1. Review on Central Nervous System Disorders and Management
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa

2. CNS System Disorders Types of central nervous system disorder:
Neurodegenerative Diseases
Mood Disorders
Psychiatric Disorders

3. Neurodegenerative Diseases
Characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both
Drugs affecting the CNS may act presynaptically by influencing the production, storage, release, or termination of action of neurotransmitters
Neurodegenerative Diseases: Types
Parkinson's disease
Alzheimer's disease

4. Parkinson Disease(PD): Clinical Feature
Parkinsonism is a progressive neurologic disorder characterized by
Tremor
Rigidity
Bradykinesia
Postural instability
Poor balance, falls

5. PD: Causes The cause of PD is unknown for most patients
However, it is correlated with destruction of DAergic neurons in the substantia nigra with a consequent reduction of DA actions in the corpus striatum that are involved in motor control
Genetic factors do not play a dominant role in the etiology of PD, although they may exert some influence on an individual's susceptibility to the disease

6. PD: Treatments
Currently available drugs offer temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease:
Levodopa and carbidopa
Selegiline and rasagiline
Catechol-O-methyltransferase inhibitors
Dopamine-receptor agonists
Amantadine

7. Levodopa and Carbidopa
Levodopa is a metabolic precursor of DA
It restores DAergic neurotransmission in the corpus striatum by enhancing synthesis of DA
Relief provided by levodopa is only
symptomatic, and it lasts only while
the drug is present in the body
Tyrosine hydroxylase
Dopamine decarboxylase

8. Levodopa and Carbidopa: Mechanism of Action
DA itself does not cross the blood-brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and is converted to DA in the brain. Large doses of levodopa are required, because much of the drug is decarboxylated to DA in the periphery
Effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa. Carbidopa diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues; thus, it increases the availability of levodopa to the CNS

9. Levodopa and Carbidopa: Mechanism of Action

10. Levodopa and Carbidopa: Pharmacokinetics
Absorbed rapidly from the small intestine
Levodopa has an extremely short half-life (1 to 2 hours)
Ingestion of meals, particularly if high in protein, interfere with the transport of levodopa into the CNS
Large, neutral amino acids (i.e., leucine and isoleucine) compete with levodopa for absorption from the gut. Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a meal

11. Levodopa and Carbidopa: Adverse Effects
Anorexia, nausea, and vomiting occur
Hypotension may also develop
Saliva and urine are a brownish color because of the melanin produced from catecholamine oxidation
Visual and auditory hallucinations and abnormal involuntary movements may occur
Levodopa can also cause mood changes, depression, psychosis, and anxiety

12. Selegiline and rasagiline
Inhibits MAO-B (which metabolizes DA) at low to moderate doses
By decreasing the metabolism of DA, they increase DA levels in the brain
If selegiline is administered at high doses, the selectivity of the drug is lost, and the patient is at risk for severe hypertension

13. Catechol-O-methyltransferase Inhibitors
Methylation of levodopa by catechol-O-methyl-transferase (COMT) to 3-O-methyldopa is a pathway for levodopa metabolism
Inhibition of COMT by entacapone or tolcapone leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of DA

14. COMT Inhibitors: Pharmacokinetics
Oral absorption occurs readily and is not influenced by food
Bound to plasma albumin, with limited volumes of distribution. Tolcapone penetrates the blood-brain barrier and inhibits COMT in the CNS
Metabolized and eliminated in the feces and urine
COMT Inhibitors: Adverse Effects
Diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, and sleep disorders

15. Dopamine-receptor Agonists
This group of compounds includes
ergot derivative (bromocriptine)
nonergot drugs (ropinirole, and rotigotine)
Durations of action longer than that of levodopa and, thus, have been effective in patients exhibiting fluctuations in their response to levodopa

