Chapter 13 and 14

Atypical drugs for therapy

Preferred therapy for schizophrenia and psychosis

Antipsychotic drugs

Primarily antagonize both D2 and 5HT2A

Antianxiety effect

When anxiety becomes excessive and contributes to neurotic behavior benzodiazepines are prescribed to decrease activity of limbic system. Anxious individuals usually calm down are less emotional and are in better mental state to deal with the situations that cause the anxiety

Benzodiazepines anxiety drugs

Used as sedatives, hypnotics, anticonvulsants, and skeletal muscle relaxants

Contraindicated

Used with caution in idividuals with glaucoma, prostate hypertrophy, urinary and intestinal obstruction.

Haloperidol

Useful in the treatment of highly agitated and manic patients. Suppress manic tics and vocalizations that characterize Gilles de la Tourettes Syndrome. Produce the highest incidence of EPS. Potential to develop tardive dyskinesia and neuroleptic malignant syndrome

Drugs that block reuptake of both serotonin and norepinephrine

Venlafaxine (effexor), desvenlafaxine (Pritiq) and Duloxetine (Cymbalta)

Exogenous or reactive depression

Depression caused by external factors or life event. Usually a period of shock and depression followed by a period of readjustment and a resolve that life must go on. Self limiting and doesnt require drug therapy.

Major Depressive Disorder (MDD)

Depression that arises from within an individual and requires psychotherapy and drug treatment.

Flumazenil (Romazicon)

A benzodiazepine receptor antagonist that may be administered intravenously to reverse the depressant effects of the benzodiazepine drugs. Used in the management of benzodiazepine overdose to antagonize the effects of excessive CNS and respiratory depression.

Psychosis

A mental condition characterize by disturbed thought processes, delusions, and hallucinations.

Mental Illness

A number of emotional and mental disturbances that involve abnormal changes in personality and behavior.

Anxiety

A state of anxiousness and hyperemotionalism that occurs with uncertainty, stress, and fearful situations. Classified: General Anxiety Disorder (GAD), panic disorder, OCD, and PTSD. Also activates he sympathetic nervous system and the reticular activating system, which in turn causes hyperarousal of the cerebral cortex.

Discontinuation Syndrome of SSRI

Discontinuation of SSRI treatment. Symptoms include dizziness, nausea, insomnia, and anxiety.

Psychomotor stimulants

Generally amphetamines or amphetamine like drugs that produce generalized CNS stimulation usually increased wakefulness and alertness. Not true antidepressants

Types of Dopamine (DA) receptors

Identified as D1-D5

4 areas of CNS where benzodiazepines exert inhibitory effects

Limbic system, reticular formation, cerebral cortex, spinal cord

Dystonic Reaction

Reaction characterized by muscle spasms, twitching, facial grimacing, or torticollis.

Anxiety

The perceived dangers may be real or due to personal insecurities of unconscious psychological conflicts

Tricyclic Antidepressants

Treating GAD, panic disorder, and OCD

Selective Serotonin Reuptake Inhibitors

are antidepressant drugs. Treatment of OCD and PTSD

Tricyclics Alpha blocking actions

cause postural hypotension, blurred vision, drowsiness

Drug Allergy

complication of phenothiazine therapy. symptoms involve skin rashes and photosensitivity, blood disorders and liver toxicity (cholestatic jaundice). Can include skin pigmentation, ocular deposits (lens and cornea) and endocrine disturbances

SSRI overdose symptoms

confusion, fever, tremor agitation, restlessness, seizures. Symptoms referred to as "serotonin syndrome."

Alpha blocking actions

may reduce blood pressure and cause postural hypotension

Tricyclics

stimulate cns and may produce restlessness, tremors, convulsions, or mania

Sertraline

Also fluoxetine are approved for premenstraula dysphroic disorder where mood disturbances occur in relation to the menstrual cycle

Lithium

An element similar to sodium that is used in the treatment of mania and bipolar mood disorder. Mood stabilizer

Mental depression

Deficiencies of norepinephrine (NE) and serotonin (5HT) in the brain are involved in the cause. Drugs that increase levels of NE and 5HT are used to treat this.

