1. Drugs for Neurodegenerative Diseases
Kaukab Azim, MBBS, PhD

2. Drug List Drugs for Parkinson’s Disease
Drugs that increase brain dopamine levels
Dopamine receptor agonists
M receptor antagonists
Levodopa
Carbidopa
Selegiline
Entacapone
Amantadine
Bromocriptine
Pramipexole
Benztropine
Drugs for Huntington’s Disease
Drugs for Alzheimer’s Disease
Haloperidol*
Diazepam*
Donepezil
* These drugs will be discusssed in other lectures

3. Learning Outcomes
By the end of the course the students will be able to
Explain the mechanism of action of each drug in each group
Describe the main effects of each drug on different organ systems
Describe the absorption, distribution and metabolism of levodopa and carbidopa
Describe the administration routes of each drug in each class
Describe the main adverse effects of each drug in each class
Explain the on/off effect and wearing-off effect of levodopa / carbidopa
Explain the therapeutic value of combining levodopa with carbidopa in Parkinson’s disease
Explain the use of dopamine agonists and antimuscarinic drugs in Parkinson’s disease
Explain the use of neuroleptic and benzodiazepines in Huntington’s disease
Explain the use of central cholinesterase inhibitors in Alzheimer’s disease

5. The Basal Ganglia in Parkinson’s Disease

6. The Basal Ganglia in Parkinson’s Disease

8. The Basal Ganglia in Parkinson’s Disease
Basal ganglia are a group of interconnected subcortical nuclei that include striatum, substantia nigra, globus pallidus and subthalamus.
Basal ganglia function via a series of reciprocal innervations among themselves and the cortex.
In Parkinson’s disease the primary defect is destruction of dopaminergic neurons in the substantia nigra.
Excitatory cholinergic interneurons are also present in the striatum. The destruction of dopaminergic neurons in the substantia nigra leads to excessive cholinergic activity of these neurons.

9. 1. Levodopa
Chemistry
The amino acid levodopa is the biosynthetic precursor of dopamine.
Mechanism of action
In the brain levodopa is taken up by dopaminergic terminals in the striatum and is converted to dopamine by levo-aromatic amino acid decarboxylase (DOPA decarboxylase) (dopamine as such cannot be used since it does not enter the brain).
Levodopa itself is largely inert. Its effects depend on the increased synthesis of dopamine in the brain and are mostly related to activation of D2 receptors.
The amino acid levodopa (dihydroxyphenylalanine) is the biosynthetic precursor of dopamine.

10. Pharmacological effects
The peripheral effects of levodopa are related to the plasma concentration of dopamine.
Pharmacokinetics
Oral bioavailability: 5% (the firs-pass effect is very large; 95% is metabolized in the gut wall and in the liver)
Additional amounts are converted into dopamine and therefore only 1% enter the brain.
The amino acid levodopa (dihydroxyphenylalanine) is the biosynthetic precursor of dopamine.

11. Adverse effects
CNS
Anxiety, agitation, insomnia or sleepiness, nightmares, euphoria or depression, confusion, delusions, hallucinations, personality changes. [clozapine is the best drug to treat these effects]
Dyskinesias (up to 80% of patients treated for more than 3 years): choreoathetosis of the face and the extremities, tics, myoclonus, tremor. [therapy is unsatisfactory. A drug holiday can help]
The amino acid levodopa (dihydroxyphenylalanine) is the biosynthetic precursor of dopamine.
Choreoathetosis is the occurrence of involuntary movements in a combination of chorea (irregular migrating contractions) and athetosis (twisting and writhing).

12. Gastrointestinal system
Anorexia, nausea and vomiting (up to 80% of patients), weight loss.
Tolerance to these effects can occur after several months.
Cardiovascular system
Palpitations, cardiac arrhythmias (about 10% of ptns)
Postural hypotension (about 25% of patients). Tolerance can develop in a few months.
Other systems
Leukopenia, agranulocytosis, hemolytic anemia.

13. Levodopa Drug interactions
High doses of pyridoxine (vit B6) enhances the extracerebral metabolism of levodopa.
Nonselective MAO inhibitors inhibit dopamine metabolism (an hypertensive crisis may ensue)
Neuroleptics that block D2 receptors reduce the efficacy of levodopa and can exacerbate motor dysfunctions.
The amino acid levodopa (dihydroxyphenylalanine) is the biosynthetic precursor of dopamine.

