Dr. Du’a Al-Zou’biDr. Du’a Al-Zou’biPharmacistPharmacist

Master degree in Master degree in pharmacologypharmacology

The symptoms of depression are feelings of sadness and hopelessness, as well as the inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts.

Mania is characterized by the opposite behavior: enthusiasm, anger, rapid thought and speech patterns, extreme self-confidence, and impaired judgment.

Major depression and dysthymia (minor): pure depression syndrome.

Bipolar disorder

Biochemicals are necessary for normal mental function◦ GABA◦ Acetylcholine (ACh)◦ Sodium, potassium, magnesium◦ Dopamine, norepinephrine, serotonin and

histamine

Is the treatment of mental disorders

Pharmacologic treatment.Non-pharmacologic treatment.

-Older generation: Tricycles. (imipramine, Clomipramine,

Amitriptyline). Tetracycles (Mirtazapine: Remeron) Monoamine oxidase inhibitors MAOIs -Newer generation: SSRIs (Citalopram, Escitalopram,

Fluoxetine, Paroxetine, Sertraline, Fluvoxamine)

SNRIs (Duloxetine, Venlafaxine)

The MAOIs are indicated for depressed patients who are unresponsive or allergic to TCAs and SSRIs or who experience strong anxiety.

These drugs are well absorbed after oral administration. Enzyme regeneration, when irreversibly inactivated, varies, but it usually occurs several weeks after termination of the drug.

a minimum of 2 weeks of delay must be allowed after termination of MAOI therapy and the initiation of another antidepressant from any other class

Considered second-line◦ For patients who fail with newer-generation

antidepressants◦ As adjunct therapy with newer-generation

antidepressants

Amitriptyline (Elavil, Endep) Doxepin (Sinequan) Imipramine (Tofranil) Chlomipramine. Desipramine (Norpramin) Nortriptyline (Aventyl, Pamelor)

Elevates mood and increase interest in social and daily relationships.

Improve mental alertness. Increase physical activity. Block alpha, histamine and M receptors.

Depression Childhood enuresis (imipramine) Obsessive-compulsive disorders

(clomipramine) Trigeminal neuralgic pain

TCAs are well absorbed upon oral administration. Because of theirlipophilic nature, they are widely distributed and readily penetrate into the CNS.

As a result of their variable first-pass metabolism in the liver, TCAs have low and inconsistent bioavailability.

These drugs are metabolized by the hepatic microsomal system (and, thus, may be sensitive to agents that induce or inhibit the CYP450 isoenzymes) and conjugated with glucuronic acid.

Ultimately, the TCAs are excreted as inactive metabolites via the kidney.

Blockade of muscarinic receptors leads to blurred vision, xerostomia (dry mouth), urinary retention, sinus tachycardia, constipation, and aggravation of angle-closure glaucoma

These agents affect cardiac conduction similarly to quinidine and may precipitate life-threatening arrhythmias in an overdose situation.

The TCAs also block α-adrenergic receptors, causing orthostatic hypotension, dizziness, and reflex tachycardia. Imipramine is the most likely, and nortriptyline the least likely, to cause orthostatic hypotension.

Sedation may be prominent, especially during the first several weeks of treatment (block histamine H1 receptors).

Weight gain is a common adverse effect of the TCAs.

The atypical antidepressants are a mixed group of agents that have actions at several different sites.

This group includes bupropion , mirtazapine, nefazodone, trazodone,vilazodone, and Vortioxetine.

Mirtazapine enhances serotonin and norepinephrine neurotransmission by serving as an antagonist at presynaptic α2 receptors.

Additionally, some of the antidepressant activity may be related to antagonism at 5-HT2 receptors.

It is sedating because of its potent antihistaminic activity, but it does not cause the antimuscarinic side effects of the TCAs, or interfere with sexual function like the SSRIs.

Fewer adverse effects than older

SSRIs◦ sertraline (Zoloft)◦ fluoxetine (Prozac)◦ citalopram (Celexa) ◦ escitalopram (Lexapro)◦ paroxetine (Paxil)◦ fluvoxamine (Luvox)

venlafaxine (Effexor)venlafaxine (Effexor) duloxetine (Cymbalta)duloxetine (Cymbalta)

All of the SSRIs are well absorbed after oral administration. Peak levels are seen in approximately 2 to 8 hours on average.