Midazolam (Versed)

An injectible benzodiazepine anesthetic often used for induction of general anesthesia or for short medical procedures like endoscopy where the state of "conscious sedation" is desired

Buspirone (BuSpar)

Antianxiety drug. Does not demonstrate useful sedative, hypnotic, anticonvulsant or skeletal muscle relaxant actions. Adverse effects: dizziness, lightheadedness, rash, tiredness. Category B drug

Stopping Convulsions

Diazepam (Valium) Lorazepam (Ativan) Clonazepam (Klonopin) are benzodiazepines considered to be drugs of choice in stopping convulsions. IM or IV injection

Short Acting Benzodiazepines

Half lives that range from 5 to 20 hours. Either they do not form active metabolites or if they do the active metabolites do not contribute significantly to the pharmacological effect. Include Alprazolam (Xanax) or Lorazepam (Ativan)

5HT2A

Antipsychotic effects

Limbic System

(Amygdala, hippocampus, hypothalamus, lower parts of cerebral cortex) are interconnected by neural pathway. Involved with emotional and behavioral responses associated with reward, punishment, anger, fear, anxiety.

Alpha Blocking Activity

(blocks alpha effects of norepinephrine and epinephrine) produces lowering of blood pressure. People taking alpha blockers for hypertension or taking other antihypertensive medication mayy experience hypotension, orthostatis hypotension, fainting

Antidepressants

(or mood elevators) drugs that can increase the level of norepinephrine or serotonin in the brain are useful in the treatment of mental depression

Gamma-aminobutyric acid (GABA)

Inhibitory neurotransmitter that functions to keep our emotions and behaviors under control

Effect of Phenothiazines

Main effects to reduce bizarre behavior, hallucinations, and irrationall thought disorders of psychosis without significantly depressing other intellectual functions

Desvenlafaxine (Pritiq)

Active metabolite of venlafaxine and has similar properties

Benzodiazepines administration

Administered orally and absorbed from the GI tract.

Atypical antipsychotic drugs

Affect and reduce the activity of 5HT2A receptors more than they interfere with D2 Receptors and associated with lower incidence EPS. Weight gain, elevated triglycerides (hyperlipidemia) and development of diabetes mellitus

Phenothiazine

Basic chemical structure of a large number of drugs similar in structure and pharmacological action. Possess anticholinergic, antihistaminic, alpha adrenergic blocking and antiemetic effects. Used for the treatment of nausea, vomiting, pruritus and allergic reactions. Administered orally (PO) and parenterallyy (IM and IV)

Benzodiazepine drugs

Bind to neuronal membranes at receptor sites (called benzodiazepine receptors) that are part of Gaba receptors. When both are bound to their receptors, more chloride ions pass into the neuron than when only gaba is bound alone

Serotonin (5HT)

Brain neurotransmitter involved in psychotic behavior.

Haldol

Butyrophenones are high potency drugs that differ chemically from the phenothiazines but produce the same type of antipsychotic effects

Duloxetine (Cymbalta)

Causes low incidence of CNS activation

Akathisia

Continuous body movement in which an individual is restless or constantly paces out

Anticholinergic Drugs (Atropine Like)

Decrease the activity of urinary and intestinal tracts and increase cardiac activity. Cause CN depression and mental disturbance. Also contraindicated

Parkinsonism

Disease or drug induced condition characterized by muscular rigidity, tremors, and disturbances of movement.

Basal Ganglia

Dopamine functions as a neurotransmitter in this part of the brain. Important for the regulation of skeletal muscle tone and movement. Blockade of dopamine receptors may increase prolactin levels which can cause menstrual irregularies in women and gynecomastia in males. Blockade of DA receptors in this can cause movement disorders referred to as EPS.

Tardive Dyskinesia

Drug induced involuntary movements of the lips, jaw, tongue, and extremities

Antianxiety Drug

Drug used to treat anxiety; these drugs are also referred to as anxiolytics.

Tricyclics Anticholinergic Effects

Dry mouth, constipation, urinary retention, and rapid heartbeat.