14. Contraindications and Precautions
Melanoma (levodopa is a precursor of melanin and can activate malignant melanoma)
Cardiac disease
Psychosis
Depression with suicidal ideation
Treatment with nonselective MAO inhibitors

15. Levodopa Therapeutic Uses
Levodopa ameliorates all signs of parkinsonism.
Bradykinesia is the most sensitive to improvement.
The drug however does not cure the disease and responsiveness fluctuates and decreases with time.
The amino acid levodopa (dihydroxyphenylalanine) is the biosynthetic precursor of dopamine.

16. Two main types of fluctuations occur over time:
The wearing-off effect (also called end-of- dose akinesia): each dose improves mobility for 1-2 hours but akinesia rapidly returns.
The on-off effect: ‘off’ periods of marked akinesia alternate with ‘on’ periods of improved mobility.
Levodopa therapy must not discontinued abruptly (a neuroleptic malignant syndrome can result)

17. 2. Carbidopa
Carbidopa is a DOPA decarboxylase inhibitor that does not cross the blood-brain barrier.
When given with levodopa, the peripheral metabolism of levodopa is reduced with the following consequences:
The half-life of levodopa is increased.
More levodopa is available for entering the brain (this reduces by about 75% the daily requirement)

18. Gastrointestinal and cardiovascular effects of levodopa are substantially reduced.
CNS adverse effects are increased.
Levodopa is usually given in combination with carbidopa

19. 3. Other drugs that increase dopamine levels
A. Selegiline
Selegiline is a selective inhibitor of MAO B (the enzyme that metabolizes dopamine) so preventing the oxidation of dopamine to 3, 4- dihydroxyphenylacetic acid (DOPAC) and hydrogen peroxide.
This increases brain dopamine levels and prevents the formation of hydroxide radicals, that may play a role in the degeneration of nigrostriatal neurons.
DA is deaminated and dehydrogenated to form 3, 4-dihydroxyphenylacetic acid ( DOPAC) by monoamine oxidase (MAO) and aldehyde dehydrogenase.
In humans there are two types of MAO: MAO-A and MAO-B.
Both are found in neurons and astroglia.
Outside the central nervous system:
MAO-A is also found in the liver, gastrointestinal tract, and placenta.
MAO-B is mostly found in blood platelets.

20. Selegiline may reduce the ‘wearing-off’ and the ‘on-off’ effects.
Adverse effects are related to increased levels of dopamine both centrally (insomnia, mood changes, dyskinesias) and peripherally (nausea, hypotension).
It is used as a single agent in mild Parkinson’s disease or, more often, as an adjunct to levodopa, so allowing a reduction of levodopa dose.

21. Other drugs that increase dopamine levels
B. Catechol-O-methyltransferase inhibitors
Entacapone and tolcapone are inhibitors of Catechol-O-methyltransferase, the enzyme that transforms methyldopa into 3- Omethyldopa in the gut and the liver.

22. Since 3-O-methyldopa competes with levodopa for active transport into CNS, this metabolite may contribute to the wearing-off and on-off effects.
By inhibiting the enzyme, more levodopa can enter the brain.
Adverse effects are related (in part) to increased levels of dopamine.
Entacapone (which is preferred because it has not been associated with hepatotoxicity) is used as an adjunct to levodopa.

23. Other drugs that increase dopamine levels
C. Amantadine
The drug is an antiviral agent that probably works by increasing the release and inhibiting the reuptake of dopamine on nigrostriatal neurons.
Adverse effects are related in part to increased levels of dopamine. It can also cause livedo reticularis (a reddish-blue mottling of the skin with edema)
It is used as a single agent in mild Parkinson’s disease or, more often, as an adjunct to levodopa.

25. 4. Dopamine Receptor Agonists
Drugs
Bromocriptine (ergot derivative), pramipexole.
Mechanism of action
Bromocriptine is a partial agonist at central and peripheral D2- receptors (the activation in mammotroph cells of the pituitary blocks prolactin secretion).
Pramipexole is an agonist at D2 and D3 receptors in brain.

26. Pharmacological effects
(All are related to activation of central and peripheral D2 receptors)
Reduction of plasma prolactin levels (within hours from administration).
Stimulation of GH release in normal subjects but blockade (for unknown reasons) of release in acromegalic subjects.
Pharmacokinetics and administration
Oral bioavailability: bromocriptine 6 % (extensive first-pass effect)
Administration: oral.

