Dopaminergic neural pathways
y Nigrostriatal tractSubstantia nigra striatum y Mesolimbic and mesocortical tractsMidbrain limbic and cerebrocortical structures y Tuberoinfundibular pathway- hypothalamus anterior pituitary y Chemoreceptor trigger zone- activation of DA receptors

Dopaminergic actions in brain

y DA agonists nausea and vomiting y DA antagonists antiemetics y Hyperprolactinemia causes amenorrhea, galactorrhea, infertility,


y Psychoses- serious distortion of thought, behavior, capacity to

recognize reality and of perception (hallucinations, delusions) y Schizophrenia
Positive symptoms- hallucinations, delusions, thought dysfunction (due to excess dopamine in mesolimbic pathway) y Negative symptoms- social withdrawal, apathy (due to deficiency in dopamine in mesocortical pathway)

y Phenothiazines y Low potency- Chlorpromazine, thioridazine y High potency- fluphenazine y Butyrophenones- haloperidol (high potency) y Thioxanthenes- Thiothixene (high potency) y Others- pimozide, molindone, reserpine y Atypical antipsychotics- clozapine, olanzapine, risperidone

y Block D2 receptors to reduce positive symptoms of schizophrenia y Low potency drugs- CPZ, thioridazine y block D2 receptors with low affinity (worsen apathy, cause EPS side effects, hyperprolactinemia) y block M receptors (dry mouth, blurring of vision, block extrapyramidal system EPS effects, parkinsonism) y adrenergic blockade (postural hypotension, sexual dysfunction) y antihistaminic (sedation) y High potency drugs- Fluphenazine, thiothixene, haloperidol y Block D2 receptors stronglyEPS symptoms and hyperprolactinemia more severe y Autonomic dysfunction less as other receptors not blocked much

Adverse effects
y Behavioral- sedation, mental confusion (low potency drugs), y y y y y y y

pseudodepression Seizures- CPZ, clozapine adrenergic blockade- postural hypotension, sexual dysfunction (impaired ejaculation) with CPZ and thioridazine Anticholinergic- dry mouth, blurring of vision, urinary retention, constipation (thioridazine mainly, also CPZ) Hyperprolactinemia- amenorrhea, galactorrhea, infertility in women; loss of libido, impotence, infertility in men (high potency drugs) Retinal deposits and browning of cision- thioridazine. CPZ can cause deposits in corneal and lens. Hypersensitivity reactions- Skin rashes, photosensitivity, cholestatic jaundice- CPZ Thioridazine, pimozide prolong QT interval (quinidine-like effect) ventricular arrhythmias, sudden death

Adverse effects
y Extrapyramidal system adverse effects- (high potency drugs)

Parkinsonism- rigidity, tremor, bradykinesia, shuffling gait benztropine y Akathisia (uncontrollable restlessness) benztropine, diphenhydramine y Acute dystonias- grimacing, spastic retrocollis or torticollis, locked jaw botulinum toxin, benztropine, promethazine, pramipexole, y Tardive dyskinesia- late occurring, sometimes even after withdrawal of drug. May subside after months or years after withdrawal or may be lifelong.

y y

Involuntary facial movements tongue thrusting, lip smacking, lip pursing, grimacing and chewing Choreoathetoid movements of limbs Discontinue or reduce dose of neuroleptic, switch to atypical antipsychotic, reduce drugs with anticholinergic properties, Diazepam may be useful.

y Neuroleptic malignant syndrome- rare but can be fatal
y y

Marked muscle rigidity, immobility, fever, fluctuating BP and HR Neuroleptic stopped. Bromocriptine, diazepam/ dantrolene useful.

y Psychoses- schizophrenia, schizoaffective states like drug induced psychoses,

y y

y y y

delusions, psychosis with Alzheimer s disease, organic brain syndromes y Symptoms may take several weeks to respond to drug treatment. Parenteral formulations of high potency drugs in case of non-compliance y Positive symptoms (hallucinations, delusions, disorganized thought) improved y Negative symptoms might be worsened(apathy, social withdrawal). Atypical antipsychotics preferred to reduce negative symptoms and if EPS is severe. y CPZ good for controlling agitation, violent behavior Mania, bipolar disorder- i.m for rapid control. Lithium/ carbamazepine started, neuroleptic withdrawn gradually. Preanesthetic medication- promethazine acts through H1 receptors to produce sedation. CPZ can be given to potentiate anesthetics, to allay anxiety but not preferred. Anesthesia- droperidol + fentanyl Anti-emetic- drug or radiation induced emesis- prochlorperazine. Promethazine for motion sickness. Intractable hiccough, tetanus, tourette s syndrome