Food has little effect on absorption (except with sertraline, for which food increases its absorption).

The majority of SSRIs have plasma half-lives that range between 16 and 36 hours. Metabolism by cytochrome P450 (CYP450)–dependent

enzymes and glucuronide or sulfate conjugation occur extensively.

Fluoxetine differs from the other members of the class by having a much longer half-life (50 hours).

Depression (main use) Bipolar disorder Eating disorders Obsessive-compulsive disorder

Severe emotional disorder that impairs the mental function of the affected individual to the point that the individual cannot participate in activities of daily living

Hallmark: loss of contact with reality Primary types:

◦ Schizophrenia◦ Mania.◦ Bipolar disorder.

Schizophrenia is a type of chronic psychosis characterized by delusions, hallucinations (often in the form of voices), and thinking or speech disturbances.

The onset of illness is often during late adolescence or early adulthood. It occurs in about 1% of the population and is a chronic and disabling disorder.

Schizophrenia has a strong genetic component and probably reflects some fundamental biochemical abnormality, possibly a dysfunction of the mesolimbic or mesocortical dopaminergic neuronal pathways.

•• Hallucinations (distortions or exaggeration of perception)•• Most frequently auditory, can also be visual, olfactory, gustatory, and tactile.•• Can be voices or thoughts that feel distinct from the person’s mind.•• Voices may be threatening or commanding (eg, commanding the person to

perform a particular action).•• Delusions (fixed false beliefs)•• Beliefs despite invalidating evidence•• May be bizarre in nature•• Often paranoid in nature which may cause suspiciousness•• Thought disorder (illogical thought and speech)•• Loosening of associations•• Tangentiality•• Thought blocking•• Concreteness•• Circumstantiality•• Perseveration•• Thinking and speech may be incomprehensible and illogical

•• Impoverished speech and thinking •• Lack of social drive (avolition) •• Flatness of emotional expression •• Apathy •• May be primary or occur secondarily to medication side

effects, mood disorder, environmental understimulation, or demoralization

•• The best strategy for differentiating primary from secondary

negative symptoms is to observe for their persistence over time despite efforts at resolving the other causes

•• Attention •• Processing speed •• Verbal, visual memory, and working

memory •• Problem solving •• There is a loss of, on average, one

standard deviation of preillness IQ, with the average IQ between

80 and 84.

Mood stabilizers: lithium carbonate, antiepileptics

Antipsychotics: Older generation

Newer generation

Older generation: Phenothiazines (thioridazine,

trifluoperazine, chlorpromazine). Phenylbutylpiperidines (Haloperidol) Newer generation: Dibenzodiazepines (Clozapine,

Olanzapine, Quetiapine) Benzisoxazoles (Risperidone) Quinolinone (Aripiprazole)

Most are readily but incompletely absorbed. Many of these drugs undergo first pass

effect. Most are lipid soluble. Protein binding (92-99)% Volume of distribution more than 7L/Kg

since sequestered in lipid compartments of the body.

Most are completely metabolized.

Some matabolites are active but parent drug is more potent except for thioridazone’s metabolite is more active than the parent.

Very little parent of drugs excreted unchanged.

Five dopaminergic systems or pathways are important for understanding schizophrenia and the mechanism of action of antipsychotic

drugs. The first pathway—the one most closely

related to behavior and psychosis—is the mesolimbic-mesocortical pathway, which projects from cell bodies in the ventral tegmentum in separate bundles of axons to the limbic system and neocortex.

The second system—the nigrostriatal pathway—consists of neurons that project from the substantia nigra to the dorsal striatum, which includes the caudate and putamen; it is involved in the coordination of voluntary movement.

Blockade of the D 2 receptors in the nigrostriatal pathway is responsible for EPS.

third pathway—the tuberoinfundibular system—arises in the arcuate nuclei and periventricular neurons and releases dopamine into the pituitary portal circulation.

Dopamine released by these neurons physiologically inhibits prolactin secretion from the anterior pituitary

. The fourth dopaminergic system— the medullary-periventricular pathway—consists of neurons in the motor nucleus of the vagus whose projections are not well defined.