27. Dopamine Receptor Agonists
Adverse effects
Dopamine-related
Anorexia, nausea and vomiting (up to 50%), stypsis (constipation).
Postural hypotension (common), cardiac arrhythmias.
Dyskinesias (after long-term use of high doses).
Headache, insomnia, nightmares, confusion, delusions, hallucinations)
Stypsis: The ability to contract or to draw together soft body tissues to stop blood flow or restrict secretion of fluids
What is stypsis ?
Stypsis is more commonly known as constipation. It consists in a difficulty in evacuating the intestines. It is a very common and diffused disturb and it is rarely a symptom of an organic disease. Usually constipation is accompanied by pain during the intestinal evacuation, loss of appetite and difficulties in digesting. If it drags on in time, it can favor the formation of hemorrhoids.
How can stypsis be treated?
In most cases, stypsis is caused by the individual’s lifestyle:
Scarce intake of liquids
Low fiber intake
Sedentary lifestyle
Keeping these aspects under control is a good way to prevent constipation.
A diet rich in vegetable fibers (i.e. fruits, vegetables and cereal) increases the volume of feces and makes their transit through the intestinal tract faster.Increasing the intake of liquids makes the feces softer: physicians recommend drinking at least 2 liters of water per day.Physical activity also helps battle constipation, especially those physical exercises which work on abdominal muscles help favor peristalsis.
When these remedies are not effective, the use of laxatives is possible. These must never be used on a regular basis or for long periods of time because they can become addictive.As an alternative, there are certain herbal extracts which can act as natural laxatives.

28. Ergot-related
Digital vasospasm (after long-term use)
Erythromelalgia (hot, red, tender, and painful feet or hands) (rare)
Pulmonary or retroperitoneal fibrosis (rare)
Contraindications and precautions
Psychotic disorders.
Cerebrovascular disorders

30. Dopamine Receptor Agonists
Therapeutic uses
Prolactin-secreting adenomas (unfortunately expansion of tumor often occurs if the drug is discontinued).
Idiopathic hyperprolactinemia and associated dysfunctions (amenorrhea-galactorrhea syndrome, infertility, hypogonadism).
Parkinson's disease.
Acromegaly
Cocaine detoxification (results are modest, at the best).

31. 5. Antimuscarinic Drugs in Parkinsonism
Benztropine and trihexyphenidyl and are centrally acting antimuscarinic drugs used for the treatment of Parkinson’s disease.

32. Mechanism of action
They likely act within the striatum on cholinergic striatal excitatory interneurons.
All subtypes of muscarinic receptors are likely present in the striatum.
The competitive blockade of these receptors decrease the cholinergic tone that is abnormally high in Parkinson’s disease, due to lack of the inhibitory activity of dopamine.

