Central Nervous System Somaya Nasser Aysha Abu Hussein Wafa Atta Aseel Nasser Aya Injas

Antidepressant

What is depression ?? Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. Also called major depressive disorder or clinical depression, it affects how you feel, think and behave and can lead to a variety of emotional and physical problems.

Theories of Depression

• Researchers do not know exactly how or why the process of neurotransmission is altered in depression, but decades of research have implicated two key monoamine neurotransmitters, noradrenaline and serotonin.

• The Biogenic Amine Hypothesis states that depression is caused by a deficiency of monoamines, particularly noradrenaline and serotonin

• According to this hypothesis, depression can be alleviated by drugs that increase the availability of noradrenaline and serotonin.

• There are other theories like The Serotonin-only Hypothesis, The Permissive Hypothesis , The Electrolyte Membrane Hypothesis and The Neuroendocrine Hypothesis.

Symptoms of depression • Intense feelings of sadness • hopelessness and despair• Inability to experience pleasure in pleasurable activities• Change in sleep patterns• Suicidal thoughts

نفسيا تعبان

Diagnoses and tests

• Depression symptoms present in most day for month . • Depression may be secondary to Organic problems like

hypothyroidism, dementia, anemia ,Psychiatric problems like schizophrenia, drug abuse, anxiety disorders , Use of depressants drugs such as alcohol .

• Tests help in rule out the problems that lead to depression Physical exam , Lab tests (test thyroid ) , Psychological evaluation , DSM-5 (Diagnostic and Statistical Manual of Mental Disorders ).

Treatment

• Psychotherapy talk therapy,” where you meet with a psychiatrist, psychologist, social worker, نفسيا تعبانة or other trained mental health professional. You will learn new ways to handle challenges and change ways of thinking that depression affects.

• Drugs (Antidepressants)

Antidepressant

• First-generation -Tricyclics antidepressants (TCAs) -Monoamine oxidase inhibitors (MAOIs) • Second-generation -Selective serotonin reuptake inhibitors (SSRIs) -Serotonin-norepinephrine reuptake inhibitors (SNRIs) • Atypical antidepressants

◦ Selective serotonin reuptake inhibitors (SSRIs)

• MOA : Antidepressant drugs that specifically inhibit serotonin reuptake so it block the reuptake of serotonin, increasing its concentrations in the synaptic cleft and its postsynaptic neuronal activity .

• Have largely replaced TCAs and MAOIs as the drugs of choice in treating depression

SSRI• Fluoxetine (Prozac® (lilly),

Fluoxicare®(pharmacare), Flutine®(teva), Prizma®(unipharm),)

• Citalopram (cipramil®(H.lundbeck), sitram® جاال (بيت

• Escitalopram (cipralex® (H.lundbeck))• Fluvoxamine (favoxil®(perrigo))• Paroxetine (seroxat ®(gsk),

paxxet®(unipharm))• Sertraline ( Lustral®(pfizer))

SSRI • Therapeutic uses • Depression • Obsessive Compulsive Disorder (OCD) • Panic disorder • Generalized Anxiety Disorder (GAD) • Post Traumatic Stress Disorder (PTSD) • Social anxiety disorder • Premenstrual dysphoric disorder • Bulimia nervosa (only fluoxetine is approved)

Adverse Effects

• Headache• Sweating• Anxiety and agitation • GI effects (nausea, vomiting, diarrhea) • Weakness and fatigue • Sexual dysfunction • Changes in weight • Sleep disturbances (insomnia or somnolence)

Paroxetine and fluvoxamine are more sedating Fluoxetine or sertraline are more activating SSRIs

Discontinuation syndrome:• All SSRIs have potential to cause discontinuation

syndrome after abrupt withdrawal ,Fluoxetine has the lowest risk of causing SSRI discontinuation

• Signs and symptoms of SSRI discontinuation syndrome , Headache, malaise, flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern

• Discontinuation syndrome can be prevented by taking medication as directed, and when discontinuing, doing so gradually.

Counseling • Patient must know that it take a few weeks before he feel the

positive effects of the medication (cause he may stop taking it if he feel that it dose not do anything …… Maximum benefit may require ≥12 weeks ) .

• do not stop the medication without counseling the doctor ( to prevent the Discontinuation syndrome) .

• Teenagers and children behavior must be watched (~ 2% children report suicidal ideation with SSRI) .