Antipsychotic effects: adverse effects

Dry mouth, constipation, visual disturbances, and sedation are due to anticholinergic and antihistaminic actions

Monoamine Oxidase (MAO)

Enzyme that inactivates norepinephrine and serotonin. Found in most body cells but in the adrenergic and serotonergic nerve endings. Break down norepinephrine and serotonin into metabolites that are then excreted by the kidneys. Prevents the buildup of excessive levels of norepinephrine and serotonin in the brain

Psychotic behavior

Excessive activity of certain brain neurotransmitters, especially dopamine and serotonin, in the cerebral cortex and limbic system appear to be responsible for this.

Development of schizophrenia

Excessive activity of neurotransmitters in the cortical and limbic pathways is involved in the development of this.

Administered Parenterally: Benzodiazepines

Exert an anticonvulsant effect on the cerebral cortex and are effective in stopping convulsions

Thioxanthenes

Exert antipsychotic effects by blocking D2 receptors more than 5HT2A. Most important is thiothixene (Navane)

Fluoxetine

First SSRI to be introduced. Oral administration. Metabolized in liver into an active metabolite that has a half life that ranges from several days to a week or more. Inhibitor of the metabolism of other drugs like anticoagulants and benzodiazepines.

FDA

Has issued a warning that all antidepressant drugs increase the risk of suicidal ideation

Long Acting Benzodiazepines

Have half lives of more than 20 hours . Form active metabolites. Include Diazepam (Valium) and Chlordiazepoxide (Librium)

Olanzapine (Zyproxa)

High potency associated with low incidence of EPS. Adverse effects: dizziness, sedation, weight gain, postural hypotension

Thiothixene

High potency drug that is associated with higher incidences of EPS. Causes less sedation and fewer anticholinergic and alpha blocking effects. Adverse Effects: include drowsiness and postural hypotension. May cause parkinsonian symptoms and other extrapyramidial disturbances of movement. Those who become allergic may develop dermatitis, obstructive jaundice,, or blood disorders (anemia and leukopenia)

Risperidone (Risperdal)

High potency that antagonizes 5HT2A more than D2 receptors. Mildly sedating and produces a low incidence of EPS. Postural hypotension and some weight gain may also occur. IM injection

Major Antidepressant drug classes

Include the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)

Mechanism of action of Antipsychotic drugs

Involves the ability of these drugs to block a specific DA receptor, the D2 receptor. This reduces dopamine activity by preventing dopamine from binding to and activating its receptors

Schizophrenia

Major form of psychosis; behavior is inappropriate. Symptoms include bizarre behavior, auditory and visual hallucinations, lack of motivation and emotional expression, diminished speech and thought processes. Cause: involves genetic defects that cause abnormal and neural development

Depression

Mental state characterized by depressed mood, with feelings of frustration and hopelessness. Decreased appetite and difficulty in sleeping also signs. Depressed individuals appear unable to cope with the demands of stresses of living. Thoughts of suicide.

Mania

Mental state of excitement, hyperactivity, and excessive elevation of mood Individuals who experience these alternating cycles of depression and mania are classified as manic depressive. Or Bipolar. High levels of norepinephrine and or serotonin may be involved

Venlafaxine (Effexor)

Moderately activating and has adverse effects similar to SSRIs. Increases in diastolic blood pressure are evident at higher doses

MAOIs

Monoamine oxidase inhibitors antidepressant drugs that inhibit MAO. Decrease the amounts of norepinephrine and serotonin that are destroyed. Permit both in the brain to increase.

Bipolar mood disorder

Mood disorder where episodes of mania and depression occur alternatively

Butyrophenones

More potent than phenothiazines. Block D2 receptors more than 5HT2A receptors. Produce a lower incidence of peripheral effects (alpha adrenergic blockade, anticholingeric, and antihistaminic) but greater movement disturbances.

Benzodiazepines.

