Drugs for Parkison’s disease and Alzheimer’s disease Drugs for Parkison’s disease and Alzheimer’s disease Department of pharmacology

Part one Antiparkisonian Drugs Part one Antiparkisonian Drugs Part two Drug for Alzheimer’s disease Part two Drug for Alzheimer’s disease

Progressive & irreversible loss of neurons from specific regions of the brain. Neurodegenerative disorders PD AD Parkinson's disease loss of neurons from structures of the basal ganglia results in abnormalities in the control of movement; Alzheimer's disease, the loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability

Antiparkisonian Drugs The feature of Parkinsonism The feature of Parkinsonism Classification of drugs Classification of drugs Levodopa Levodopa Mechanism of Action Mechanism of Action Pharmacological effects and therapeutic application Pharmacological effects and therapeutic application Pharmacokinetics Pharmacokinetics Adverse effects Adverse effects Drug interactions and Contraindications Drug interactions and Contraindications

What’s Parkinson’s disease? Parkinson’s disease is a progressive degenerative disorder of the central nervous system. degenerative disorder

6 Parkinson`s disease Katharine Hepburn Muhammad AliJohnny CashMichael J. Fox Pope John Paul II

Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons The architecture of the neuron A dying neuron

nigra caudatum ○ (D 2 R) DA Ach(MR) striatum (-) (+) motor neurons in anterior horn of spinal cord skeletal muscle contraction

nigra caudatum ○ (D 2 R) DA Ach(MR) striatum (+) motor neurons in anterior horn of spinal cord skeletal muscle contraction (-)

The symptoms of Parkinson’s disease Four Cardinal Signs Four Cardinal Signs T remor T remor R igidity R igidity A kinesia and bradykinesia A kinesia and bradykinesia P ostural instability P ostural instability

The feature of Parkinsonism Parkinson's disease (PD) is the most prevalent type (approximately 80%) of Parkinsonism. A clinical syndrome pathologically characterized by lesions of the basal ganglia that produce abnormalities in motor activities.

The feature of Parkinsonism PD is related to the loss of neurons in the substantia nigra that provide dopaminergic innervation to the striatum (caudate end putamen )

The feature of Parkinsonism PD is a progressive neurological disorder PD is a progressive neurological disorder common symptoms common symptoms akinesia akinesia bradykinesia bradykinesia rigidity rigidity resting tremor resting tremor Poor balance, falls Poor balance, falls

16 Pathophysiology What`s happening in PD

NORMALParkinsonism

18 Degeneration of pigmented, Dopaminergic neurons of SN Histochemical staining of SN Normal PD

19 How to treat PD Supplement dopamine--levodopa Directly stimulate dopaminergic receptor Anticholinergic drugs B. Surgical treatment A. Pharmacotherapy

Drugs Treatment of Parkinson’s Disease Drugs that replace dopamine (e.g. levodopa, usually used concomitantly with peripherally acting dopa decarboxylase inhibitor, e.g. carbidopa) Drugs that mimic the action of dopamine (e.g. bromocriptine, pergolide and others in development)

Classification of drugs Levodopa and enhancer Levodopa and enhancer Agonist of dopaminergic receptor Agonist of dopaminergic receptor COMT and MAO inhibitors COMT and MAO inhibitors Anticholinergics of CNS Anticholinergics of CNS Amantadine Amantadine

Antiparkisonian Drugs Levodopa Mechanism of Action Pharmacological effects and therapeutic application Pharmacokinetics Adverse effects Drug interactions and Contraindications

Dopamine can be used to treat PD? Why ?

Levodopa Levodopa is the metabolic precursor of dopamine. Levodopa is the metabolic precursor of dopamine. Levodopa is still the gold standard antiparkinsonian agent. Levodopa is still the gold standard antiparkinsonian agent.

L-DOPA rescues Parkinsonian rabbits Rabbits treated with reserpine The same rabbits 15 minutes after treatment with L-DOPA

Levodopa Metabolism

Mechanism of Action Mechanism of Action Levodopa is the natural precursor to dopamine in the brain. Levodopa is the natural precursor to dopamine in the brain.