• The patient must know the side effects and he must communicate with the doctor if other side effects appeared (may be dangerous )

• The patient must asked if he take another medications to prevent any drugs interactions

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

• MOA : Inhibit the reuptake of both 5-HT and NE , Venlafaxine and desvenlavfaxine are potent inhibitor of 5-HT reuptake and, at medium to higher doses, is an inhibitor of NE reuptake

Duloxetine inhibit serotonin and norepinephrine reuptake at all doses. Uses • treating depression in patients where SSRIs are ineffective• Effective against chronic painful symptoms, such as

backache and muscle aches (This pain is modulated by 5-HT and NE pathways in the CNS)

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

• Duloxetine (Cymbalta®lilly) • Venlafaxine (viepax® dexcel, Effexor®

newpharm)• Desvenlafaxine • Levomilnacipran

Adverse effects • Side effects of venlafaxine and

desvenlafaxine , Nausea, headache, sedation, dizziness, insomnia Sexual dysfunction , Constipation

• Adverse effects of Duloxetine Nausea , Dry mouth , Constipation , Insomnia , Sexual dysfunction , Risk for an increase in either blood pressure or heart rate

Atypical antidepressants

Bupropion: Mechanism of action: weak dopamine nor-

epinephrine reuptake inhibitor.

Therapeutic use: smoking cessation, cocaine withdrawal and antidepressant.

Side effects: dry mouth, nervousness, tremors and seizures at high doses

Atypical antidepressants

Mirtazapine:

Mechanism of action: blocks α2 presynaptic receptors and serotonin receptors.

Therapeutic use: antidepressant.

Side effects: sedation, increased appetite and weight gain.

Atypical antidepressants

Nefazodone & Trazodone:

Mechanism of action: weak inhibitors of serotonin reuptake and serotonin receptor blockers.

Therapeutic use: antidepressants.

Side effects: sedation (H1 blockers), orthostatic hypotension, dizziness.

Nefazodone is hepatotoxic.

Tricyclic Antidepressants (TCAs)

• Imipramine• Clomipramine• Desipramine• Trimipramine• Amitriptyline• Maprotiline • Nortriptyline• Protriptyline• Amoxapine• Doxepin

Mechanism of action

• Inhibition of neurotransmitter reuptake : TCAs are potent inhibitors of the neuronal reuptake of norepinephrine and serotonin.

** Maprotiline and desipramine are relatively selective inhibitors of norepinephrine reuptake

• Blocking of receptors : TCAs also block α-adrenergic, histaminic, and muscarinic receptors causing many adverse effects

Actions

• Elevate mood.• Improve mental alertness.• Increase physical activity, and reduce morbid

preoccupation in 50-70% of individuals with major depression .

>> Slow withdrawal to minimize discontinuation syndromes and cholinergic rebound effects

Therapeutic uses • TCAs are effective in treating moderate to severe

depression .• TCAs particularly amitriptyline have been used to

help prevent migraine headache and treat chronic pain disorders .

• Low doses of TCAs (especially doxepin) can be used to treat insomnia

• Imipramine has been used to control bed-wetting in children (> 6 years) by causing contraction of the internal sphincter of the bladder

Adverse effects

• Blockade of muscarinic receptors causes blurred vision, xerostomia, urinary retention, sinus tachycardia, constipation.

• Block α-adrenergic receptors, causing orthostatic hypotension, dizziness, and reflex tachycardia .

• Blockade of H1 receptors leads to sedation. • Affect cardiac conduction which may precipitate life-

threatening arrhythmias in overdose• Weight gain• Sexual dysfunction

Monoamine Oxidase Inhibitors (MAOIs)

• Isocarboxazid• Phenelzine• Tranylcypromine• Selegiline

Mechanism of action

• MAOIs form stable complexes with MAO causing irreversible inactivation .

• This causes increased stores of norepinephrine, serotonin, and dopamine within the neuron and diffusion of excess neurotransmitter into the synaptic space .

• These drugs inhibit MAO not only in the brain but also in the liver and gut that catalyze oxidative deamination of drugs and potentially toxic substances .

** Selegiline and tranylcypromine have an amphetamine-like stimulant effect that may produce agitation or insomnia

Therapeutic uses • Indicated for depressed patients who are

unresponsive or allergic to TCAs or who experience strong anxiety.

• Treatment of a special subcategory of depression called atypical depression .