33. Antimuscarinic Drugs in Parkinsonism
Clinical uses
Antimuscarinic drugs may improve sialorrhea, tremor and rigidity but have little effect on bradykinesia
They are less effective than dopaminergic drugs but may be helpful as adjunct therapy. They can also reduce parkinsonism, acute dystonias and akathisia caused by neuroleptics and other dopamine antagonists (but they can exacerbate tardive dyskinesia).
Akathisia
Akathisia is closely related to dyskinesia. Akathisia is an extreme form of internal or external restlessness. It may be a complete inability to sit still, with an undeniable urge to be moving constantly. Or it may be an entirely inner feeling of jitteriness or shakiness. Akathisia can be exhausting and debilitating. In fact, severe akathisia may put an individual at risk for suicide, simply because it can be so unbearable.
Tardive akathisia refers to akathisia that occurs after long-term medication use, and may become permanent.
Dystonia
Dystonia is a muscle tension disorder involving very strong muscle contractions. These uncontrollable muscle contractions can cause unusual twisting of parts of the body, especially the neck. The condition can be extremely painful and can affect any part of the body, including the eyes. If it appears after several years of medication use, it is called "tardive dystonia," and may become permanent.
Tardive Akathisia & Tardive Dyskinesia
The class of drugs that are known as dopamine antagonists (antipsychotic or neuroleptic medications used primarily for treating mental illness) have been implicated in a number of different movement disorders such as tardive dyskinesia.
Tardive dyskinesia results as a side-effect of using the aforementioned medications. Akathisia is likewise the result of the side effects of dopamine antagonists, but the nature of a patient's symptoms differ.
Characteristics of Tardive Dyskinesia
When first identified in the late 1950s, tardive dyskinesia was thought to be a disorder of the oro-facial and jaw muscles. The original term was bucco-linguo-masticatory, or "cheek-tongue-chewing" syndrome. Today, researchers have established that tardive dyskinesia can affect other muscles as well. In addition to the arms and fingers (which make "fluttering," typing-like motions), the torso, legs and feet may be involved. Of greatest concern however is the effect on muscles that regulate swallowing and breathing, which can result in potentially life-threatening situations. In all cases these movements, although involuntary, are relatively slow and seemingly deliberate, which is one reason these patients find it difficult to function in social settings.
Characteristics of Akathisia
While patients with tardive dyskinesia may have difficulty sitting still, those with akathisia often have difficulty sitting at all. The disease was first noted in 1903, 50 years before antipsychotic medications were introduced. A doctor named Hasovec observed a pair of patients who exhibited symptoms of psychoneurosis. (It is now known that akathisia can be the result of withdrawal from opiates, such as morphine.
Fifty-one years later, another doctor named Steck observed similar symptoms in patients who had been treated with the new antipsychotic medications that a corporation called Smith, Kline and French had just introduced. The symptoms he observed included:
Shifting weight from one foot to another
Walking in place
Foot shuffling
Leg swinging or repeated crossing
In the most extreme cases, these patients must pace around, remaining in an agitated state of motion at all times. This compulsion is largely due to feelings of intense paranoia and undefined anxiety. For this reason, it has often been misdiagnosed as a mental state, for which additional drugs are prescribed, making the problem even worse. Violent and even suicidal tendencies have been reported among these patients, especially when the condition is due to the use of neuroleptic medications.
Treatment
In both cases, the most effective treatment is prevention. As tardive dyskinesia and akathisia are both "late-appearing" conditions, symptoms can appear long after a medication has been discontinued, or at any point during treatment. Sometimes, the symptoms are the result of withdrawal from a drug, appearing when dosage is reduced or a second drug is introduced. In other cases, "drug holidays" may help to alleviate symptoms.
Both disorders may be prevented through the use of newer "atypical" neuroleptic medications such as clozapine. This has been known to have serious side effects of its own, primarily agranulocytosis, which can result in pneumonia-like symptoms. In addition, Dr. Peter Breggin, author of Medication Madness, reports that such "second-generation" medications do not prevent the development of such symptoms and, at best, only delay their onset. Dr. Breggin, who is frequently called upon as an expert witness in legal actions involving such medications, also reported seeing symptoms develop after only a few doses.
There have been indications that the use of the hormone melatonin and vitamin B6 may help to alleviate symptoms.

34. Adverse effects
Adverse anticholinergic effects are both:
Central: drowsiness, restlessness, confusion, agitation , delusions, hallucinations.
Peripheral; xerostomia, blurring of vision, urinary retention, constipation, tachycardia, increased intraocular pressure.
(Elderly people are especially at risk).

35. Drugs for Huntington’s Disease
Huntington’s disease (or Huntington’s chorea) is an autosomal dominant hereditary disorder characterized by choreiform movements and progressive mental impairment, usually beginning in middle age.
The pathogenesis of the disease is related to the degeneration of GABA neurons in the striatum which leads to disinhibition of thalamic nuclei and to an increase of thalamic input to the cortex.
Choreiform movements: Involuntary, forcible, rapid, jerky movements which are mostly manifestations of basal ganglia diseases

36. Drugs used in Huntington’s disease
Dopamine receptor antagonists
Neuroleptics (haloperidol , chlorpromazine) antagonize the excessive dopaminergic activity in basal ganglia and are also helpful to improve motor function and to relieve paranoia and delusional states that often accompany the disease.

37. Amine depleting drugs
Reserpine, which can block the vesicular storage of dopamine
(Benzodiazepines which potentiate central GABA activities should help but the results have been somewhat disappointing).

38. Drugs for Tourette’s Syndrome
Tourette’s syndrome is a hereditary tic disorder that begins in childhood. It involves multiple tics including respiratory and vocal ones which begin as grunting or barking noises and progress into compulsive utterances.
Echolalia is common and coprolalia may occur in some patients.
It is probably an autosomal dominant trait.

39. Echolalia is the automatic repitition of vocalization made by another person
Coprolalia is involuntary swearing or the involuntary utterance of obscene words or socially inappropriate and derogatory remarks
Drugs used in Tourette’s syndrome include:
Neuroleptics (haloperidol, olanzapine, etc.)
Clonidine (it is effective in some patients only)
Nn blocking drug (mecamylamine)

43. Alzheimer's and the Brain
Alzheimer's disease leads to nerve cell death and tissue loss throughout the brain. As the disease progresses, brain tissue shrinks and the ventricles (chambers within the brain that contain cerebrospinal fluid) become larger. The damage disrupts communication between brain cells, crippling memory, speech, and comprehension.

