

— Adverse effect

— Dyskinesia, nausea and hallucinations

— MAO- B inhibitor and MAO-A should be avoided------------ hypertensive crisis

— COMT inhibitors

— Tolcapone and entacapone

— Use along with levodopa in advance disease who have develop fluctuations

— Smoother response, more prolong on – time  and

— Option of reducing total daily levodopa dose

—  

— Dopamine facilitator

— Amantadine

— Developed originally as an antiviral agent

— Has been found to ameliorate akinesia, rigidity and tremor in parkinsonism

— MOA

— Acts by releasing dopamine from its neuronal storage

— Activity in the basal ganglia is increase

— Indicated in early Stage of PD

— Or use along with other antiparkinsonism drugs

— ADR

— Gi disterbance

— CNS effect visual disterbance, dizziness and confusion

— Central anticholinergics

— Higher centeral anticholenergic action

— Reduces unbalanced cholinergic activity in striatum

— Tremor is benefited more than levodopa

— Used in mild cases and when levodopa in contraindicated

— Combination with levodopa to reduce its dose

— Also use in drug induced parkinsonism

— Antihistaminis like orphenadrine, promethazine are use in PD for their anticholinergic action

— Summary

— Points to remember

— None of the present drugs alter basic pathology of PD

— Initiation of levodopa therapy should be delayed as far as possible

— Monotherapy with selegiline or anticholinergics or amantadine- in mild cases. Newer drugs like Ropirinole etc can also be used

— In detoriation phase – levodopa and carbidopa. Slow and careful initiation

— Benefit from drug therapy wear off – dyskinesia develops. Later on/off phenomenon develops – patients problem becomes same as with drugs or without drugs

— Peripheral decarboxylase inhibitors decreases early, but not late complications

— DA agonist like ropinirole are used to supplement levodopa to prevent on/off phenomenon and reduce levodopa dose

— COMT inhibitors like entacapone are added to levodopa carbidopa to prolong their action and to reduce on/off