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ANTI MANIC DUGS

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PHARMACOLOGY OF ANTIMANIC DRUGS ASADULLAH R.Ph, CRCP 2012-MPHIL-1795
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Page 1: ANTI MANIC DUGS

PHARMACOLOGY OF ANTIMANIC DRUGS

ASADULLAH R.Ph, CRCP

2012-MPHIL-1795

Page 2: ANTI MANIC DUGS

Mania Madness, frenzy “A Phase of Bipolar disorders characterized by

expansiveness, elation, agitation, hyper excitability, hyperactivity, and increased speed of thought or speech(flight of ideas)”.

A mood disorder, In a senses opposite to depression. “A period of seven or more days of unusually

and continuously effusive and open elated or irritable mood, where the mood is not caused by drugs/medication or a medical illness and

(a) is causing obvious difficulties at work or in social relationships and activities, or

(b) requires admission to hospital to protect the person or others, or

(c) the person is suffering psychosis.”

Page 3: ANTI MANIC DUGS

Bipolar disorder Bipolar disorder, or manic-depressive

illness (MDI), is one of the most common, severe, and persistent mental illnesses. Bipolar disorder is a serious lifelong struggle and challenge.

Bipolar disorder is characterized by periods of deep, prolonged, and profound depression that alternate with periods of an excessively elevated or irritable mood known as mania.

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BPI

classic manic-depression

Psychosis, Severely impaired function

BPIIdepression

alternating with periods of hypomania

Less Psychoactive

but more depressive

phase

Unipolar major depressive disorder and bipolar disorder share depressive symptoms, but bipolar disorder is defined by episodes of mania or hypomania.

Bipolar disorder constitutes 1 pole of a spectrum of mood disorders that includes including bipolar I (BPI), bipolar II (BPII), cyclothymia (oscillating high and low moods), and major depression.

Page 5: ANTI MANIC DUGS

Manic Episode characterized by at least 1 week of profound

mood disturbance, characterized by elation, irritability, or expansiveness . At least 3 of the following symptoms must also be present:

Grandiosity Diminished need for sleep Excessive talking or pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Increased level of goal-focused activity at home,

at work, or sexually Excessive pleasurable activities, often with

painful consequences

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Hypomanic Episode Hypomanic episodes are characterized

by an elevated, expansive, or irritable mood of at least 4 days’ duration. At least 3 of the following symptoms are also present:

Grandiosity or inflated self-esteem Diminished need for sleep Pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Psychomotor agitation at home, at work, or sexually Engaging in activities with a high potential for painful

consequences

Page 7: ANTI MANIC DUGS

Neurobiology OF MANIA AND BIPOLAR DISORDER*Ambiguous till date

Biogenic amine neurotransmitters:

Noradrenergic system:

NE turnover increase in the cortical and thalamic areas of BD subjects where decrease in depression

Serotogenic system:

Reduced 5-hydroxytryptamine (5- HT)1A receptor binding potential in raphe and hippocampus- amygdala of brain in depressed patients

Dopaminergic system DA agonists are effective antidepressants and are able to

precipitate mania. D2 receptor found in caudate, putamen, nucleus accumbens,

cerebral cortex and hypothalmus is negativly coupled to adenylyl cyclase. Older antipsychotics act through blockage of D2 receptors , which eventualy result in extrpyramidal system (muscle rigidty , involuntry movement, pseudoparkinsonism)

Page 8: ANTI MANIC DUGS

Cholinergic system cholinergic tone decrease during mania , pilocarpine

elicit pupillary constriction , The response of pilocarpine enhance after lithium and

VPA ,adding evidence on the effects of lithium perhaps potentiating brain cholinergic systems

relative inferiority of noradrenergic compared to cholinergic tone was associated with depression, while the reverse was associated with mania

Receptor

Nature Pathway

D 2 Inhibitory Presynaptic: decr Ca+ conductPostsynaptic:Gi, incr K+ conduct ,decr cAMP

M 3 Excitatory Gq ,incr IP3 & DAG

Alpha 1 Excitatory Gq ,incr IP3 & DAG

5 HT-2 Excitatory Gq ,incr IP3 & DAG

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cellular signaling pathways interact at various levels, allow the cell to receive, process, and respond to information

signaling pathways represent major targets for a number of hormones, including glucocorticoids, thyroid hormones, and gonadal steroids , may explain mood disorder with alterd hormonal level.

