-Not enough dopamine is being sent out by the substantia nigra b/c of dead dopamine neurons in the subst. nigra

-characterized by bradykinesia (slowness of movement), rigidity, impaired postural balance, and tremors of the limbs at rest

-Due to both environmental and genetic factors

-The first case of a substance causing Parkinson's was in abusers of the synthetic opoid meperidine

-It is a progressive disorder(Loss of dopaneurons occur a decade before symptoms show and the loss continues relentlessly)

-Treatments only treat symptoms, not the neurodegeneration

-Best treatment is Levodopa and Carbidopa together

-"Off" periods are of freezing and rigidity; "on" periods are of normal or dyskinetic (involuntary) movement

-The most common side effect of levodopa is the dyskinesia and hallucinations (due to increased DA which causes schizo-like states)

Mechanism of Action: Bromocriptine (Parlodel)

Ergot derivative

Class: Dopamine Receptor Agonist

Adverse effects: Nausea, peripheral edema, and hypotension; Cognitive side effects: Excessive sedation, vivid dreams, hallucinations

Other: Does not compete with levodopa, all DA agonists last longer than levodopa, 

Clinical use: DA agonists are first line agents in Parkinson's disease expecially in younger individuals

-Thought disorder characterized by 1 or more episodes of psychosis (impairement in reality testing)

-Positive symptoms (abnormal function)-delusions, hallucinations, disorganized speech, and catatonic behavior

-Negative symptoms (reduction or loss of function)-affective flattening, alogia, and avolition

-Usually affects people in their late teens and early 20's

-Pathogenesis is explained with the dopamine hypothesis

-Dopamine hypothesis-the illness is caused by increased and dysregulated levels DA neurotransmission in the brain

-Patients who take drugs that increase DA levels or activate DA receptors like amphetamines, cocaine, and apomorphine all have schizo-like states that subside when the dose is lowered

-The mesolimbic system is responsible for positive symptoms of schizophrenia

-Drugs used to manage psychosis are called neuroleptics or antipsychotics

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Chlorpromazine (Thorazine)

phenothiazine

Class: Antipsychotic agent

Adverse Effects: Parkinsonian symptoms, neuroleptic malignant syndrome (catatonia, stupor, fever, and autonomic instability, myoglobinemia, and death), tardive dykinesia (characterized by repetitive, involuntary, stereotyped movements of the facial musculature, arms, and trunk), Anticholinergic symptoms (dry mouth, constipation, urinary retention), orthostatic hypotension, failure to ejaculate, sedation

Contraindications-Parkinson's disease, myelosuppression, severe toxic central nervous system depression or comatose states

Clincal Use:Psychotic disorder, nausea and vomitting

-Eliminating rates of these drugs are erratic b/c they are eliminated in multiphasic patterns and are not strictly first-order

-injected intramuscular (IM) in the deep gluteal muscle

-inhibits the action of anti-Parkinsons drugs

-potentiates the effect of benzodiazepines and centrally acting antihistamines 

-Only taken every 2-4 weeks b/c of long half life (meant for non-compliant patients)

-Risk of extrapyrimidal symptoms is lower with the IM versus oral dosage form

-low anticholinergic activity

-Symptoms include the relatively common, prominent motor symptoms and loss of consciousness seen in tonic–clonic seizures, as well as paroxysmal changes observed in a variety of nonmotor functions—such as sensation, olfaction, vision—and higher-order functions—such as emotion, memory, language, and insight.

-Caused by overstimulation of glutamatergic pathways starting with overactivation of AMPA receptors and progressing to overactivation of NMDA receptors

-Inhibiting AMPA receptor prevents seizure onset; inhibiting NMDA receptor decrease seizure intensity and duration

-Clozapine has a lower chance of having extrapyrimidal symptoms compared to Haldol

-Clozapine is better than Haldol in treating schizophrenia (especially negative symptoms)

-Paroxetine is an SSRI and Venlafaxine is a SNRI (inhibits both NE and SE and is used when SSRIs are ineffective)

-Venlafaxine protects against the pain that comes along with depreession and Paroxetine does not

-Paroxetine inhibts CYP450 and Venlafaxine is a weak inhibitor of CYP450

-Both treat depression and anxiety

-Venlafaxine can also treat panic disorder

-Paroxetine can also treat OCD

-Both are G protein transmembrane

-Activation of D1 lead to increased cAMP; activation of D2 inhibits cAMP generation

-D1 class contains d1 and d5 receptors; D2 class contains d2, d3, and d4 receptors

-D2 receptors are the main target for drugs that treat schizophrenia

-Entacapone is a COMT inhibitor that allows more L-DOPA to cross the BBB and thus allows for more dopamine to eventually be made in a longer amount of time; Selegiline has the same affect but instead inhibits MAO-B and in high doses MAO-A

-Entacapone and Selegiline are used in Parkinson's disease

-Selegiline forms amphetamine which is toxic and can lead to insomnia and confusion (especially in the elderly)

-Enhance activation of GABA A receptor by GABA (and at high concentrations can act as agonist)