This system may be involved in eating behavior. The

fifth pathway—the incertohypothalamic pathway—forms connections from the medial zona incerta to the hypothalamus and the amygdala. It appears to regulate the anticipatory motivational phase of copulatory behavior in rats.

Receptrs blocker by antipsychotics: dopamine, serotonine, alpha, muscarine

and histamine.

Antipsychotic effects Extrapyramidal effects. Increased prolactine release. Anttiemetic effect. Antimuscarinic effect. Orthostatic hypotension. Alter tempretureregulatory

mechanism. Antipruritic effects.

Treatment of serious mental illnesses◦ Bipolar affective disorder◦ Depressive and drug-induced psychoses◦ Schizophrenia◦ Autism

Nausea and vomiting

Neuroleptic malignant syndrome (NMS)◦ Potentially life threatening◦ High fever, unstable BP, myoglobinemia

Extrapyramidal symptoms (EPS)◦ Involuntary muscle symptoms similar to those of

Parkinson’s disease◦ Treatment necessitates discontinuation of the

antipsychotic agent and supportive therapy. Administration of dantrolene or bromocriptine may be helpful.

Tardive dyskinesia:◦ Patients display involuntary movements, including

bilateral and facial jaw movements and “fly-catching” motions of the tongue.

Drowsiness Confusion sometimes results. Those antipsychotic agents with potent

antimuscarinic activity often produce dry mouth, urinary retention, constipation, and loss of visual accommodation.

Others may block α-adrenergic receptors, resulting in lowered blood pressure and orthostatic hypotension.

The antipsychotics depress the hypothalamus

Significant weight gain Some antipsychotics have been associated

with mild to significant QT prolongation.

Lithium salts are used acutely and prophylactically for managing bipolar patients.

Lithium is effective in treating 60% to 80% of patients exhibiting mania and hypomania. Although many cellular processes are altered by treatment with lithium salts, the mode of action is unknown.

The therapeutic index of lithium is extremely low, and lithium salts can be toxic.

Common adverse effects may include headache, dry mouth, polydipsia, polyuria, polyphagia, GI distress (give lithium with food), fine hand tremor, dizziness, fatigue, dermatologic reactions, and sedation.

Adverse effects due to higher plasma levels may indicate toxicity and include ataxia, slurred speech, coarse tremors, confusion, and convulsions.

Thyroid function may be decreased and should be monitored.

Unlike other mood stabilizers, lithium is renally eliminated,

It may be the best choice in patients with hepatic impairment.

The antiepileptics: Valproic acid. Lamotrigine. Oxcarbazepine. Topiramate. They are commonly preferred to lithium.???

Other evidence has shown that the older antipsychotic drugs:

Risperidone. Olanzapine, can also be effective in treating mania and

hypomania.

Provide simple explanations about the drug.

Advise patients to avoid abrupt withdrawal

Advise patients to change positions slowly to avoid postural hypotension and possible injury

The combination of drug therapy and psychotherapy is emphasized because patients need to learn and acquire more effective coping skills

Only small amounts of medications should be dispensed at a time to minimize the risk of suicide attempts

Antidepressants◦ Inform patients that it may take several weeks

to see therapeutic effects◦ Monitor patients closely during this time,

assess for suicidal tendencies, and provide support

◦ Assist elderly or weakened patients with ambulation and other activities because falls may occur because of drowsiness or postural hypotension

Antidepressants (cont’d)◦ Tricyclics may need to be weaned and

discontinued before undergoing surgery to avoid interactions with anesthetic drugs

◦ Monitor for adverse effects, and discuss with patients

◦ Encourage patients to wear medication ID badges naming the drugs being taken

Antidepressants (cont’d)◦ Caffeine and cigarette smoking may decrease

effectiveness of medication therapy

Antipsychotics ◦ Instruct patients to wear sunscreen because of

photosensitivity◦ Tell patients to avoid taking antacids or

antidiarrheal preparations within 1 hour of a dose

◦ Inform patients to avoid alcohol or other CNS depressants with these medications

Antipsychotics Long-term haloperidol therapy may result

in tremors, nausea, vomiting, or uncontrollable shaking of small muscle groups; report these symptoms to the physician