(e.g. the frequent onset of bipolar disorder in puberty, triggering of episodes in the postpartum period)

G Protein abnormalities:Postmortem brain studies have reported increased levels

of the stimulatory G protein (Gαs) accompanied by increases in post-receptor stimulated adenylyl cyclase (AC) activity in BD.

Signal pathways abnormalities*

Page 10: ANTI MANIC DUGS

The protein kinase C signaling pathway:PKC is one of the major intracellular mediators of signals

generated upon external stimulation of cells via a variety of neurotransmitter receptors M1, M3, M5 α1 5-HT2A . PKC induce the hydrolysis of various membrane phospholipids.

increased PKC activity and translocation found in different experiments of BD brains moreover attenuation of PKC activity may play a role in the antimanic effects of lithium and VPA.

Novel selective PKC inhibitors if devolped may have very useful action against mania. Tamoxifen is underinvestigation.

Abnormalities of calcium signaling Calcium ions play a critical role in regulating the synthesis and

release of neurotransmitters, neuronal excitability, elevations in both resting and stimulated intracellular Ca2+

levels in platelets, lymphocytes and neutrophils of patients with BD.

*The underlying neurobiology of bipolar disorder, world psychiatry

HUSSEINI K MANJI,1 JORGE A QUIROZ,1 JENNIFER L PAYNE,1 JASKARAN SINGH,1 BARBARA P LOPES,1 JENILEE S VIEGAS,1 and CARLOS A ZARATE1

Page 11: ANTI MANIC DUGS

Genes associated with mania and BP include: Glycogen synthase kinase 3 (GSK-3):GSK3β is a central regulator of the circadian clock.

Negative mutation in the CLOCK gene normally contributing to circadian periodicity in humans results in behavior mimicking mania.

ANK3(ANKYRIN G):ANK3 is an adaptor protein found at axon initial

segments that regulates the assembly of voltage-gated sodium channels.

CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel)

ANK3 and subunits of the calcium channel are down-regulated in mouse brain in response to lithium, which indicates a possible therapeutic mechanism of action

Genetic abnormalities*

Page 12: ANTI MANIC DUGS

Diacylglycerol kinase eta (DGKH) gene:

GWAS published by 2011 pointed first intron of diacylglycerol kinase eta (DGKH) gene, a key protein in the lithium-sensitive phosphatidyl inositol pathway.

Lithium-mediated inhibition of GSK3β is thought to result in downregulation of molecules involved in cell death and upregulation of neuroprotective factors.

Genetic abnormalities*

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1:Stephen Soreff, MD President of Education Initiatives, Nottingham, NH; Faculty, Boston University, Boston, MA and Daniel Webster College, Nashua, NH

Page 14: ANTI MANIC DUGS

CLINICAL FEATURES OF MANIACharacteristic Clinical appearanceMood Elevated or irritable

Talk Fast, pressurized, flight of ideas

Energy Excessive

Ideas Grandiose, self-confident, delusions of wealth, power, influence or of religious significance, sometimes persecutory

Cognition Disturbance of registration of memories

Physical Insomnia, mild to moderate weight loss, increased libido

Behaviour Disinhibition, increased sexual activity, excessive drinking or spending

Hallucinations Fleeting auditory or, more rarely, visual

Differential Diagnosis

∂ Acute intoxication with recreational drugs, such as amfetamines, amfetamine derivatives (MDMA: Ecstasy), and cocaine can mimic mania.

∂ Chronic use of cannabis can induce manic like features.

∂ Cushing's syndrome had a secondary manic illness

∂ corticosteroids can induce mania ∂ Dopamine agonists (e.g. bromocriptine) are

also known to sometimes induce secondary mania.

∂ The excited phase of catatonic schizophrenia can sometimes be mistaken for mania.

Page 15: ANTI MANIC DUGS

Drug Mania Mixed Maintenance

Depression

Lithium X X

Valporate XR X

Carbamazepine

X X

Lamotrigine X

Arippiprazole X X X

Ziprasidone X X

Resperidone X X

Asenapine X X

Quetiapine X X

Chlorpromazine

X

Olanzapine X X X

TreatmentPharmacotherapy

Table. FDA-Approved Bipolar Treatment Regimens

Page 16: ANTI MANIC DUGS

Anixloytic

•Lorazepam, Clonazepam

Mood Stabilizer

•Lithium carbonate

Anticonvulsant

•Carbamazepine, valporate sodium, Divalporate sodium,Lamotrigine,

Atypical

antipsychotics

•Risperidone,Olanzapine,Quetiapine ,Airpiprazole,Asenapine

Typical

Antipsychotics

•Loxapine.Chlorpromazine, Fluphenazine

Page 17: ANTI MANIC DUGS

Atypical antipsychotics risperidone (2003), quetiapine ,

ziprasidone and aripiprazole (2004)

Olanzapine 2000

Divalporex 1994

Lithium 1970

Acute treatment of mania: an update on new medications.

