visceral regulation, pain perception, and motor control

Projections to forebrain are involved in modulating mood, arousal, and cognition

Pain pathways

Forebrain: mood, arousal, and cognition

Through norepinephrine receptors located presynaptically alpha-2

Will decrease cAMP --> decrease protein kinase activity --> less phosphorylation of tyrosine kinase 

Outer membrane of mitochondria within neurons, glia, liver, and GI tract

Distribution varies between different tissues

Only in brain and periphery cells that synthesize 5-HT

Action of enzyme yields 5-hydroxytryptophan

Through serotonin receptors presynaptically (5HT1B/D) and somatodendritic cells (5HT1A)

Will lead to decrease in cAMP and less cAMP activated protein kinase which normally phosphorylates and activates the enzyme 

Will decrease cAMP

Somatodendritic and post synaptic and in periphery

Behavioral action (stimulation helps prevent depression)

Decrease cAMP

Presynaptic and postsynaptic and in the periphery

Behavioral; vasoconstriction 

Used for migraines

Increase IP3 and DAG

Postsynaptic and in the periphery

Behavioral; platelet aggregation; smooth muscle contraction 

Ion Channel

Area postrema and peripheral nerves

Emesis

Increase cAMP

Postsynaptic and in the periphery

GI motility

Norepinephrine will bind a2 presynpatic neurons on serotonergic terminals and block serotonin release

Serotonergic inhibition of norepinephrine release occurs via 5HT2A recetpors on noradrenergic neurons 

5HT2A receptors on dopaminergic neurons so stimulation of those will inhibit dopamine release too 

Imipramine was first developed to treat schizophrenia but inhibits serotonin reuptake and norepinephrine reuptake

Iproniazid was an agent initially used to treat TB, but later shown to have antidepressant effects by inhibiting MAO 

Reserpine CAUSED depression in a number of patients 

Patients who respond to SSRI might stop responding if they have a diet low in tryptophan, precursor for serotonin 

Depression associated with loss of neurtrophic support and that antidepressants will increase neurogenesis and synaptic connectivity in areas like the hippocampus

Pain and stress might lead to decreased BDNF 

Direct injection of BDNF seems to have anti-depressant properties 

Increased cortisol

Thyroid dysregulation

Sex hormone deficiency

SSRIs - primary mechanism is preventing reuptake of serotonin at presynaptic terminal

Pharmacologic effect shortly after dosing but therapeutic effect will occur over 2-4 weeks 

May represent time it takes for desensitization of presynaptic receptors

With time, somatodendritic receptors and presynaptic receptors will desensitize

5HT2 receptors DO desensitize; 5HT1A receptors DO NOT desensitize

Desensitization of 5HT2 receptors might actually reduce side effects

active metabolite will have 1/2 life of 8 days 

Fluoxetine would need to be discontinued 4 weeks before switching to a MAO inhibitor 

sudden discontinuation of short half life SSRI's such as paroxitine and sertraline can lead to this syndrome

Characterized by dizziness, and tingling, or numbing in the skin

1-2 days after stopping; may persist for a week

Can occur with any drug that increases serotonin, including some unlikely candidates such as opioids, but more likely to arise when drugs are used in combination. Combination of MAO-inhibitors with an SSRI would be very likely to cause this syndrome

Sx: hyperthermia, muscle rigidity, CV collapse, flushing, and diarrhea 

Blockade of 5 HT reuptake by platelets --> inadequate availability of this amine for hemostatic mechanisms on demand

SSRIs reduce risk of clotting and repeat MI when used to treat cardiac patients for post-MI depression 

SSRIs increase risk of bleeing when combined with aspirins or NSAIDs, but this could be beneficial in patients at risk for thrombosis 

Most common are pharmacokinetic

Paroxetine and fluoxetine are potent inhibitors of cytochrome P450 (CYP2D6) that metabolizes tricyclics which can cause serious elevation and toxicity

Fluvoxamine inhibits cytochrome p450 (CYP3A4) metabolizes other drugs like diltiazem

Citalopram is relatively free of interactions 

The most serious interaction is with MAOis to produce serotonin syndrome 

5HT/NE Reuptake Inhibitors

Venlafaxine inhibits 5HT transporter and NE transporter only at high doses

These drugs don't bind histamine, adrenergic, or muscarinic receptors and are therefore better tolerated than tricyclic antidepressants

Major depression

Atypical depression (venlafaxine)

General Anxiety

Stress urinary incontinence

Vasomotor symptoms of Menopause

pain of diabetic neuropathy (duloxetine) 

Pharmacokinetics of SNRIs

Which one is protein bound?

Venlafaxine has active metabolite generated by cytochrome P450 enzyme - half life is 11 hours

Metabolite desvenlafaxine is marketed separately and doesn't undergo additional extensive oxidative metabolism 

Duloxetine is extensively metabolized by CYP2D6 and should therefore not be administered to patients with hepatic insufficiency

Duloxetine highly protein bound

Relatively mild compared to tricyclic antidepressants; some overlap with SSRIs like nausea, but will also have noradrenergic effects like high blood pressure, heart rate,

CNS: insomina, anxiety, agitation 

High doses of venlafaxine would be more likely to have adverse cardiac effects

Discontinuation and serotonin syndrome also possible with this class

Venlafaxine is a substrate, not an inhibitor of cytochrome P450

Duloxetine is a moderate inhibitor of CYP2D6 so it can elevate tricyclics

Most serious adverse effect is interaction with MAOis to produce serotonin syndrome

