Lecture 32 - 3rd Asessment - Anti Park In Son Drugs

Pharmacology & Toxicology Dept Dr. Mariam Yousif 18/12/2006

OBJECTIVES # What is Parkinson's disease (PD)? # Pathogenesis of PD? # Treatment of PD? Drugs that increase dopaminergic activity Drugs that inhibit striatal cholinergic activity

PD is a progressive disorder of movement that occurs mainly in the elderly. PD is a degenerative disease of the basal ganglia causing tremor at rest, muscle rigidity and hypokinesia, often with dementia.

Who Gets Parkinson's Disease? It may be caused by a combination of factors both inside the body (such as genetic factors) and from the environment (toxins in food or air, for example). No one can predict who will get PD.

Symptoms of Parkinson's Disease A person with PD may have one or more symptoms. The most common symptoms are listed below:

-Tremor at rest, usually starting in the hands (‘pill-rolling’ tremor), which tends to diminish during voluntary activity. Tremor: is shaking in one or both hands, arms, or legs or the jaw, usually when the person is not moving. Seven out of 10 people with PD have tremor.

Symptoms of Parkinson's Disease -Postural instability: The person may tend to lean too far forward or too far backward when standing and walking, causing instability. -Bradykinesia: slow initiation of movement.

-Muscle rigidity: reflected as resistance to passive limb movement.

-Suppression of voluntary movements (hypokinesia) - Commonly associated with dementia. -Parkinsonian patients walk with a shuffling gait.

Nerve cells in the basal ganglia send messages that signal the body to move.

Underlying Pathophysiology PD is often idiopathic, but may follow stroke or virus infection.

PD associated with loss of dopaminergic neurons in the basal ganglia.

It can be drug-induced, e.g. neuroleptics (chlorpromazine), Reserpine which depletes the nigrostriatal neurons of their dopamine content; can produce a Parkinsonian-like syndrome.

PD can be induced by MPTP, a neurotoxin affecting dopamine neurons.

Neurochemical Changes PD affects the basal ganglia, 1960 the neurochemical origin of PD was shown.

Dopamine content of the substantia nigra and corpus striatum in postmortem brains of patients with PD was extremely low , associated with loss of dopaminergic neurons in the substantia nigra and degeneration of nerve terminals in the striatum.

Substantia Nigra and Parkinson's Disease

Neurochemical Changes Other monoamines, such as noradrenaline, 5-HT were much less affected than dopamine.

Cholinergic neurons of the corpus striatum are also involved in PD. Acetylcholine release from the striatum is strongly inhibited by dopamine, it is suggested that hyperactivity of these cholinergic neurons (associated with the lack of dopamine) leads to the symptoms of PD.

Neurotoxins ‘frozen addict’ syndrome, the cause was the compound 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), which was a chemical contaminant produced in the synthesis of a heroin substitute.

MPTP causes irreversible destruction of nigrostriatal dopaminergic neurons in various species.

Treatment for Parkinson's Disease There is no cure for PD at this time, but there are many ways, including medicine, to help control symptoms of PD.

Treatment for Parkinson's Disease (1) Enhancing striatal dopaminergic activity using drugs that increase dopaminergic activity between substantia nigra and corpus striatum. (2) Inhibiting striatal cholinergic activity using drugs that inhibit striatal cholinergic activity.

Treatment for Parkinson's Disease Drugs that increase dopaminergic activity Levodopa (L-dopa) - First line treatment. -Used instead of dopamine, which does not cross the blood brain barrier. -It is a precursor from which dopamine is produced by decarboxylation. -It crosses the blood-brain barrier, undergoes decarboxylation and increases the content of releasable dopamine.

Treatment for Parkinson's Disease Levodopa (L-dopa) -The plasma half life is 1-3 hours, extensive metabolism in the wall of the intestine. Also metabolized in blood and peripheral tissues. -Only about 1% of the administered dose is left to enter the brain and produce therapeutic effects. -Dopamine is the major peripheral product of levodopa metabolism and is responsible for most of the peripheral adverse effects.

Conversion of levodopa to dopamine and other metabolites.