Case School of Medicine, Mood Disorders Program, University Hospitals Case Medical Center, 11400 Euclid Avenue, Suite 200, Cleveland, OH 44106, USA. [email protected]

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Page 18: ANTI MANIC DUGS

In use since the 1870s. Initially used to treat depression, gout,

and neutropenia, and for cluster headache prophylaxis,

In 1940s FDA banned the use of lithium because of fatalities but lifted in 1970.

Narrow therapeutic index that predisposes poisoning with relatively minor changes in medications or health status.

May protect and preserve the hippocampal volumes, also claimed neuroprotective.

Mood Stabilizer

LITHIUM:

Page 19: ANTI MANIC DUGS

Pharmacokinetics

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Indications & Uses Acute manic or mixed episodes in patients

with BPI and BPII. Major Depression Schizoaffective and Schizophrenic

Disorders Disorders of Impulse Control Psychiatric Disorders in Children Neutropenia and Anemiasecondary to antineoplastic drugs Hyperthyroidismradioactive iodine, surgery, propylthiouracil are

preferred.a

SIADH Demeclocycline is preferred for syndrome of inappropriate

ADH secretion.

Page 21: ANTI MANIC DUGS

Contraindication

Renal or cardiovascular disease, Severe debilitation, dehydration, sodium

depletion, Concomitant therapy with diuretics; very

high risk of lithium toxicity under such conditions.

History of Leukemia

Page 22: ANTI MANIC DUGS

Mechanism of Action:Effects on Electrolytes and Ion Transport Lithium is closely related to sodium in properties. It can substitute for sodium in generating action potentials

and in Na+-Na+ exchange across the membrane. It inhibits the latter process, but does not significantly affect the Na+/Ca2+ exchange or Na+/K+ ATPase .

Effects on Neurotransmitters Lithium appears to enhance some of the actions of

serotonin, though findings have been contradictory. Its effects on norepinephrine are variable. The drug may

decrease norepinephrine and dopamine turnover, and these effects.

Lithium also appears to block the development of dopamine receptor supersensitivity that may accompany chronic therapy with antipsychotic agents.

Finally, lithium may augment the synthesis of acetylcholine, perhaps by increasing choline uptake into nerve terminals.

Page 23: ANTI MANIC DUGS

Mechanism of Action:Effects on Second messenger: One of the best-defined effects of lithium is its action on

inositol phosphates. IP3 and DAG are important 2nd messengers for both -

adrenergic and muscarinic transmission. Lithium inhibits several important enzymes in the normal recycling of membrane phosphoinositides, including

conversion of IP2 to IP1 (inositol monophosphate) and the conversion of IP to inositol.

This block leads to a depletion of phosphatidylinositol-4,5-bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects of transmitters on the cell will diminish in proportion to the amount of activity in the PIP2-dependent pathways.

Iisolated brain tissue study indicate that lithium can inhibit norepinephrine-sensitive adenylyl cyclase. Such an effect

could relate to both its antidepressant and its antimanic effects

Page 24: ANTI MANIC DUGS

Lithium may uncouple receptors from their G proteins; indeed, two of lithium‘s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and TSH receptors from their G proteins.

Page 25: ANTI MANIC DUGS

May start with lower dose to minimize adverse drug reactions

900-2400 mg/day divided q6-8hr (immediate release tabs) OR 900-1800 mg divided q12hr PO if using extended release tabs

Desirable serum lithium concentrations are 0.6-1.2 mEq/L; although higher serum concentration may be needed not to exceed 1.5 mEq/L

Administration: Take preferably with foodMonitor Serum lithium 12 hr after dose; 2

times/week until serum concentration and clinical condition stabilizes; thereafter q2month

Dosage:

