Stimulants

1.Stimulants like Cocaine and methylphenidate (Ritalin)

   block the reuptake of:

2. A major difference between the antidepressants and

    the stimulants is:

3. MAOI's enhance the effects of DA by:

1. Norepinephrine, 5HT, and DA.

2. Most antidepressants do not block the reuptake of

    DA. With the exception of Bupropion (Wellbutrin) and

    MAOI's. Bupropion is the only antidepressant that

    blocks DA reuptake. Bupropion can also lower the

    seizure threshold.

3. Blocking its metabolism (not reuptake). One way

    that this is clinically important is that DA receptor

    stimulation is linked to addictive behavior. This is

    why bupropion and MAOI's may be used to treat

    nicotine addiction. 

Tricyclic Antidepressants

1. Block the reuptake of:

2. Block which three receptors:

3. What side effects are associated with these drugs?

1. Block NE and 5HT reuptake.

2. They differ from all other reuptake blockers because

    they block muscarinic, alpha-adrenergic, and

    histaminic receptors.

Note the difference between blocking reuptake and blocking the receptor.

3.  TCAs are associated with dry mouth, sedation, tachycardia, and other important side effects like seizures-they lower the seizure threshold. TCAs may be very toxic.

Seratonin/Norepinephrine Reuptake Inhibitors (SNRIs) known for what two things?

1. They Block NE and 5HT reuptake.

2. They have a low toxicity.

Selective Serotonin re-uptake inhibitors (SSRI's)

What two things are SSRI's known for?

Give an example of a SSRI:

1. They block 5HT reuptake and they have a low

    toxicity.

2.  Fluoxetine (Prozac) is an SSRI.

Atypical Antidepressants

What are two things to remember with regard to Atypical Antidepressants?

1. Think of Bupropion when thinking of atypical

    antidepressants-it blocks DA (which is very unusual

    for these drugs) and maybe NE.

2. All other atypicals block 5HT reuptake and have +/-

    effects on NE reuptake.

MAOIs (Monoamine Oxidase Inhibitors)

How many types are there and what do they block?

Which type is Safer?

Give an example of a MAOb medication:

1. There are two types of MAOIs-

    MAOa-which blocks metabolism of (and enhances

    the effects of) NE and 5HT.

    MAOb-Which blocks DA metabolism (eg. see chapter

    8-selegiline).

2. MAOb are safer that MAOa. But is important to

    remember that MAOIs are very toxic.

3. Selegilene is an MAOb (this drug is discussed with

    the Anti-Parkinson medications).

Be prepared to discuss seratonin syndrome...reference the following article:

http://www.nytimes.com/2007/02/27/healt...y.htm?_r=2

This became a landmark case that had a huge impact on US health care. Among other things, it let to dramatic changes in maximal number of hours, rules for supervision, and other work conditions in all US residency training programs.)

Summary on flip side

This case involved an 18yo girl taking nardil (phenelzine) who came to the hospital with elevated temp received demerol which lead to increased aggitation. She was restrained which lead to increased muscle tension causing temp to soar to lethal levels.

Triggering Medications:

SSRI's-Zoloft, Prozac and Paxil

SNRI's-Effexor

TCA's

MAOIs

As well as narcotics like fentanyl and tramadol,OTC cough and cold remedies containing dextromethorphan, the anticonvulsant valproate; triptans like Imitrex used to treat and prevent migranes,the antibiotic Zyvox (linezolide), antinausea drugs, the PD drug L-dopa, the weight-loss drug Meridia (sibutramine), lithium, the dietary supplement tryptophan, St. John’s wort and ginseng; and several drugs of abuse, including ecstasy, LSD, amphetamines, the hallucinogens foxy methoxy and Syrian rue.

There are three categories of symptoms:

Cognitive-behavioral symptoms like confusion, disorientation, agitation, irritability, unresponsiveness and anxiety.

Neuromuscular symptoms like muscle spasms, exaggerated reflexes, muscular rigidity, tremors, loss of coordination and shivering.

Autonomic nervous system symptoms like fever, profuse sweating, rapid heart rate, raised blood pressure and dilated pupils.

Treatment:

The first step is to stop the offending drugs. It is crucial to seek immediate care, preferably in a hospital.

Most cases require only treatment of symptoms like agitation, elevated blood pressure and body temperature, and a tincture of time.

More severe cases are treated with drugs that inhibit serotonin and chemical sedation. caution should be taken r/t physical restraints to control agitation because they could enforce isometric muscle contractions that cause a severe buildup of lactic acid and a life-threatening rise in body temperature.