Most important antianxiety drug. Diazepam (Valium) and chlordiazepoxide (librium) were first introduced and available over 50 years. Marked as hypnotics. Decrease the excitability and the functional activity of specific areas of the brain and the spinal cord

Extrapyramidal Syndrome (EPS)

Movement disorders such as akathisia, dystonia, and parkinsonism caused by antipsychotic drug therapy

SSRI adverse effects

Nausea, diarrhea, dry mouth, anorexia, sexual dysfuunction, reduced sexual interest and delayed orgasm. CNS effects: headache, nervousness, insomnia, tremors, weight gain.

Hyperpolarization

Negatively charged. This of neurons reduces neuronal excitability and consequently produce a depressant effect on those neurons

Serotonin

Neurotransmitter in the brain involved in regulation of anxiety

Aripiprazole

Newer atypical drugs. Main action is antagonism of both D2 and 5HT2A receptors. High potency drug associated with low incidences of sedation, EPS, and autonomic and metabolic disturbances. Side Effects: dizziness, headache, constipation, anxiety, sleep disturbances. Decrease sweating and cause increased body temp and fever especially during physical exertion

Site of Action of Antipsychotic Drugs

On neural pathways involving the cerebral cortex and limbic system.

Limbic System

Plays a major role in the regulation and control of emotions. In stressful and uncertain situations, the activity of the this system dramatically increases.

Fluvoxamine

Produces a sedating effect

Clozapine (Clozaril)

Provides moderate antipsychotic potency with low incidence of EPS. Higher incidences of sedation, seizures, weight gain, and agranulocytosis. Latter effect a decrease in white blood cells (WBCs)

Chlorpromazine

Revolutionized the treatment of mental illness

SSRIs

Selective serotonin reuptake inhibitors a class of antidepressant drugs. Block the reuptake of serotonin (5HT) back into the serotonergic nerve endings. Increases concentration of 5HT in synaptic cleft increased stimulation of serotonin receptors. Preferred therapy for treatment of major depression. Treatment of PTSD and OCD

SNRIs

Serotonin norepinephrine reuptake inhibitors class of antidepressant drugs. Block reuptake of serotonin and block reuptake of norepinephrine to increase the levels of both serotonin and nonrepinephrine. Treatment of general anxiety, chronic pain disorders, fibromyalgia

Four classes of antipsychotic Drugs

The Phenothiazine, butyrophenone, and thioxanthine drugs are referred to as typical because they all primarily block D2 receptors. Produce higher incidence of EPS because they block dopamine. Remaining drug class is referred to as atypical antipsychotic drugs. They reduce serotonin activity more than they reduce the activity of dopamine and lower incidence of EPS

Drugs to treat anxiety

The benzodiazepines and buspirone (antianxiety drugs)

Monoamine Theory of Mental Depression

Theory that mental depression is caused by low levels of norepinephrine and serotonin (monoamines)

Neuroleptic Malignant Syndrome (NMS)

Toxic syndrome associated with the use of antipsychotic drugs. Characterized by muscular rigidity, catatonia (patient appears frozen in position) and autonomic nervous system instability.

Duration of action: Benzodiazepines

Two groups: long acting and short acting

Relaxation of Skeletal muscle

Treating back injuries, spinal cord injuries, muscular dystrophy, and cerebral palsy.

Physiologic and behavioral changes

Trembling, sweating, nausea, loss of appetite, rapid heartbeat, emotionalism are caused by activation of the limbic and sympathetic nervous systems.

TCAs

Tricyclic antidepressants a class of antidepressant drugs. Triple ring structure. Main action: block reuptake of norepinephrine and serotonin back into the neuronal nerve endings. Accumulation of these neurotransmitters in the synaptic clefts. Increases level of neuronal activity of norepinephrine and serotonin and alleviates the symptoms and dysfunctions of depression

Amphetamines (& CNS stimulants)

increase activity of the reticular formation which cause increased wakefulness and hyperactivity.

Cimetidine (Tagamet)

inhibits the microsomal drug metabolizing enzymes and has been shown to inhibit the metabolism of diazepam and other benzodiazepines.

Tertiary amines

three substitutions on the nitrogen. increase brain levels of serotonin more than norepinephrine. More sedation than secondary amines.

Secondary amines

two substitutions on the nitrogen. Mainly increase brain levels of norepinephrine more than serotonin