antidepressants samaiya mushtaq chem 5398. depression types symptoms diagnosis causes treatment

33
ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398

Upload: lynn-carpenter

Post on 22-Dec-2015

219 views

Category:

Documents


1 download

TRANSCRIPT

Page 1: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

ANTIDEPRESSANTSSamaiya Mushtaq

CHEM 5398

Page 2: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

DEPRESSION

Types Symptoms Diagnosis Causes Treatment

Page 3: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

TYPES OF DEPRESSION

Major depression Chronic depression (Dysthymia) Atypical depression Bipolar disorder/Manic

depression Seasonal depression (SAD)

Page 4: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

SYMPTOMS persistently sad, anxious, or empty moods loss of pleasure in usual activities (anhedonia) feelings of helplessness, guilt, or worthlessness crying, hopelessness, or persistent pessimism fatigue or decreased energy loss of memory, concentration, or decision-making

capability restlessness, irritability sleep disturbances change in appetite or weight physical symptoms that defy diagnosis and do not

respond to treatment (especially pain and gastrointestinal complaints)

thoughts of suicide or death, or suicide attempts poor self-image or self-esteem (as illustrated, for

example, by verbal self-reproach)

Page 5: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

DIAGNOSIS

Extensive patient and family history Blood test for hypothyroidism Current medication DSM-IV

One of the first two symptoms Five other symptoms

Page 6: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

CAUSES OF DEPRESSION

Genetics Death/Abuse Medications

Page 7: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

TREATMENT FOR DEPRESSION

Psychotherapy Electroconvulsive therapy Natural alternatives Medication

SSRIs MAOIs TCAs SNRIs NDRIs TeCAs

Page 8: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

NEUROTRANSMITTERS AND THE CATECHOLAMINE HYPOTHESIS

Neurotransmitters pass along signal Smaller amount of neurotransmitters causes

depression

Page 9: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

MONOAMINE OXIDASE (MAO) AND DEPRESSION

MAO catalyze deamination of intracellular monoamines MAO-A oxidizes epinephrine, norepinephrine,

serotonin MAO-B oxidizes phenylethylamine Both oxidize dopamine nonpreferentially

MAO transporters reuptake extracellular monoamine

Page 10: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

MONOAMINE OXIDASE INHIBITORS (MAOIS)

History Isoniazid Iproniazid

Current Drugs Mechanism of Action Side Effects Isoniazid

Iproniazid

Page 11: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

MAOIS ON THE MARKET

MAO Inhibitors (nonselective) Phenelzine (Nardil) Tranylcypromine (Parnate) Isocarboxazid (Marplan)

MAO-B Inhibitors (selective for MAO-B) Selegiline (Emsam)

Page 12: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

MAOIS MECHANISM OF ACTION

MAO contains a cysteinyl-linked flavin

MAOIs covalently bind to N-5 of the flavin residue of the enzyme

Page 13: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment
Page 14: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

MAOIS SIDE EFFECTS

Page 15: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

MAOIS SIDE EFFECTS

Side effects have put MAOIs in the second or third line of defense despite superior efficacy

MAO-A inhibitors interfere with breakdown of tyramine High tyramine levels cause hypertensive crisis

(the “cheese effect”) Can be controlled with restricted diet

MAOIs interact with certain drugs Serotonin syndrome (muscle rigidity, fever,

seizures) Pain medications and SSRIs must be avoided

Page 16: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

THE RECEPTOR SENSITIVITY HYPOTHESIS

Supersensitivity and up-regulation of post-synaptic receptors leads to depression

Suicidal and depressed patients have increased 5HT-α2 receptors

Page 17: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

TRICYCLIC ANTIDEPRESSANTS (TCAS)

History Imipramine

Current Drugs Mechanism of Action Side Effects

Imipramine

Page 18: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

TCAS ON THE MARKET

Amitriptyline Desipramine (Norpramin) Doxepin (Sinequan) Imipramine (Tofranil, Tofranil-PM) Nortriptyline (Pamelor) Protriptyline (Vivactil) Trimipramine (Surmontil)

Page 19: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

TCAS MECHANISM OF ACTION

TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake

TCAs also allow for the downregulation of post-synaptic receptors

All TCAs and SSRIs contain an essential amino group that appears to interact with Asp-98 in hSERT

Page 20: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

TCAS SIDE EFFECTS

Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth, blurred vision, constipation, urinary retention and impotence

Histamine H1 receptor antagonism - sedation and weight gain

Adrenergic α receptor antagonism - postural hypotension

Direct membrane effects - reduced seizure threshold, arrhythmia

Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety)

Page 21: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

TCAS SIDE EFFECTS

Nonselectivity results in greater side effects

TCAs can also lead to cardiotoxicity Increased LDH leakage Slow cardiac conduction

