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

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

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

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

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

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

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

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

Levodopa and Carbidopa: Mechanism of Action

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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.

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.

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.