y D2 and 5-HT blockade, also weak muscarinic,

adrenergic and

H1blockade y extrapyramidal symptoms, tardive dyskinesia, Neuroleptic Malignant Syndrome rare . y Suppresses both positive and negative symptoms of schizophrenia due to D2 and 5HT2 blockade respectively. y All agents show varying degree of postural hypotension, weight gain y Clozapine- Agranulocutosis may be fatal, can cause seizures, sialorrhea. y Used in refractory schizophrenia, or if TD is present. y Risperidone- more incidence of EPS, hyperprolactinemia among atypical antipsychotics, TD lower risk y Olanzapine- glucose intolerance

y Reserpine, an antihypertensive depletes brain amines causes depression. y Actions of antidepressant drugs 5HT actions

increase NE and/or

y Amine hypothesis of depression- Depression may arise from deficiency in NE and/or 5HT y But, antidepressant shows effects in 2 weeks and optimal response in 4 weeks . Beneficial effects may be due to compensatory responses to initial increase in levels of biogenic amines. y Some drugs do not appear to have significant effects on brain amines.

y MAO inhibitors

Non-selective (MAO type A and B)phenelzine, tranylcypromine y Selective (MAO type A)moclobemide y Tricyclic antidepressants (TCAs)
y NE and 5-HT reuptake inhibitors-

imipramine, amitriptyline, clomipramine, doxepin y NE > 5HT reuptake inhibitorsdesipramine, nortriptyline, amoxapine

y Selective serotonin reuptake inhibitors

(SSRIs)- fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram y Heterocyclics/ Atypical antidepressants- bupropion, nefazodone, trazodone, mirtazapine, venlafaxine

MAO inhibitors
y Monoamine oxidase type A metabolizes NE & 5-HT, tyramine. Type B

metabolizes DA. y Non-selective- tranycypromine y Side effects- anticholinergic, orthostatic hypotension, impotence, weight gain y Overdose- agitation, confusion, hallucinations, mania y Interactionsy Cheese reaction- foods like cheese, beer etc contain tyramine not degraded large amounts of NE released not degraded hypertensive crisis y Hypertensive crises with L-DOPA, TCAs , reserpine, guanethidine y Pethidine, dextromethorphan- hyperthermia, HTN, seizures y Serotonin syndrome with SSRIs y Moclobemide- selective type A inhibitor, mild interactions, safer in overdose

Tricyclic antidepressants
y Extensive first pass metabolism in liver. Imipramine desipramine,

amitriptyline nortriptyline y Adverse effects y M block, block dry mouth, blurred vision, urinary retention, constipation, postural hypotension, tachycardia, sexual dysfunction y May induce mania/ hypomania in patints with bipolar disorder y Sedation, decrease seizure threshold, weight gain y Also cause quinidine-like effects cardiotoxicity, ventricular arrhythmias y Withdrawal syndrome- malaise, vertigo, muscle pain, nightmares. Gradual withdrawal recommended. y Usesy Major depressions, phobic and panic anxiety states y Obsessive-compulsive disorder (OCD)- specially clomipramine y Neuropathic pain, enuresis- imipramine y Other uses Migraine- amitriptyline, Pruritis- doxepin

TCAs- Drug interactions
y Hypertensive crisis, hyperthermia, coma, convulsions and death with MAOIs y Marked motor impairment with alcohol, additive sedation with other CNS depressants. y Prevent anti-HTN effect of guanethidine and clonidine. y Treatment of poisoningy Symptoms- autonomic side effects, muscle spasms,

excitement, delirium. Triad C- coma convulsions, cardiotoxicity (arrhythmias) y Physostigmine to reverse anticholinergic symptoms y Propranolol or lidocaine to treat arrhythmias y Diazepam to control convulsions, delirium

Selective serotonin reuptake inhibitors (SSRIs)
y Extensive metabolism in liver. Fluoxetine (t ½ - 2days)


(longer t ½ - 1 week). Once daily dosing possible. y Adverse effectsy Anxiety, insomnia (may need sedative) y Sweating, tremors, bruxism (grinding teeth) y Nausea, diarrhea, weight loss y sexual dysfunction (anorgasmia), seizures y Withdrawal syndrome - vertigo, malaise y Usesy Major depressions, anxiety states (panic, phobias, social) y Bulimia y OCD, and alcoholism.