Mechanism of Action Mechanism of Action Exogenous levodopa, unlike dopamine, can cross the blood-brain barrier is converted into dopamine by an aromatic amino acid decarboxylase (AAD) Exogenous levodopa, unlike dopamine, can cross the blood-brain barrier is converted into dopamine by an aromatic amino acid decarboxylase (AAD)

Mechanism of Action Mechanism of Action primarily within the presynaptic terminals of dopaminergic neurons in the striatum. primarily within the presynaptic terminals of dopaminergic neurons in the striatum.

Levodopa Alter release, it is either transported back to dopaminergic terminals by the presynaptic uptake mechanism or metabolized by MAO and COMT. Alter release, it is either transported back to dopaminergic terminals by the presynaptic uptake mechanism or metabolized by MAO and COMT.

31 Therapeutic effects What we can do? GUT Blood

32

Carbidopa Levodopa + Carbidopa = without emesis

Carbidopa Carbidopa is an inhibitor of dopa decarboxylase. Carbidopa is an inhibitor of dopa decarboxylase. Because it is unable to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of levodopa to dopamine. Because it is unable to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of levodopa to dopamine. As a result, when carbidopa and levodopa are given concomitantly. As a result, when carbidopa and levodopa are given concomitantly.

Carbidopa Virtue: a. It can decrease the dosage of levodopa. b. It can reduce toxic side effects of levodopa. c. A shorter latency period precedes the occurrence of beneficial effects.

Levodopa Pharmacological effects and therapeutic application Pharmacological effects and therapeutic application Levodopa is very effective in reducing all the signs and symptoms of PD. Levodopa is very effective in reducing all the signs and symptoms of PD.

Levodopa Pharmacological effects and therapeutic application Pharmacological effects and therapeutic application When administrated to the early stage PD patient, When administrated to the early stage PD patient, the improvement in tremor, rigidity, and bradykinesia may be nearly complete. the improvement in tremor, rigidity, and bradykinesia may be nearly complete.

Pharmacological effects and therapeutic application As the disease progresses, dopamine production diminishes As the disease progresses, dopamine production diminishes Levodopa

Pharmacological effects and therapeutic application Larger doses of oral levodopa are needed to produce the same dopamine Larger doses of oral levodopa are needed to produce the same dopamine Levodopa

Levodopa In the longer term, the progressive nature of PD inevitably causes levodopa to become less effective, In the longer term, the progressive nature of PD inevitably causes levodopa to become less effective, and may give rise to periods where the clinical symptoms of PD are inadequately controlled. and may give rise to periods where the clinical symptoms of PD are inadequately controlled.

Levodopa Patients may begin to experience sudden fluctuations in symptom control: changing from full symptom control (known as 'on' -time) to periods of reduced voluntary movement ( 'off' - time). Patients may begin to experience sudden fluctuations in symptom control: changing from full symptom control (known as 'on' -time) to periods of reduced voluntary movement ( 'off' - time).

Pharmacokinetics 1.Administered orally, levodopa is rapidly absorbed from the small bowel by an active transport system for aromatic amino acids. Levodopa

Pharmacokinetics 2. Levodopa short half-life in plasma (l-2 hours). Ingestion of meals, particularly if high in protein content, interferes with the transport of levodopa into CNS. Ingestion of meals, particularly if high in protein content, interferes with the transport of levodopa into CNS. Levodopa

Pharmacokinetics 3.Some amino acids (such as leucine and isoleucine) may compete with levodopa for transporters in small bowel and blood-brain barrier.

Pharmacokinetics 4. Thus levodopa should be taken on an empty stomach.

Levodopa Adverse effects Stimulation of dopamine receptors in peripheral system. In gastrointestinal system: anorexia, nausea, and vomiting. In gastrointestinal system: anorexia, nausea, and vomiting. In cardiovascular system: tachycardia, ventricular extrasystoles, and hypotension. In cardiovascular system: tachycardia, ventricular extrasystoles, and hypotension.

For the long term user, involuntary movements. For the long term user, involuntary movements.Levodopa Adverse effects Stimulation of dopamine receptors in peripheral system.

Psychiatric symptoms : agitation, anxiety, elation and insomnia, depression, delusions, hallucinations, suicidal behavior. Psychiatric symptoms : agitation, anxiety, elation and insomnia, depression, delusions, hallucinations, suicidal behavior.Levodopa Adverse effects Stimulation of dopamine receptors in peripheral system.