45. Drugs for Alzheimer’s Disease
Alzheimer’s disease (AD) is a type of progressive dementia characterized by an progressive loss of cognitive functions associated with an excessive number of senile plaques in the brain.
In AD there is a progressive atrophy and degeneration of subcortical cholinergic neurons, particularly those in the basal forebrain (nucleus basalis of Meynert) that provide cholinergic innervation of the whole cerebral cortex.
The above mentioned deficit has given rise to the ‘cholinergic hypothesis’ which states that a deficiency of acetylcholine is critical in the genesis of symptoms of AD.
Neurofibrillary Tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as tauopathies. Little is known about their exact relationship to the different pathologies.
Neurofibrillary tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate, or group, in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as PHF, or "paired helical filaments"). The precise mechanism of tangle formation is not completely understood, and it is still controversial whether tangles are a primary causative factor in disease or play a more peripheral role.
Alzheimer's Disease Overview
Alzheimer's disease (AD) is the most common cause of dementia in industrialized nations. Dementia is a brain disorder that interferes with a person's ability to carry out everyday activities.
The brain of a person with Alzheimer's disease (see Multimedia file 1) has abnormal areas containing clumps (senile plaques) and bundles (neurofibrillary tangles) of abnormal proteins. These clumps and tangles destroy connections between brain cells.

This usually affects the parts of the brain that control cognitive (intellectual) functions such as thought, memory, and language.

Levels of certain chemicals that carry messages around the brain (neurotransmitters) are low.

The resulting losses in intellectual ability are called dementia when they are severe enough to interfere with everyday functioning.
Alzheimer's disease affects mainly people aged 60 years or older.
The risk of developing Alzheimer's disease continues to increase with age. People aged 80 years, for example, have a significantly greater risk than people aged 65 years.

About 5 million people in the United States and more than 30 million people worldwide have Alzheimer's disease. Many others have mild, or minimal, cognitive impairment, which frequently precedes dementia.

The number of people with Alzheimer's disease is expected to rise substantially in the next few decades because of the aging of the population.

The disease affects all races and ethnic groups.

It seems to affect more women than men.
Alzheimer's disease is a progressive disease, which means that it gets worse over time. It cannot be cured or reversed by any known treatment.
The symptoms often are subtle at first.

Over time, people with the disease lose their ability to think and reason clearly, judge situations, solve problems, concentrate, remember useful information, take care of themselves, and even speak.

Changes in behavior and personality are common.

People with mild Alzheimer's disease usually require close supervision and help with everyday tasks such as cooking, shopping, and paying bills.

People with severe Alzheimer's disease can do little on their own and require complete full-time care.
Because of this, Alzheimer's disease is considered a major public health problem.
The cost of caring for people with the disease is estimated at over $100 billion per year in the United States. The average yearly cost per affected person is $20,000 to $40,000, depending on the severity of the disease.

That cost doesn't take into account the loss of quality of life for the affected person, nor the physical and emotional toll on family caregivers
Alzheimer's Disease Causes
We do not know exactly what causes Alzheimer's disease. There is probably not one single cause, but a number of factors that come together in certain people to cause the disease.
Most experts believe that Alzheimer's disease is not a normal part of aging. 

While age is a risk factor for the disease, age alone does not seem to cause it. 

Family history is another risk factor. The disease does seem to run in some families. However, fewer than 10% of cases of Alzheimer's disease are familial. Familial Alzheimer's disease often occurs at a younger age, between ages 30 and 60 years. This is called early-onset familial Alzheimer's disease.
At least 3 different genes have been linked to Alzheimer's disease.
The one we know the most about controls production of a protein called apolipoprotein E (apoE), which helps in distribution of cholesterol through the body. 

Everyone has one of the 3 forms of the apoE gene. While one form seems to protect from AD, another form seems to increase the risk of developing the disease. 

The other genes-apart from ApoE-are known to be mutated in some people with the disease. These actually cause the disease in a few rare cases. 

Probably there are other genes that contribute to Alzheimer's disease, but we haven't found them yet.
Much of the research in Alzheimer's disease has focused on why and how some people develop deposits of the abnormal protein in their brains. Once the process is understood, it may be possible to develop treatments that stop or prevent it.

46. Donepezil, galantamine and tacrine are cholinesterase inhibitors approved for treatment of AD.
Donepezil and rivastigmine selectively inhibits cholinesterase in the CNS with less effect on cholinesterases in peripheral tissues.
These drugs can slow the deterioration of cognitive functions, even if they do not affect the underlying neurodegenerative process.
Adverse effects include insomnia, nausea, vomiting and diarrhea.

47. GOOD LUCK