A 55-year-old teacher began to experience changes in mood. He was losing interest in his work and lacked the desire to play his daily tennis match. He was preoccupied with feelings of guilt, worthlessness, and hopelessness. In addition o the phychiatric symptoms, the patient complained of muscle aches throughout his body. Physical and laboratory tests were unremarkable. After 6 weeks of therapy with Fluoxetine (Prozac), the patient's symptoms resolved. However, the patient complains of sexual dysfunction. Which of the following drugs might be useful in this patient?

A. Fluvoxamine

B. Sertaline

C. Citalopram

D. Mirtazapine

E. Lithium

D. Sexual dysfunction commonly occurs with TCAs,

    SSRIs, and SNRIs. Mirtazapine is largely free from

    sexual side effects.

A 25-year-old woman has a long history of depressive symptoms accompanied by body aches. Physical and laboratory tests are unremarkable. Which of the following drugs might be useful in this patient?

A. Fluoxetine

B. Sertraline

C. Phenelzine

D. Mirtazapine

E. Duloxetine

E. Duloxetine is an SNRI that can be used for

    depression accompanied by neuropathic pain. MAOs

    and SSRIs have little activity against neuropathic

    pain.

A 51-year-old woman with symptoms of major depression also has narrow-angle glaucoma. Which of the following antidepressants should be avoided in this patient?

A. Amitriptyline

B. Sertraline

C. Bupropion

D. Mirtazepine

E. Fluvoxamine

A. Because of its potent antimuscarinic activity,

    amitriptyline should not be given to patients with

    glacoma because of the risk of acute increase in

    ocular pressure. The other antidepressants all lack

    antagonist activity at the muscarinic receptor.

A 36-year-old man presents with symptoms of compulsive behavior. If anything is out of order, he feels that "work will not be accomplished effectively or efficiently." He realized that his behavior is interfering with his ability to accomplish his daily tasks but cannot seem to stop himself. Which of the following drugs would be most helpful to this patient?

A. Imipramine

B. Fluvoxamine

C. Amitriptyline

D. Tranylcypromine

E. Lithium

B. SSRIs are particularly effective in treating obsessive-

    compulsive disorder; fluvoxamine is approved for this

    condition. The other drugs are ineffective in the

    treatment of OCD.

They potentiate the actions of norepinephrine and/or serotonin in the brain by blocking neurotransmitter reuptake

What is the biogenic amine theory of depression?

 How may down-regulation of presynaptic inhibitory receptors affect biogenic amine synthesis and release?

1. The biogenic theory of depression proposes that

    depression is due to a deficiency of monoamines

    (norepi & serotonin) at certain key sites in the brain.

2. This down-regulation will increase synthesis hence

    release leading to increased availability post

    synapse.

What are the pharmacologic similarities and differences between TCAs and SSRIs?

Include the indications and adverse effects in your discussion.

SSRIs are considered to have fewer side effects and less severe ones than TCAs. SSRIs can cause headache, sweating, anxiety, and agitation, GI effects, weakness and fatigue, sexual dysfunction, changes in weight, and sleep disturbances.

SSRIs are often used for depression but also for OCD, panic disorders, generalized anxiety disorder, PTSD, social anxiety disorder, bulimia, and premenstrual dysphoric disorder.

TCAs are often used for major depression. It is occasionally used for panic disorders and for bedwetting in children. Its adverse effects are blurred vision, dry mouth, urinary retention, constipation, aggrevation of glaucoma, and most severely arrhythmias. TCAs also block NEPI reuptake. TCAs also block muscarinic, histaminic and alpha receptors. TCAs therefore are much more toxic than SSRIs.

Both block 5-HT reuptake.

Pay attention to difference between blocking reuptake of neurotransmitter and blocking receptors.

Name two Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) (provide generic and trade names).

When might these medications be indicated instead of SSRIs or TCAs?

Cymbalta (duloxetine)
Effexor XR (venlafaxine)

SNRIs are sometimes effective in relieving physical symptoms of pain (neuropathic).

What are the trade names of the atypical antidepressants bupropion, mirtazapine, nefazodone, and trazodone?

When might these agents be be preferred over TCAs, SSRIs, or SNRIs?  

Bupropion (Wellbutrin): dopamine and norepinephrine reuptake inhibitor, considered to be low risk for drug-drug interactions.Note that this is only drug that blocks DA reuptake. Why is this important -- it can be used for addictive behavior (eg. smoking cessation).

(Mirtazapine (Remeron): antagonism of the 5-HT3 receptor, is sedating so may help with people who are having difficulty sleeping

Nefazodone (Serzone): selectively blocks postsynaptic serotonin 5-HT2A receptors and moderately inhibits serotonin and norepinephrine reuptake, used because it may lead to an increase in serotonin release.

