Antidepressants and Lithium (Walworth) - 10/12/16 Flashcards
Describe the monoamine hypothesis of mood as it pertains to clinically useful antidepressant drugs.
Depressed mood results from decreased monoamine nerve transmission (serotonin, dopamine, norepinephrine).
1950s - RESERPINE introduced for HTN
- Found to induce depression in 10-15% of patients
- Binds tightly to vesicles and inhibits VMAT (monoamine reuptake transporter) → nerve endings cannot concentrate and store monoamines in vesicles → monoamines in cytoplasm degraded by MAO
- Result: little or no active transmitter released from nerve endings → depletion of monoamines by reserpine leads to DEPRESSION
Depression represents a decreased availability of either 5-HT or NE or both. Where do they originate from?
Major steps in the synthesis and catabolism of serotonin
Serotonergic neurons have cell surface transporters for tryptophan.
- In cytoplasm of neuron, tryptophan → 5-hydroxytryptophan (5-HT)
-
5-HT decarboxylated to serotonin
- Serotonin may be taken back up through reuptake transporter… otherwise,
- Serotonin subject to metabolism by MAO
Major steps in the synthesis and catabolism of norepinephrine
- Noradrenergic neurons ahve cell surface transporters for tyrosine
- Tyrosine → DOPA by tyrosine hydroxylase
- DOPA → DOPAMINE → NOREPI
Like serotonin, NE is also subject to metabolism and also subject to reuptake via reuptake transporters
Describe mechanisms of action by which clinically useful antidepressants are thought to act
AA converted to NTs and packaged into vesicles by vesicular monoamine transporter VAT (in this figure).
→ NT released into synaptic cleft
Antidepressant sites of action:
-
Block reuptake of NTs into presynaptic cell
- SSRIs
- SNRIs
- TCAs
-
Block breakdown of NTs in the cytoplasm of releasing cell
- MAOIs
- Block serotonin receptors on post-synaptic cells
- Describe limitations to the monoamine hypothesis of depression and possible explanations
- Possible explanation for limitation
- Limitations
- Antidepressants act rapidly at sites of action YET clinical effects require 3 or more weeks of therapy :(
- While reserpine rapidly depletes NT, several weeks of treatment are required to induce depression
- Possible explanation for discrepancy between rapid action of antidepressants and slow clinical response: presynaptic autoreceptors
-
Binding of NTs to autoreceptors activates negative feedback mechanisms:
- Inhibits synthesis of monoamines
- Inhibits release of monoamines from vesicles
Autoregulatory Mechanisms
Acute Treatment vs. Long-Term Treatment
Acute Treatment
- TCA or SSRI blocks ability of transporter to take up NT
- Under this condition, elevation of NT shown to occupy additional presynaptic autoreceptors → inhibitory effect on synthesis and release enhanced
- Result: low level of signaling in post synaptic cell continues
Long-Term Treatment
- Continuous exposure to NT → Sensitization of autoreceptors occur
- Loss of signaling through autoreceptors releases inhibition of NT synthesis and release
- RESULT: elevate NT at post synaptic cell and generate therapeutic level of signaling
** Treatment with antidepressants for several weeks typically required to gain therapeutic benefit
Summarize - sites of action of major classes of antidepressants
- NE synthesized by noradrenergic neurons while serotonin synthesized by serotonergic neurons
- Both thought to contribute to modulation of mood
Identify the SSRIs and their major characteristics including mechanism, clinical uses and adverse effects
Selected serotonin reuptake inhibitors = first line antidepressants
- Fluoxetine (Prozac)
- Paroxetine (Paxil)
- Sertraline (Zoloft)
- Citalopram
- Escitalopram (Lexapro) [S-enantiomer of citalopram]
- Fluvoxamine
Mechanism:
- Inhibit 5-HT reuptake selectively as compared to NE reuptake
- Relatively selective for 5-HT transporter, thus side effects limited to effects on 5-HT-mediated responses
Used clinically for:
- MDD
- Anxiety disorder
- OCD
- PTSD
- PMDD (Premenstrual dysphoric disorder)
- Bulimia
Adverse Effects (result from elevation of serotonin in various tissues of body in addition to CNS)
- Nausea
- Headache
- Anxiety
- Agitation
- Insomnia
- Sexual dysfunction
- Extrapyramid effects (early in treatment)
- Seizures with gross overdose
- Serotonin Syndrome with MAOI
Identify the SNRIs and their major characteristics including mechanism, clinical uses, and adverse effects
SNRIs
- Venlafaxine (Effexor)
- Duloxetine (Cymbalta)
Mechanism
- Inhibit reuptake transporters for both 5-HT and NE
Clinical Uses
- Major depression
- Chronic pain
- Fibromyalgia
- Menopausal symptoms
Adverse Effects
- Nausea
- Headache
- Anxiety
- Agitation
- Insomnia
- Sexual dysfunction
- Extrapyramidal effects (early in treatment)
- Seizures with gross overdose
- Serotonin syndrome with MAOI
- Anticholinergic
- Sedation
- Hypertension (venlafaxine)
Identify the TCAs and their major characteristics including mechanism, clinical uses, and adverse effects.