Levodopa Levodopa Drug interactions Contraindications Drug interactions Contraindications Vitamin B6 increases the peripheral breakdown and reduces its effectiveness. Vitamin B6 increases the peripheral breakdown and reduces its effectiveness.

Levodopa Levodopa Drug interactions Contraindications Drug interactions Contraindications Monoamine oxidase (MAO) inhibitor can increase conversion of dopamine to catecholamine thus may cause hypertensive crisis. Monoamine oxidase (MAO) inhibitor can increase conversion of dopamine to catecholamine thus may cause hypertensive crisis.

Contraindications Melanoma Melanoma Glaucoma Glaucoma Severe cardiovascular Severe cardiovascular Psychotic disorders Psychotic disorders

Agonist of dopaminergic receptor drugD1D2 Bromocripine partial antagonist agonist agonist Ｒ opinirole agonist Pramipexoleagonist Pergolideagonistagonist

Agonist of dopaminergic receptor All the four drugs are well absorbed orally, and have similar therapeutic actions. All the four drugs are well absorbed orally, and have similar therapeutic actions. Ｔ hey are particularly effective in the treatment of on/off phenomena. Ｔ hey are particularly effective in the treatment of on/off phenomena.

Agonist of dopaminergic receptor All the drugs may produce hallucinosis ， confusion ， orthostatic hypotension. All the drugs may produce hallucinosis ， confusion ， orthostatic hypotension.

MAO inhibitors Selegiline is a selective inhibitor of MAO isoenzyme, MAO-B. Selegiline is a selective inhibitor of MAO isoenzyme, MAO-B. While both isoenzymes MAO-A and MAO-B are present in the periphery ． While both isoenzymes MAO-A and MAO-B are present in the periphery ．

MAO inhibitors MAO-B is the predominant form in the striatum and is responsible for the majority of oxidative metabolism of dopamine in the striatum. MAO-B is the predominant form in the striatum and is responsible for the majority of oxidative metabolism of dopamine in the striatum.

Selegiline A selective inhibitor of MAO-B, which predominates in DA-containing regions of the CNS and lacks unwanted peripheral effects of non-selective MAO inhibitors. A selective inhibitor of MAO-B, which predominates in DA-containing regions of the CNS and lacks unwanted peripheral effects of non-selective MAO inhibitors. It enhances and prolongs the antiparkinsonism effect of levodopa. It enhances and prolongs the antiparkinsonism effect of levodopa. It may reduce mild on-off or wearing-off phenomena. It may reduce mild on-off or wearing-off phenomena.

Selegiline It enhances and prolongs the antiparkinsonism effect of levodopa. It enhances and prolongs the antiparkinsonism effect of levodopa. It may reduce mild on-off or wearing-off phenomena. It may reduce mild on-off or wearing-off phenomena.

Selegiline Long-term trials showed that the combination of selegiline and levodopa was more effective than levodopa along in relieving symptoms and prolonging life. Long-term trials showed that the combination of selegiline and levodopa was more effective than levodopa along in relieving symptoms and prolonging life.

Anticholinergics of CNS Imbalance between the dopaminergic and the cholinergic activity in the striatum may play an important role in pathogenesis of PD ． Imbalance between the dopaminergic and the cholinergic activity in the striatum may play an important role in pathogenesis of PD ．

Anticholinergics of CNS Diminished dopaminergic activity, a relative overactive cholinergic activity may contribute to the symptoms in PD patients. Diminished dopaminergic activity, a relative overactive cholinergic activity may contribute to the symptoms in PD patients.

Anticholinergics of CNS Thus cholinergic antagonists could be beneficiary for PD patients by blocking the cholinergic activity ． Thus cholinergic antagonists could be beneficiary for PD patients by blocking the cholinergic activity ．

Anticholinergics of CNS Several drugs :Artane, benztropine. These anticholinergic drugs are less efficacious than levodopa and play an adjuvant role in PD therapy. These anticholinergic drugs are less efficacious than levodopa and play an adjuvant role in PD therapy.

Anticholinergics of CNS Several drugs :Artane, benztropine. The adverse effects of these drugs are results of their anticholinergic properties, similar to those caused by high dose of atropine The adverse effects of these drugs are results of their anticholinergic properties, similar to those caused by high dose of atropine

Anticholinergics of CNS Several drugs :Artane, benztropine. They shouldn't be used in patients with glaucoma, prostatic hypertrophy. They shouldn't be used in patients with glaucoma, prostatic hypertrophy.