Treatment for Parkinson's Disease Levodopa (L-dopa) - Extensive peripheral metabolism of levodopa requires large doses of to be given to produce therapeutic effects in the brain, but such doses produce many adverse effects.

LEVODOPA Therapeutic effectiveness 80% of patients show initial improvement with levodopa, particularly of rigidity and hypokinesia. Unwanted effects Two main types of unwanted effects: # Dyskinesia # ‘on-off’ effects

UNWANTED EFFECTS OF LEVODOPA Dyskinesia Involuntary movements develop in the majority of patients within 2 years of starting levodopa therapy. Movements usually affect the face and limbs and can become very severe. They disappear if the dose is reduced, but this causes rigidity to return.

UNWANTED EFFECTS OF LEVODOPA ‘On-off’ effect (mobility / immobility) Rapid fluctuations in clinical state can occur where hypokinesia and rigidity may suddenly worsen. -Sustained-release preparations or coadministration of COMT inhibitors (entacapone) can counteract fluctuations in plasma concentration of levodopa.

Acute Effects of Levodopa Nausea & anorexia: Domperidone, a peripherally acting dopamine antagonist, to prevent this effect. Psychological effects: by increasing dopamine activity in the brain, can produce a schizophrenialike syndrome, with delusions and hallucinations.

Treatment for Parkinson's Disease Peripheral adverse effects of levodopa reduced by combining it with a peripheral dopa decarboxylase inhibitor such as carbidopa or benserazide, which reduce the peripheral metabolism of levodopa, so that it can be used at lower doses. Neither carbidopa nor benserazide cross the blood brain barrier, therefore, interfere with levodopa metabolism only in the periphery.

Treatment for Parkinson's Disease Some of the peripheral adverse effects of levodopa can also be reduced by coadministration of the dopaminergic D2 antagonist, domperidone, which does not cross the blood brain barrier.

Drugs that increase dopaminergic activity Selegiline, MAO inhibitor, selectively blocks MAO-B, can be used to inhibit dopamine metabolism selectively in the brain. MAO-B is the predominant MAO isoform responsible for metabolizing dopamine in the brain. Long term trials showed that combination of selegiline and levodopa more effective than levodopa alone in relieving symptoms.

Drugs that increase dopaminergic activity COMT inhibitors: entacapone, tolcapone: used to increase central levodopa concentration.

Drugs that increase dopaminergic activity Dopamine Receptor Agonists Bromocriptine, is a potent agonist at dopamine (D2) receptors in the CNS. Other e.g. Pergolide Bromocriptine is often added to levodopa when levodopa alone does not adequately prevent the symptoms or when patients experience severe ‘on-off’.

Amantadine Acts by increasing dopamine release.

Drugs that inhibit striatal cholinergic activity (Muscarinic receptor antagonists) Atropine and related drugs were the main treatment of PD, until levodopa was discovered. Benzatropine, less peripheral effect than atropine.

DRUG LIST Levodopa Carbidopa Benserazide Entacapone Bromocriptine Pergolide Selegiline Amantadine Benzatropine Tolcapone Domperidone

NEURAL TRANSPLANTATION PD is the first neurodegenerative disease for which neural transplantation was attempted in 1982. Various approaches have been tried, based on the injection of dissociated fetal cells directly into the striatum. Trials in patients with PD have mainly involved injection of midbrain neurons from aborted human fetuses. Success rate has been variable, but reasonably encouraging. Still in experimental phase, may be effective, results are variable.

Other Methods That Can Help Medicine is key to controlling the symptoms of PD, but there are many other things healthcare providers will consider to help a person with PD. Some of these are listed below: Physical therapy : Exercises can help keep strength and flexibility in the arms, legs, and bodies of people with PD. Speech therapy : Pronouncing words and speaking loudly enough for other people to hear can become a problem for people with PD. There are specific speech exercises that can help. Occupational therapy : When PD makes performing certain tasks difficult, occupational therapy provides alternate ways or tools for doing them. Education : A great way to help someone with PD is to find out more about it. Support and counseling: To provide information and support to manage day-to-day problems.