-Acts selectively at GABA A receptors with B2 and B3 subunits

-Induces anesthesia rapidly following bolus IV injection

-Like Barbs, it crosses the BBB rapidly

Mechanism of Action: GABA B receptor agonist

Therapeutic indications: Muscle relaxant (primarily used to treat spasticity associated with motor neuron disease, multiple sclerosis, or spinal cord injury)

-Does not cross BBB

-They extend the half-life of levodopa and facilitate the enry of the drug into the brain

-Tolcapone reduces the side effects of Carbidopa

-Is a noncompetitive NMDA receptor antagonist used to treat Alzheimer's disease

-Slows the rate of clinical detoriation in patients with moderate to severe Alzheimer's disease

-Treats partial and tonic-clonic seizures, status epilepticus, and amnesia induction

-Is a benzodiazepine

-Used to ablate seizures acutely because of adverse effects

-Used in the prep of invasive procedures as a rapid-onset and short-acting anxiolytic/sedative/amnestic (preanesthetic and IV general anesthetic)

-Is a benzodiazapine

-Used to mitigate chronic, severe anxiety, and anxiety asscociated with some forms of depression and schizophrenia (anxiety disorders)

-Used to treat phobias

-Used for insomnia

-Is a benzodiazapine; all benzodiazepines used for insmonia both facilitates sleep onset and increases the overall duration of the sleep

-Is a benzodiazepine

-Used to mitigate chronic, sever anxiety, and anxiety related to some depressions and schizophrenia

-Used as a treatment for anxiety disorders, status epilepticus, muscle relaxant, IV general anesthetic, and alcohol withdrawal, used to induce amnesia

-Used to alleviate muscle spasm caused by physical trauma as well as muscle spasticity associated with neuromuscular degenerative diseases such as mutliple sclerosis ( muscle relaxant)

-Reduces the tremors, agitation, and other effects of alcohol withdrawal 

-Treats partial and tonic-clonic seizures

-Used for alcohol withdrawal and anxiety disorders

-Reduces the tremors, agitation, and other affects of acute alcohol withdrawal

-Glaucoma

-Hypertension

-Used for irritable bowel syndrome (IBS)

-Treats the constipation of irritable bowel syndrome by enhancing GI motility

-Is a serotonin recepetor antagonist

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Clinical Applications: Bipolar Affective Disorder

Adverse Effects: Acute lithium intoxication (nausea, vomiting, diarrhea, renal failure, neuromuscular dysfunction, ataxia, tremor, confusion, delirium, and seizures), severe bradyarrythmia, hypotension, sinus node dysfuntion, hyperkalemia, pseudotumor cerebri, increased intracranial pressure and papilledema, seizure, polyuria, nephrogenic diabetes insipidus, hypothyroidism, goiter, ECG and EEG abnormalitites, diarrhea, nausea, muscle weakness, transient visual field scotoma, renal impairment, acne

Contraindications: Severe debilitation, dehydration, or sodium depletion, significant cardiovascular disease, severe renal impairment, lactation

Therapeutic considerations: Narrow therapeutic window and wide range of adverse effects, acute lithium intoxication is a medical emergency and dialysis may be necessary, NSAIDs or hyponatremia can lead to lithium reabsorption in proximal tubules, lithium inhibits potassium entry into myocytes, lithium has been shown to reduce suicide in patients with bipolar disorder

Clinical Applications: Depression, anxiety, OCD, post-traumatic stress disorder, pain syndromes

Adverse Effects: serotonin syndrome if used with MAOIs (hyperthermia, muscle rigidity, myoclonus, and rapid fluctuation in mental status and vital signs), may cause mania in a bipolar person, sexual dysfunction, GI distress

Contraindications: Concomitant use with MAOIs

Therapeutic considerations: First line agent in treatment, SSRIs are more selective than tricyclic antidepressants (TCAs) and have fewer adverse effects and a larger therapeutic index

Clinical application: Alzheimer's disease

Adverse effects: Hypertension, constipation, dizziness, headache

Contraindications: Hypersensitivity to memantine

Therapeutic considerations: Slows the rate of clinical progression of moderate to severe Alzheimer's disease

Clinical Applications: Refractory epilepsy (especailly partial and tonic-clonic seizures)

Adverse effects: Aplastic anemia, bone marrow depression, hepatic failure, Steven-Johnsons syndrome, photosensitivity, GI irritation, abnormal gait, dizziness

Contraindications: Blood dyscrasia and liver disease

Therapeutic considerations: Lacks the behavioral adverse effects of other NMDA antagonists; is an extremely potent antiepileptic drug and lacks sedative effects; is associated with fatal aplastic anemia and liver failure; its use is restricted to patients with refractory epilepsy

Clinical applications: Nausea

Adverse effects: Cardia arrhythmia, bronchospasm, increased liver enzyme, constipation, diarrhea, fatigue, headache

Contraindications: Hypersensitivity to ondansetron

Therapeutic considerations: Potent anti-emetic that is frequently used as an adjunct to cancer chemotherapy or in cases of refractory nausea

-Direct agonist at GABA-A receptors on alpha subunits

-Antagonist at AMPA glutamate receptors