Trazodone (Desyrel): antagonist at all of the following receptors except 5-HT1A where it acts as a partial agonist similarly to buspirone and tandospirone but with greater intrinsic activity in comparison, used because it may lead to an increase in serotonin release

Tricyclic antidepressants block norepi and serotonin reuptake into neuron causing increase monoamines in synaptic cleft resulting in antidepressant effect. TCAS include amitriptyline, clomipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, & trimipramine. TCAS blocks, alpha-adrenergic, histaminic, and muscarinic receptors. TCAs elevate mood, improve mental alertness, increase physical activity, and reduce morbid preoccupation.
 TCAs are named because of their chemical structure (tricyclic compounds).  TCAs also block 5HT and NEPI reuptake but also have many other effects that separate them from the SNRIs (namely muscarinic, adrenergic, and histaminic receptor blocking properties).

Therapeutic uses: tx depression, control bed-wetting in children (older 6 yrs), tx migraine headaches and chronic pain.

Adverse effects: blurred vision, xerostomia (dry mouth), urinary retention, and constipation, aggravation of narrow-angle glaucoma, serious arrhythmias, orthostatic hypotension, dizziness, tachycardia, weight gain, and erectile dysfunction.

Know which of these side-effects are due to anticholinergic effects and which are due to alpha-receptor blockade.

Precautions: manic-depressed pts and very young and very old pts.

What 2 MAO inhibitors (MAOIs) are currently available in the US (provide generic and trade names)?

Name a muscle relaxant, narcotic, and inhalational anesthetic agent that should never be used with MAOIs.

What other medications commonly administered during the intraoperative period should be used cautiously in patients taking MAOIs?

1. Nardil, Parnate

2. Contraindicated Muscle Relaxant: Flexeril

    Contraindicated Narcotic: Demerol-it produces

    hypertensive crisis, convulsions and coma. 

    Contraindicated Inhalation Agent: Halothane.

3. Epinephrine-due to increase BP Phenylephrine

    produces elevated BP, atropine, ephedrine. 

Summary: Halothane + meperidine (Demerol) contraindicated.

Anticholinergics and drugs with anticholinergic effect should also be avoided if possible (this includes atropine, glycopyrrolate, and pancuronium (muscle relaxant)).

Avoid indirect acting sympathomimetics because of unpredictable or exaggerated effects (eg, ephedrine).

Do use direct acting catecholamines and other vasoactive drugs but start with very small doses and proceed carefully.

What are other important points concerning the pharmacology of MAOIs? See for example:

HTTP://books.google.com/books?id=BOqlw_...ia&f=false

MAOIs act by inhibiting the activity of the enzyme monoamine oxidase (MAO). MAO usually functions as “safety valve” to inactivate any excess nuerotransmitter (NEPI, DA, Serotonin). This then prevents the breakdown of monoamine neurotransmitters and increases their availability within the presynaptic neuron.

MAOIs can either bind permanently or irreversibly to MOA, if bound permanently it takes a minimum of two weeks for the body to replace these enzymes.

Anesthesia considerations should be taken if pt is on MAOIs especially in regard to use of, sympthomimetics, inhaled drugs, narcotics (especially Meperidine), barbiturates, and anticholinergics. If needed direct-acting sympathomimetics should be used versus indirect-acting (d/t increased intraneuronal storage of NEPI).

MAOI’s should not be co-administered with SSRI’s due to risk of “serotonin-syndrome” which is life-threatening.

What are the indications and mechanisms of action of lithium?

Which second messenger system is associated with lithium?

What special problems are associated with the perioperative management of patients who have been taking lithium?

Lithium is an antimanic agent used in the treatment of manic-depressive patients and manic episodes. Mechanism of action is not readily known, although some theories have been postulated. One being that Lithium significantly enhances norepinephrine reuptake from the synaptic cleft by presynaptic neurons and degradation by MAO. Supporting the fact that mania results from excesses of norepinephrine.

Lithium is believed to attenuate signaling via receptors coupled to the PIP2 (phosphatidylinositol bisphosphate) second-messenger system. Lithium interferes with the resynthesis of PIP2, leading to its depletion in neuronal membranes.

Patients taking lithium need to have adequate fluids pre/post and intraoperatively to avoid hemoconcentration and resultant toxicity due to lithium’s narrow therapeutic window (0.6-1.4 mEq/L). Na+ levels also need to be monitored since proximal tubule reabsorption of lithium is competitive with sodium. Decreased NMB and barbiturate doses may be needed.

pre/post and intraoperatively = perioperatively

Lithium may potentiate effects of NDMRs. Be aware that lithium may affect renal, thyroid and parathyroid function.