Trihexyphenidyl(Artane) 1.Action mechanism blocking M receptors in CNS function of cholinergic nerves in nigrostriatum restoring balance between dopaminergic and cholinergic neurons. blocking M receptors in CNS function of cholinergic nerves in nigrostriatum restoring balance between dopaminergic and cholinergic neurons.

Trihexyphenidyl(Artane)2.Effect: Less efficious than levodopa. Less efficious than levodopa. More effective on tremor, less effective on bradykinesia and rigidity. More effective on tremor, less effective on bradykinesia and rigidity.

3.Use alone for: alone for: mild patients mild patients patients of discontinuation of L-dopa due to adverse effects, Parkinsonian syndrome induced by phenothiazides patients of discontinuation of L-dopa due to adverse effects, Parkinsonian syndrome induced by phenothiazides all Parkinsonian disorders in combination with L-dopa all Parkinsonian disorders in combination with L-dopa

4.side effects similar to those of atropine. similar to those of atropine. scopolamine scopolamine

Amantadine Amantadine Amantadine is an antiviral drug used for the treatment of influenza. Amantadine is an antiviral drug used for the treatment of influenza. It was found later that amantadine has an antiparkinsonism effect. It was found later that amantadine has an antiparkinsonism effect. Amantadine appears to enhance the synthesis, release, or re-uptake of dopamine from the surviving neurons. Amantadine appears to enhance the synthesis, release, or re-uptake of dopamine from the surviving neurons.

Amantadine Amantadine It is used an initial therapy of mild PD. It is used an initial therapy of mild PD. It also may be helpful as an adjunct in patients on levodopa with dose-related fluctuations. It also may be helpful as an adjunct in patients on levodopa with dose-related fluctuations.

Amantadine Therapeutic uses and mechanism of action Amantadine may be more efficacious than the anticholinergic atropine derivatives but is less effective than levodopa. It has been used alone to treat early PD and as an adjunct in later stages.

Drug for Alzheimer’s disease Drug for Alzheimer’s disease

75 ALZHEIMER'S DISEASE

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. What is AD? Slide 4

What is AD? Slide 5 Although the risk of developing AD increases with age – in most people with AD, symptoms first appear after age 60 – AD is not a part of normal aging. It is caused by a fatal disease that affects the brain.

Alzheimer’s disease Alzheimer’s disease Damage of acetylcholineneurons Damage of acetylcholine neurons Destroys memory and thinking skills

79 “Cholinergic hypothesis “ A deficiency of acetylcholine is critical in the genesis of the symptoms of AD Involving multiple neurotransmitter systems, including serotonin, glutamate, and neuropeptides Neurochemistry

80 “Cholinergic hypothesis “ In AD there is destruction of not only cholinergic neurons but also the cortical and hippocampal targets that receive cholinergic input. Neurochemistry

Classification of drugs Acetylcholinesterase Inhibitors: tacrine Acetylcholinesterase Inhibitors: tacrine Agonist of M-receptor: xanomeline Agonist of M-receptor: xanomeline Enhancer of growth factor of neurons: ATT 082 Enhancer of growth factor of neurons: ATT 082 Enhancer of Metabolism and protective agent of neurons: piracetam Enhancer of Metabolism and protective agent of neurons: piracetam

Acetylcholinesterase Inhibitor tacrine Acetylcholinesterase inhibit (block) The concentration of acetylcholine in the brain The concentration of acetylcholine in the brain Improvement symptoms of Alzheimer's disease

83 Tacrine A potent, centrally acting inhibitor of AChE Oral tacrine in combination with lecithin produces modest improvement on memory performance Side effects (significant and dose-limiting) Abdominal cramping, anorexia, nausea, vomiting, and diarrhea (1/3) Elevations of serum transaminases ( 50% )

84 Donepezil A selective inhibitor of AChE in the CNS with little effect on AChE in peripheral tissues. Produces modest improvements in cognitive scores in AD patients and has a long half-life, allowing once- daily dosing

Agonist of M-receptor xanomeline xanomeline Improvement symptoms of think skill and Improvement symptoms of think skill and behavior

TO grasp Levodopa: Mechanism of Action Pharmacological effects and therapeutic application Pharmacokinetics Adverse effects Drug interactions and Contraindications