Adverse effects• Drowsiness• Orthostatic hypotension• Drug-food and drug-drug interactions : Individuals receiving a MAOI are unable to degrade

tyraminecausing the release of large amounts of stored catecholamines from nerve terminals, resulting in “hypertensive crisis”

• Phentolamine and prazosinare helpful in the management of tyramine-induced hypertension

Psychosis

Psychosis

• Psychosis: a mental disorder caused by brain • dysfunction

• Schizophrenia : • Type of psychosis characterized by:• Delusions• Hallucinations (often in the form of voices)• Thinking or speech disturbances

Diagnosis of psychosis: At least two of the characteristic symptoms:

Grossly disorganized behaviorNegative symptoms (blunted affect, anhedonia, apathy, social isolation, poor

hygiene, poor memory, impaired attention and poor cognition)Deterioration in functionDuration at least 6 months

Antipsychotic drugs

Affect dopamine by blocking dopamine receptors.

*First generation antipsychotics ◦low potency◦high potency

*Second generation antipsychotics

Antipsychotic drugs

*Many of these agents also block cholinergic, adrenergic, and histaminergic receptors causing adverse effects

1. Antipsychotic actions2. Extrapyramidal effects3. Antiemetic effects4. Anticholinergic effects5. Other effects

First generation antipsychotic: *Low potency◦Chlorpromazine: has anticholinargic effect,

antihistamine(sedation) ◦Prochlorperazine: has antiemetic effect ◦Thioridazine: has anticholinergic effect

*High potency◦Haloperidol: has antiemetic effect◦Fluphenazine◦Pimozide◦Thiothixene◦Loxapine◦Trifulperazine

First generation antipsychotic:

*Competitive blockers of D2 receptors

*Associated with movement disorders, especially the ones with stronger binding to dopamine receptors

Second generation antipsychotic:

*Risperidone*Olanzapine: has anticholinergic,antihistamine effect

*Quetiapine: has anti histamine effect

*Clozapine: has anticholinergic,antihistamine effect##s.e: Bone marrow suppression,

Seizures,Cardiovascular side effects

*Aripiprazole

Second generation antipsychotic:

*block both dopamine and serotonin receptor.*fewer EPS than first generation *min. risk of deblitating movement disorder

than first generation*Associated with a higher risk of metabolic side effects like diabetes, hypercholesterolemia and weight gain

Side effect:1.Extrapyramidal side effects2.Tardive dyskinesia3.Antipsychotic malignant syndrome4.Drowsiness occurs due to CNS depression and antihistaminic effects5.Antimuscarinic activity produces dry mouth, urinary retention,

constipation6.Blocking α-adrenergic receptors results in orthostatic hypotension7.The antipsychotics depress the hypothalamus, affecting

thermoregulation and causing amenorrhea, galactorrhea, gynecomastia, infertility, and impotence

8. Weight gain 9. Hyperglycemia and hypercholesterolemia (second generation

atipsychotics)

Opioids

Opioids are the drug of choice for sever or chronic pain.

Mechanism of action:They work by binding to opioid μ receptors,

thus relieving pain.

Opioids are divided into:

Strong agonists.

Moderate/low agonists.

Mixed agonist-antagonists & partial agonists.

Strong agonists -Morphine-Meperidine-Methadone-Fentanyl-Heroin -Others.

Morphine:

Mechanism of action: Next to acting as μ receptor agonist, they also act at κ receptors, and decreases the release of substances P and thus modulating pain perception.

Therapeutic effects: Analgesic and antitussive.

Side effects: respiratory depression, hypotension, vomiting, tolerance and physical dependence.

Meperidine:

Mechanism of action: strong μ receptor agonist.

Therapeutic use: analgesic for acute pain.

Adverse effects: respiratory depression, (anxiety, tremors, muscle twitches upon repeated administration).

Methadone:

Mechanism of action: μ receptor agonist.

Therapeutic use: analgesia, controlling withdrawal symptoms of morphine and heroin.

Causes less euphoria and dependence than morphine.

Fentanyl:

Mechanism of action: μ receptor agonist.

Therapeutic uses: anesthesia induction, labor and post operative analgesic.

Side effects: hypoventilation.**Has a hundred fold the analgesic potency of

morphine.

Heroin: Synthetic derivative of morphine.It is three times more potent than

morphine, and causes more euphoria.

*** It has NO medical use.

Others:

Oxycodone.

Oxymorphone.

Hydromorphone.

Hydrocodone.