Page 26: ANTI MANIC DUGS

Interaction:Drug Severity Possible interaction

Sibutramine Contraindicated

Increase toxicity by Pharmacodynamics synergism

Candesarttan Use Alternative

Increase Li level

Linezolid Use Alternative

Increase serotonin level by inhibiting MAO

Locaserin Use Alternative

Both Increase serotonin level

Furazolidone Use Alternative

Increase serotonin level

Tranylcypromine

Use Alternative

Increase serotonin level

Vilazodone Use Alternative

Serotonin syndrome

Aspirin Monitor closely

Decrease renal clearence of Li

Carbamazepine

Monitor closely

Risk of neurotoxicity

Citalopram Monitor closely

Enhance serotonergic effect

Haloperidol Monitor closely

Risk of neurotoxicity

Page 27: ANTI MANIC DUGS

COMMON SE: GI distress ,Upper LiCo3,Lower SR Hand tremor, poor coordination Sedation/lethargy Weight gain Polyuria / polydipsia Cognitive (memory ,concentration

Serious AE Renal:

Nephrogenic Diabetes insipidus ,Tubular interstitial nephritis(treatment thiazide diuretic/amiloride) compensatory goiter without true hypothyroidism Neurological disorders ataxia, mental confusion,

delusion, hallucinations Teratogenic (Pregnancy Category D)

Side Effect:

Page 28: ANTI MANIC DUGS

The likelihood of toxicity increases with increasing serum Lithium levels.

Threshold level:1.5mEq/l Serum

Over Dose/Poisoning:

Signs of toxicity: Below 2.0mEq/l

Diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination

Higher Level 2.0/3.0mEq/l

giddiness, ataxia, blurred vision, tinnitus and a large output of dilute urine

Treatment:

No Specific Antidote, discontinue drug, Eliminate ion

Follow protocol as for Barbiturate poisoning, Correct fluid /Electrolyte

Page 29: ANTI MANIC DUGS

FDA Seizure/Epilepsy 78, BiPolar disorder ‘96

1st marketed AED, Effective ant manic, BP depression

Therapeutic effect level 50-125 mg/l

Fetal Hepatotoxic ,pancreatitis (free radical effect)

Not to used for Posttraumatic seizure

Best for rapid-cycling and acute-mania

Anticonvulsants:VALPROIC ACID

Page 30: ANTI MANIC DUGS

Bioavailability: 81-89% of delayed-release

Peak Plasma Concentration: 115-145 mcg/mL (IV)

Protein Bound: 10-19%

Volume of distribution: 92 L

Metabolism: Liver, Excretion: Liver

Metabolites: 2-propyl-3-ketopentanoic acid

Half-Life: 6-16 hr; 10-67 hr (neonates)

Pharmacokinetics:

Page 31: ANTI MANIC DUGS

•Indication& Dosage: Bipolar ManiaInitial 25 mg/kg/day PO Increase rapidly to achieve lowest therapeutically

effective dose,Maximum: 60 mg/kg/day Partial SeizuresPO: 10-15 mg/kg/day PO initially, THEN up to 30-

60 mg/kg/day Migraine, Prophylaxis250 mg PO q12hr Status Epilepticus SchizophreniaMaximum dose for an adult is 60mg/kg daily except 1g/kg/daily for

migraine*

Dose adjustment require in hepatic impairement.*Abbott Laboratories. Depakene (valproic acid) solution and liquid-filled capsules prescribing information. North Chicago, IL; 2009

Nov.

Page 32: ANTI MANIC DUGS

•Mechanism Of Action: GABA level in the brain facilitate glutamic acid decarboxylase

(GAD), the enzyme responsible for GABA synthesis,

An inhibitory effect on the GABA transporter GAT-1b thus blocking degradation of GABA.

hyperpolarize membrane potentials by increasing membrane k conductance.1(katzung

pharmacology)

Page 33: ANTI MANIC DUGS

Doripenum, eratopenum, imipenem, meropenem,vorinostat, have serious interaction ,increase hepatic metabolism1 .

Protein bounded drugs increase free VPA level e.g. Aspirin, carbamazepine,warfarin,digoxin etc

VPA decrease level of liver metabolized drugs(cytochrome p450) e.g. carbamazepine, phenytoin,TCA,lamotrigine

P450 inducers decrease VPA level.

Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats journal of health sciences 2007

Drug interaction:

Page 34: ANTI MANIC DUGS

Teratogenic potential : Pregnancy Category: D; known to cause

neural tube defects in fetus Lactation: excreted in milk

Page 35: ANTI MANIC DUGS

Carbamazepine :

An anticonvulsant and specific analgesic for trigeminal neuralgia,psychomotor, seizure.