Tricyclic Antidepressants 

Inhibit NE and 5HT reuptake, however clomipramine will inhibit primarily serotonin reuptake and desipramine is more selective for norepinephrine

Not commonly used because of adverse effects and toxicity 

Used for depression that doesn't respond to more commonly used antidepressants 

At lower doses, may be used to treat pain 

Imipramine has been used for bed wetting (enuresis)

Clomipramine has been used for OCD, but no longer preferred treatments

Most are dosed once a day and at night because of sedating effects

Extensively metabolized by P450 system so can inhibition by fluoxetine can cause toxicity

Sedation, anticholinergic (dry mouth, tachycardia, urinary retention), alpha adrenergic blockade (postural hypotension), antihistamine H1 receptors (weight gain + sedation), sexual side effects common particularly with clomipramine fairly specific for serotonin receptor; also discontinuation syndrome because of choilnergic rebound and serotonin syndrome if combined with SSRIs or MAOinhibitors 

Anticholinergic effects more common with tertiary amines like amitriptyline and imipramine than with secondary amines like desipramine and nortriptyline

Can be a major problem with this class

Coma, convulsions, cardiotoxicity (quinidine like effect leading to conduction delays)

NaHCO3 antidote to reverse cardiac toxicity 

Does this by increasing number of open sodium channels, thereby partially reversing fast sodium channel blockade 

Confusion and hallucinations can occur in elderly that are very susceptible to anticholinergic effects 

Can be elevated when administered with drugs that inhibit CYP2d6 (duloxetine and fluoxetine) or in patients that have polymorphism for this enzyme

Anticholinergic or antihistamine effects might be additive with other OTC medications with these effects

Antihypertensive medications may exacerbate postural hypotension 

Blocks 5HT2A antagonist

Blocks reuptake of serotonin

Therefore enhance 5HT transmission at postsynaptic 5HT1A receptors and other 5HT2 receptors

These effects are only at high doses though

At much lower doses, antagonist at histamine and alpha adrenergic receptor

Most common use in current practice as a hypnotic (sedative effect from blocking histamine and alph adrenergic receptors)

Treating insomnia with low doses of trazodone might be used with other antidepressants

PK: bioavailability is low because it is rapidly metabolized, so if it were used, it would require 2x/day dosing, but more often it's administered 1 a day at a low dose for its sedative properties 

Sedation

GI upset (less pronounced than SSRIs and SNRIs)

Sexual side effects are uncommon (blockade of 5HT2 receptors)

Alpha adrenergic blockade will lead to hypotension and priaprism 

Nefazodone is an analogue used to be used but no more because liver toxicity

5HT2 Receptor Antagonist

Drugs block 5HT2A/2C and 5HT3 receptors

Blockade of presynaptic receptors would enhance release of norepinephrine and serotonin 

Enhances serotonergic transmission at primarily 5HT1 receptors

Blockade of 5HT2A/2C and 5HT3 receptor will have less side effects

Could be used in melancholic depression

Because of antihistamine properties, the drug is sedating, so it could be used in depressed patients with trouble sleeping

Also enhances appetite

Half life is 20-40 hours

It is usually dosed once a day in the evening because of sedative effects

Increased appetite, weight gain, and sedation

Mirtazapine doesn't interfere with sexual function because it works at 5HT2A/2C receptors 

Unique structure leads to different side effect profile

Resembles amphetamine and has CNS activating properties

Release of NE and to a lesser extent DA

Modest inhibitor of DA and NE reuptake 

Not associated with sexual side effects (doesn't have to do with serotonin)

Side effects may include agitation, insomnia, and anorexia 

Some cytochrome p450 type interactions

Should not be combined with MAOi

Monoamine oxidase inhibitors (phenelzine and tranylcypromine are in current use in the US) - both irreversibly inhibit both MAO A and MAO B

NE and 5HT preferentially catabolized by MAO A

Selegiline is selective MAO B used in PD

Higher doses of selegeline may have anti depressant activity probs because it loses isozyme specificity 

Inhibting MAO-A activity appears to be more important relevant for antidepressant benefit 

Other agents in this class include RIMA (reversible inhibitors of monoamine oxidase type A)

Rarely used because of toxicity and potential for food interactions

Used for treatment of depression unresponsive to other agents

Effective against atypical depression 

Anxiety, social anxiety, and panic disorder 

Selegeline for PD; higher concentrations will be used for depression 

blockade of both isozymes inhibits metabolism of tyramine -- releases NE -- dramatic hypertension

Competitive, reversible MAO-A selective drugs are much less likely to have this side effect

MAOi can cause serotonin syndrome through interactions with drugs that may release serotonin, including meperidine and other opiates, sympathomimetics, TCAs, L-DOPA, and SSRIs 

Tranylcypromine resembles amphetamine and selegeline has an amphetamine like metabolite so they can cause CNS overdose stimulation

Postural hypotension - may be due to elevated DA and false transmitter called octopamine

Weight gain - desensitization of serotonergic satiety mechanisms but is highly speculative 

SSRIs, SNRIs, tricyclics, and meperidine with MAOi will cause serotonin syndrome

Delirium, coma

hypertension, tachycardia, sweating

Myoclonus, hyperreflexia, tremor

allow 2 weeks after most serotonergic drugs; 4-5 weeks with fluoxetine before switching to MAOi

MAOi must be discontinued 2 weeks before another serotonergic agent 

Tyramine

Sympathetic drugs like pseudoephedrine also contraindicated