Equivalency between opioids

How would it differ if we used parenteral or oral dosage forms of the same opioid?

Dose equianalgesic to 10 ml parenteral morphine.

Parenteral dose (ml) Oral dose (ml) Opioid

10 30 Morphine

75 300 Meperidine 10 3-5 Methadone***0.1-0.2 N/A Fentanyl 1 N/A Oxymorphone 1.5 7.5 Hydromorphone N/A 30 Hydrocodone N/A 20 Oxycodone

https://palliative.stanford.edu/opioid-conversion/equivalency-table/

Moderate/low agonist

• Codeine

Good antitussive activity at doses that do not cause analgesia Metabolized to morphine in the body by CYP2D6 causing analgesic

effects (30% that of morphine) Causes euphoria Lower abuse potential than morphine at commonly used doses• *** BRONCHOLOTE FORTE SYRUP (pseudoephedrine HCl

20mg,diphenydramine 10mg,codeine 5mg ):for cough accomanied py nasal or auditory congestion.

• *** PULMADRIN (triprolidine HCl 1.25mg, pseudoephedrine HCl 30mg , codeine 10mg ): antihistamine decogestant and antitussive

• ***NUROFEN PLUS(ibuprofen 200mg,codeine 10mg) :migraine ,headache,dental paine ,backage and muscular paine,manstrual, rheumtic paine.

Mix agonist –antagonist & and partial agonist

Drugs that stimulate one receptor but block another . The effects of these drugs depend on previous exposure to

opioids :

In individuals who have not recently received opioids (naïve patients), mixed agonist-antagonists show agonist activity and are used to relieve pain

In patient with opioid dependence, the agonist-antagonist drugs may show primarily blocking effects and produce withdrawal symptoms

Pentazocine • Mechanism of action: Acts as an agonist on κ receptors and a weak

antagonist at μ and δ receptors .• Therapeutic effects : promotes analgesia by activating receptors in

the spinal cord, and it is used to relieve moderate pain • Side effects: Produces less euphoria than morphine In angina, pentazocine increases the mean aortic pressure and

pulmonary arterial pressure increasing the work of the heart .Tolerance and dependence develop on repeated use

• At higher doses :respiratory depression,increase blood pressure and can cause

hallucinations, nightmares, dysphoria, tachycardia, and dizziness

Burenorphine

• Mechanism of action: Partial μ receptor agonist. has less severe and shorter duration of withdrawal symptoms compared to methadone Has a long duration of action because of its tight binding to the μ receptor

• Therapeutic effects: opiate detoxification

• Side effects:Respiratory depression that cannot easily be reversed by naloxone ,Nausea ,Dizziness

Opioid antagonists

opioid antagonists

Bind with high affinity to opioid receptors but fail to activate the receptor-mediated response

Administration of opioid antagonists produces no profound effects in normal individuals

In patients dependent on opioids, antagonists rapidly reverse the effect of agonists, such as morphine or any full μ-agonist causing symptom of opiate withdrawal

Naloxone

Mechanism of action : . a competitive antagonist at μ, κ, and δ, receptors rapidly displaces all receptor-bound opioid molecules reversing their effects.

Therapeutic effects :Used to reverse the coma and respiratory depression of opioid overdose

Within 30 seconds of IV injection of naloxone the respiratory depression and coma characteristic of high doses of morphine are reversed causing the patient to be revived and alert

Short half life (30-80 min) Can cause withdrawal symptoms in opioid abusers

Naltrexone

Similar effects to naloxone with a longer duration of action A single oral dose can block Heroin effects for up to 48 hours Can cause hepatotoxicity

Other analgesics

Tramadol Mechanism of action: μ-opioid receptor ,Weakly inhibits reuptake of

norepinephrine and serotonin . Therapeutic effects :Centrally acting analgesic Used to manage

moderate to moderately severe pain .• Adverse effects : Less respiratory depression than morphine . Anaphylactoid reactions. Toxicity through drug-drug interactions with medications, such as

SSRIs and TCAs or in overdose leads to CNS excitation and seizures .

Contrindication :Tramadol should be avoided in patients taking MAOIs .

*** Zaldiar (tramadol hydrochloride and paracetamol )*** Tramal (tramadol hydrochloride )

Tapentadol Mechanism of action :binds the μ-opioid receptor and is also a

norepinephrine reuptake inhibitor Therapeutic effects: Centrally acting analgesic that Used to manage

moderate to severe pain