y Drug interactions
y Serotonin syndrome includes muscle rigidity, myoclonus,

hyperthermia, ANS instability, mental changes and seizures. Has been reported for SSRIs when used with MAOIs, TCAs y Paroxetine, fluvoxamine, fluoxetine inhibit CYP 450 liver enzymes elevating plasma levels of opioids, beta-blockers calcium channel blockers, antifungals, alprazolam, oral contraceptives. Sertraline, citalopram have less propensity to inhibit liver enzymes. y Deaths due to overdose rare.

and generation drugs (Heterocyclics)
y Mechanism of action

nd 2

rd 3

Mirtazapine blocks presynaptic a2 receptors, preventing feedback inhibition of transmitter release. y Nefazodone and trazodone block 5HT reuptake, 5HT antagonists.

Venlafaxine enhances 5HT activity at low doses and NE at higher doses y Bupropion- NE/DA reuptake inhibitor

y Adverse Effects y Mirtazapine- sedation, weight gain y Trazodone, nefazodone- sedation, liver failure (nefazodone) y Venlafaxine- sedation, sexual dysfuncton, hypertension y Bupropion- nausea, insomnia, seizures, aggravation of psychoses, contraindicated in eating disorders.

Drug choice
y TCAs, venlafaxine- greater efficacy than SSRIs y SSRIs preferred over TCAs because tolerated better y Sedation greatest with amitriptyline, doxepin,

trazodone, mirtazapine y Autonomic side effects in amitriptyline, doxepin y Sexual dysfunction with SSRIs, venlafaxine y SSRIs safe in overdose, once daily dosing y Choice of drug depends on patient acceptance (toleration of side effects) y MAOI in atypical depression

y A mental illness characterized by mood instability y Also known as manic-depressive illness

manic behavior is one extreme and depression is the other. y Lithium is a mood stabilizer, drug of choice. May need as adjunts antidepressants to improve depression phase and sedative drugs initially during mania. y Slow onset (2 weeks), narrow therapeutic index y Back-up drugs- valproate, carbamazepine. In pregnancy- gabapentine, lamotrigine.

Mechanism of action
‡ Lithium inhibits

recycling of inositol to form PIP2.
‡ This second

messenger system is involved in ACh, NE, and 5HT receptors.
‡ Uncouples receptors

from G proteins eg renal V2 receptors of ADH (vasopressin) polyuria, TSH receptors hypothroidism

Adverse effects, Drug interactions
y Tremor, ataxia, choreoathetosis, motor incoordination, nystagmus-

y y y y y y

monitor serum levels (0.5-1.5 mEq/L). y Serum levels- 2 mEq/L toxicity y muscle twitchings, delirium, coma, convulsons y Hemodialysis, osmotic diuretics effective Acne, edema, visual dysfunction, seizures Hypothyroidism, goiter, inhibits Nephrogenic diabetes insipidus polydipsia, polyuria(responds to amiloride) Teratogenicity-fetal goiter, lethargy, cyanosis, and possible hepatomegaly in infant. Cardiac anomalies rare. Diuretics like thiazides cause compensatory reabsorption of Li+ due to similarity with Na+ lithium toxicity. Neuroleptics combined with Li+ can cause more EPS symptoms

Clinical problems
y A 38-year-old patient with paranoid schizophrenia is discovered by his

Department of Mental Health caseworker during a routine home visit lying in his bed with a temperature of 103 degrees. The patient is disoriented and so rigid the caseworker is unable to stand him up. Which of the following is the most likely cause of such a presentation? y a. An increase in the dose of haloperidol received three days earlier y b. Minor surgery two days earlier y c. Patient stopped taking his medications for two weeks y d. Patient has been drinking four to five beers every night y e. Patient has been in close contact with a a friend who has pneumococcal

Clinical problems
y A 45-year-old woman with a chronic mental illness seems to be constantly

chewing. Her tongue darts in and out of her mouth and occasionally she smacks her lips. She also grimaces, frowns, and blinks excessively. y These abnormal movements are seen, characteristically, in y a. Tourette s syndrome y b. Akathisia y c. Tardive dyskinesia y d. Parkinson s disease y e. Wilson s disease y What medication has she received for the past 25 years? y a. Diazepam y b. Phenobarbital
y c. Clozapine y d. Perphenazine y e. Amitriptyline

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