TCAs
- Imipramine (5-HT >> NE)
- Amitriptyline
- Clomipramine
- Desipramine (NE >> 5-HT)
- Nortriptyline
Mechanism
Like SNRIs, TCAs also target re-uptake of both NE and 5-HT
Tend to interact with variety of other receptors → broad range of side effects
- ADDITIONALLY, TCAs have some antagonism at post synaptic alpha 1 AR
Clinical Uses
- Major depression
- Chronic pain
- OCD (clomipramine)
Adverse Effects
- Nausea
- Headache
- Anxiety
- Agitation
- Insomnia
- Sexual dysfunction
- Extrapyramidal effects (early in treatment)
- Seizures with gross overdose
- Serotonin syndrome with MAOI
- Alpha-block (orthostatic hypotension)
- Muscarinic block
- Sedation
- Weight gain
- Arrhythmias and seizures with OD
Describe the mechanism, therapeutic use and toxic effects of MAOIs.
MAOIs
- Phenelzine
- Tranylcypromine
Mechanism
- Inhibit monoamine oxidase (MAO)
- Phenelzine combines irreversibly with MAO → long-lasting inhibition
- Tranylcypromine does NOT bind irreversibly, but still has prolonged effect
Clinical Uses
- Used to treat major depression unresponsive to other drugs
Adverse Effects
- Hypertensive reactions in response to indirectly acting sympathomimetics
- Hyperthermia
- CNS stimulation (agitation, convulsions)
- Hypertensive crisis with tyramine-containing foods
- Serotonin syndrome with SSRI
- Orthostatic hypotension
Identify and describe distinctive properties of serotonin receptor antagonists.
5-HT2 antagonists
- Nefazodone
- Black box warning due to hepatotoxicity
- Trazodone
- Prodrug, converted to 5-HT_2A antagonists_
Clinical Uses
- Major depression
- Hypnosis (trazodone)
Adverse Effects
- Sedation
- Due to histamine receptor blockade
- Alpha-block (orthostatic hypotension)
- Result of alpha receptor blockade
Identify and describe distinctive properties of heterocyclic antidepressants.
Heterocyclic antidepressants
- Bupropion
- Enhances both NE and DA neurotransmission
- Mechanism: unclear
- Mirtazapine
- Antagonist at 5-HT2A/2C and 5-HT3 receptors
- Antagonist of presyanptic alpha 2 autoreceptor, enhances release of NE and 5-HT
Clinical Uses
- Major depression
- Smoking cessation (buproprion)
- Sedation (mirtazapine)
- Blocks presynaptic alpha 2 receptors on both NE and serotonergic neurons
Adverse Effects
- Bupropion –> Lowers seizure threshold
- Mirtazapine –> Sedation
What differentiates SNRIs from TCAs?
Propensity of these drugs to interact with other receptors including muscarinic, alpha adrenergic, and histamine receptors
Interactions lead to broader spectrum of side effects aka undesirable pharmacological effects are different
(Broader pharmacological effects of SNRIs and TCAs are the same)
Note: Mirtazapine has activity as an antagonist at serotonin receptors but also at H1 receptors –> acount for sedative properties
Lithium: pharmacodynamics
Lithium enters cells via sodium channels
Substitutes for sodium in generation APs and in sodium exchange across membranes
Cycle of inositol regeneration following signaling events that trigger production of inositol triphosphate also influenced by inositol
Antidepressant Drug List