16. Amantadine
It has several effects on a number of neurotransmitters implicated in causing PD, including increasing the release of DA, blockading cholinergic receptors, and inhibiting the NMDA receptors
The drug may cause restlessness, agitation, confusion, and hallucinations
Orthostatic hypotension, urinary retention, peripheral edema, and dry mouth also may occur

17. Alzheimer's Disease (AD)
AD are progressive loss of memory and disordered cognitive function. Alterations in behavior and a decline in language function can also be observed in the early stages of AD. The impairment in cognitive abilities occurs gradually
Its prevalence rises sharply with age, from about 5% at 65 to 90% or more at 95

18. AD: Treatments
Pharmacologic intervention for AD is only palliative and provides modest short-term benefit
Currently available anti-AD agents are
Acetylcholinesterase inhibitors
NMDA-receptor antagonist
Palliative care: focuses on relieving and preventing the suffering of patients

19. Acetylcholinesterase (AchE) Inhibitors
These group of AD drugs block the breakdown of ACh and increase the availability of ACh in synapses
These drugs are palliative only and do not cure or prevent neurodegeneration
Available drugs: tacrine, rivastigmine, and galanthamine
Adverse effects: Nausea, diarrhea, vomiting, and insomnia

20. NMDA-receptor Antagonist
Memantine acts by physically blocking the NMDA receptor associated ion channel
In short term, memantine reduces the rate of memory loss in AD dementia in patients with moderate to severe cognitive losses
Often given in combination with an AChE inhibitor
Adverse effects: Confusion, agitation, and restlessness

21. Mood Disorders The most common mood disorder is major depression
Major depression is a common disorder that continues to result in considerable morbidity and mortality despite major advances in treatment
Characterized by exaggerated mood associated with physiological, cognitive, and psychomotor disturbances

22. Depression
Depression is a common psychiatric condition and a serious disorder that afflicts million of adults worldwide
Symptoms of depression:
intense feelings of sadness, and hopelessness
inability to experience pleasure in usual activities
changes in sleep patterns and appetite
loss of energy
suicidal thoughts

23. Depression: Cause Antidepressant Drugs
Depression is due to a deficiency of monoamines, such as 5-HT and NE, in the key regions of brain
Key regions involved in depression:
Hippocampus
Frontal Cortex
Antidepressant Drugs
Antidepressant agents:
Selective Serotonin Reuptake Inhibitors (SSRI)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
Atypical Antidepressants
Tricyclic Antidepressants (TCA)
Monoamine Oxidase Inhibitor (MAOI)

24. SSRI Drugs Name of few SSRIs: SSRIs block the reuptake of serotonin
Fluoxetine
Fluvoxamine
Paroxetine
Citalopram
SSRIs block the reuptake
of serotonin
Increased level of 5-HT
in the synaptic cleft
Greater postsynaptic
neuronal activity

25. SSRIs: Pharmacokinetics & Adverse Effects
Well absorbed after oral administration
Metabolized by CYP450-dependent enzymes
Adverse effects include headache, anxiety and agitation, weakness and fatigue, and sleep disturbances
Large intakes of SSRIs may cause seizures

26. SNRIs: Mechanism of Actions
Name of few SNRI drugs:
Venlafaxine
Duloxetine
Selectively inhibit the reuptake of both 5-HT and NE
Increased level of 5HT and NE in the synaptic cleft
Greater postsynaptic
neuronal activity

27. SNRI: Pharmacokinetics and Adverse Effects
Metabolized in the liver
Excreted in the urine
Adverse effects: Nausea, dizziness, insomnia, dry mouth, and constipation
At high doses, venlafaxine may increase blood pressure and heart rate

28. Atypical Antidepressants
Mixed group of agents that have actions at several different sites
Few atypical antidepressant drugs:
Bupropion (DA and NE reuptake inhibitor)
Mirtazapine (enhances 5-HT and NE neurotransmission)
Nefazodone, Trazodone (5-HT reuptake inhibitor)
Pharmacokinetics
Metabolized by CYP450 enzyme
Short half-life, may require more than once-a-day dosing
Adverse effects:
Dry mouth, sweating, nervousness
Bupropion produce seizures at high doses
Mirtazapine is markedly sedating