Stabilizes inactivated state of sodium channels, thereby making neurons less excitable

May reduce activity of necleus ventralis of the thalamus or decrease synaptic transimisssion or summation of temporal stimulation

dose range: 800-1200 mg/day PO in divided doses

Therapeutic range: 4-12 mg/L [16.9-50.8 micromoles/L] Maximum dose of 1600 mg/day

Pregnency category D, enter in breast milk.

Page 36: ANTI MANIC DUGS

Atypical Antipsychotics

QUETIAPINEA 2nd genration psychotropic agent, convenience evidence

for mania treatment

AbsorptionBioavailability: 100%,Peak Plasma Time:1.5 hr;6 hr XR DistributionProtein Bound: 83%,Vd: 6-14 L/kg Metabolism Hepatic CYP3A4 EliminationHalf-life elimination: 6 hr Excretion: Urine 73%; feces 20%

Page 37: ANTI MANIC DUGS

Indications & Dosage:

Bipolar I Disorder, ManiaMonotherapy or as an adjunct to lithium or

divalproexDose :400-800 mg/day Bipolar I Disorder, MaintenanceImmediate-release: 400-800 mg/day PO q12hr Insomnia (Off-label)Usually start 25 mg PO qHS Major Depressive DisorderDosage range: 150-300 mg/day Alcohol Dependence (Off-label)25-50 mg PO qHS; not to exceed 300 mg

Page 38: ANTI MANIC DUGS

Mechanism of Action:

interact with serotonin (5HT2) and dopamine D1 and D2 receptors.

higher selectivity for 5HT2 relative to D2 to low EPS

high affinity at histaminergic and adrenergic alpha1 receptors, with a lower affinity at adrenergic alpha2 receptors.

Page 39: ANTI MANIC DUGS

Drug Interaction:

Increased risk of drowsiness and postural hypotension when used with alcohol.

CYP3A4 inducers Phenytoin,CBZ decrease level

CYP3A4 inhibitors Ketoconazole ,erythromycin increase level.

Pregnancy Category: C Neonates exposed in 3rd trimester are at

risk for EPS or withdrawal symptoms Lactation: excreted in breast milk, breast

feeding is not recommended

Page 40: ANTI MANIC DUGS

Tardive dyskinesia : Tardive dyskinesias are involuntary movements of the

tongue, lips, face, trunk, and extremities. TD can be caused by long-term treatment with

dopamine antagonists. Neuroleptics, Amisulpride, antiemetic metoclopramide, a potent D2 dopamine receptor antagonist, may cause TD, particularly in elderly patients. antihistamines, fluoxetine,

Atypical antipsychotics particularly Quetiapine and clonazapine are used to reduced the tardive dyskinesia.*

* A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia Emsley R, Turner HJ, Schronen J, Botha K, Smit R, Oosthuizen PP.

Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa

Page 41: ANTI MANIC DUGS

Ziprasidone : 2nd generation antipsychotic Used for bipolar I, schizophrenia, Acute

agitation MOA:Antagonist at dopamine (D2), serotonin

(5HT1D, 5HT2A) receptorsAgonist at serotonin 5HT1A receptorModerately inhibits reuptake of

norepinephrine and serotoninAlso has alpha-blocking & antihistaminic

activity Risk of QT prolongation. Less chance of hyperglycemia or diabetes

and EPS.

Page 42: ANTI MANIC DUGS

Loxapine : 1st generation antipsychotics Dibenzoxazepine antipsychotic; blocks mesolimbic D1 and

D2 receptors in the brain; also has anti-serotonin 5HT2 activity

extrapyramidal disease, parkinsonian, somnolence, tardive dyskinesia

10—20 mg PO q 24hr Inhaled preparation is in pipeline ,10mg Od, but FDA has

Pulmonary saftey concerns1 Loxapine, as with all other antipsychotics has label

warning “Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death”2

European medicine agency recmnded loxapine for the rapid control of agitation in adult with BP or schizophernia.(2012)

1 . Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder. Citrome L. New York Medical College, Valhalla

2. Antipsychotic drugs: sudden cardiac death among elderly patients.

Narang P, El-Refai M, Parlapalli R, Danilov L, Manda S, Kaur G, Lippmann S.2010

Page 43: ANTI MANIC DUGS

Prospective antimanic drugs:

Tamoxifena nonsteroidal antiestrogen used

to treat breast cancer, is a potent and selective PKC inhibitor that crosses the blood-brain barrier.

AsenapineIncrease level of dopamine, NE

and acetylcholine in cortical and limbic brain areas. also prevent from depression and protect cognitive function.

Page 44: ANTI MANIC DUGS

GRATULATE FOR ATTENTION


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