High potency can lead to mania Contraindicated with

persons with bipolar disorder or manic depression

Page 22: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

TETRACYCLIC ANTIDEPRESSANTS (TECAS)

Current Drugs Mirtazapine (Remeron)

Mechanism of Action Same as TCAs

Side Effects

Page 23: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Most commonly prescribed class Current drugs Mechanism of action Side effects

Serotonin

Page 24: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

SSRIS ON THE MARKET

citalopram (Celexa) dapoxetine (Priligy) escitalopram (Lexapro) fluoxetine (Prozac) fluvoxamine (Luvox) paroxetine (Paxil) sertraline (Zoloft) zimelidine (Zelmid) (discontinued) indalpine (Upstene) (discontinued)

Fluoxetine 1:1

Sertraline

Page 25: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

SSRIS MECHANISM OF ACTION

Exact mechanism remains uncertain Ser-438 residue in the human serotonin

transporter (hSERT) appears to be a determining factor in SSRI potency

Antidepressants interact directly with hSERT http://www.mayoclinic.com/health/antidepres

sants/MM00660

Page 26: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

SSRIS SIDE EFFECTS

Page 27: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

SSRIS SIDE EFFECTS

Many disappear within 4 weeks (adaption phase)

Side effects more manageable compared to MAOIs and TCAs

Sexual side effects are common SSRI cessation syndrome

Brain zaps Sexual dysfunction

Page 28: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)

Slightly greater efficacy than SSRIs Slightly fewer adverse effects than SSRIs Current drugs

Venlafaxine (Effexor) Duloxetine (Cymbalta)

Mechanism of Action Very similar to SSRIs Works on both neurotransmitters

Side effects Similar to SSRIs Suicide

Venlafaxine 1:1Duloxetine

Page 29: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment
Page 30: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITORS (NDRIS)

Current drugs Bupropion (Wellbutrin)

Mechanims of Action Similar to SSRIs and SNRIs More potent in inhibiting dopamine Also anα3-β4 nicotinic antagonist

Adverse effects Lowers seizure threshold Suicide Does not cause weight gain or sexual

dysfunction (even used to treat the two)

Bupropion 1:1

Page 31: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

ASSIGNED READING An Introduction to Medicinal Chemistry, by

Graham L. Patrick, Chapter 20, pp. 593-8. Kelly, John. Novel therapeutic targets for the

treatment of depression. Current Medicinal Chemistry: Central Nervous System Agents (2003), 3(4), 311-322.

Optional Reading:

Wong, David T.; Perry, Kenneth W.; Bymaster, Frank P. Case History: The Discovery of Fluoxetine Hydrochloride (Prozac). Nature Reviews Drug Discovery (2005), 4(9), 764-774.

Krishnan, K. Ranga. Revisiting monoamine oxidase inhibitors. Journal of Clinical Psychiatry (Memphis, TN, United States) (2007), 68(Suppl. 8), 35-41.

Page 32: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

HOMEWORK QUESTIONS

1. Many of the medications to treat depression are thought to involve systems utilizing the monoamine neurotransmitters, noradrenaline, dopamine, and serotonin (5-HT). Draw the structures of these neurotransmitters. Why are they called monoamines? Illustrate their structural resemblance to one another.

2. Monoamine oxidase inhibitors (MAOIs) increase CNS synaptic concentrations of these monoamines by inhibiting an enzyme responsible for their degradation. Draw the reaction scheme for the biological degradation of noradrenaline by monoamine oxidase.

3. Illustrate how the TCAs and SSRIs might resemble the monoamine neurotransmitters, providing one example of each class of antidepressant.

Page 33: ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment

REFERENCES http://ajp.psychiatryonline.org/cgi/reprint/157/11/1901

http://www.webmd.com/depression/

http://pn.psychiatryonline.org/content/41/24/21.full

http://www.mayoclinic.com/health/maois/MH00072

http://www.springerlink.com/content/b9b8668ff59f89d7/fulltext.pdf

http://www.emsam.com/pi_emsam.pdf

http://www.nevdgp.org.au/info/topics/depression_theory.htm

http://www.uspharmacist.com/content/t/psychotropic_disorders/c/11467/

http://www.jbc.org/content/284/15/10276.full.pdf+html

http://www.aafp.org/afp/981200ap/cadieux.html

http://www.mayoclinic.com/health/antidepressants/MH00071

http://books.google.com/books?id=R0W1ErpsQpkC&pg=PA565&lpg=PA565&dq=tcas+mechanism+of+action&source=bl&ots=oASle2Z-pr&sig=36CB_3JY4uD3LIYvqXWmAb3nliY&hl=en&ei=HzfFS9OrB4Tu9gTD6_ixDg&sa=X&oi=book_result&ct=result&resnum=8&ved=0CCoQ6AEwBw#v=onepage&q=tcas%20mechanism%20of%20action&f=false

http://www.informaworld.com/smpp/content~content=a916036122&db=all