29. Tricyclic Antidepressants (TCAs)
Name of few TCAs:
Imipramine
Clomipramine
Desipramine
Nortriptyline
Protriptyline
TCAs: Mechanism of Action
TCAs are potent inhibitors of the neuronal reuptake of 5-HT and NE into presynaptic nerve terminals
By blocking the major routes of neurotransmitter removal, the TCAs increase monoamines in the synaptic cleft

30. TCAs: Pharmacokinetics
Well absorbed upon oral administration
Lipophilic nature, widely distributed and readily penetrate into the CNS
Initial treatment period is typically 4 to 8 weeks
Metabolized by the hepatic microsomal system
Excreted as inactive metabolites via the kidney
TCAs: Adverse Effects
Blurred vision, dry mouth, and constipation
Orthostatic hypotension, and dizziness
Weight gain is a common adverse effect

31. MAO Inhibitors Name of few MAO inhibitors:
Phenelzine
Selegiline
MOA: Form stable complexes with the enzyme, causing irreversible inactivation. This results in increased stores of 5-HT, NE, and DA within the neuron and subsequent diffusion of excess NT into the synaptic space
Pharmacokinetics:
Well absorbed after oral dosing, but antidepressant effects require at least 2 to 4 weeks of treatment
Metabolized and excreted rapidly in the urine
Adverse effects: Drowsiness, orthostatic hypotension, blurred vision, dry mouth, and constipation

32. Psychiatric Disorder Psychotic illnesses include various disorders
Schizophrenia is a particular type of psychosis, that is, a mental disorder caused by some inherent dysfunction of the brain
It is characterized by delusions, hallucinations, and thinking or speech disturbances
The illness often initially affects people during late adolescence or early adulthood and is a chronic and disabling disorder
It has a strong genetic component and probably reflects some fundamental biochemical abnormality

33. Antipsychotic Drugs Classical 'typical' antipsychotics
chlorpromazine, haloperidol, fluphenazine, thioridazine
Recent 'atypical' antipsychotics
clozapine, risperidone, sertindole

34. Antipsychotic Drugs: Mechanism of Action
All antipsychotic drugs are antagonists at dopamine D2 receptors but most also block other monoamine receptors, especially 5-HT2
Antipsychotic potency generally runs parallel to activity on D2-receptors, but other activities may determine side-effect profile
Take days or weeks to work, suggesting that secondary effects may be more important than direct effect of D2-receptor block

35. Antipsychotic Drugs Pharmacokinetics: Adverse effects:
After oral administration, they show variable absorption
Readily pass into the brain, have a large volume of distribution, and are metabolized by the cytochrome P450 system in the liver
Adverse effects:
Extrapyramidal motor disturbances and endocrine disturbances
Sedation, hypotension and weight gain, dry mouth, blurred vision, hypotension are also common

36. Study Questions
Study Question1. Which one of the following combinations of antiparkinson drugs is an appropriate therapy?
A. Amantadine, carbidopa, and entacapone.
B. Levodopa, carbidopa, and entacapone.
C. Pramipexole, carbidopa, and entacapone.
D. Ropinirole, selegiline, and entacapone.
E. Ropinirole, carbidopa, and selegiline.

37. Study Question 2. Peripheral adverse effects of levodopa, including nausea, hypotension, and cardiac arrhythmias, can be diminished by including which of the following drugs in the therapy?
A. Amantadine.
B. Bromocriptine.
C. Carbidopa.
D. Entacapone.
E. Ropinirole.

38. Study Question 3. Modest improvement in the memory of patients with Alzheimer's disease may occur with drugs that increase transmission at which of the following receptors?
A. Adrenergic.
B. Cholinergic.
C. Dopaminergic.
D. GABAergic.
E. Serotonergic.