Antidepressants Flashcards
What is different about the central amine/monoamine neurotransmission vs GABA/Glutamate neurotransmission in the brain? What does that mean in terms of neuronal activity?
NE/Da/5HT released primarily from varicosities!!!!
Large amounts release as opposed to from individual axon terminals
2 Types of neuronal activity result from release from varicosities:
1) Post-synapses nearby get majority of NT and have fast APs
2) some diffuses away at lesser concentrations and leads to tonic control of neutrotransmission for slow tonic firing –> Leads to integration of informaiton over longer periods of time
Describe the steps in the synthesis and release of Serotonin. What is the RLS? What controls levels?
Tryptophan ingested and then Tryptophan hydroxylase reaction is rate limiting step!
5HT is made through several more enzymatic steps –> packaged into vesicles with VMAT transporter –> Vesicle release
Controlled by:
- Presynaptic Autoreceptor – 5HT1D –> binds serotonin and inhibits release of more
- *-MAO** – degrades serotonin in synapse and extracellular space
-Reuptake Transporter
Describe the steps in the synthesis and release of NE. What is the RLS? What controls the levels?
Tyrosine made into L-DOPA w/ Tyrosine Hydroxylase (RLS!!) and then in the Dopamine
Da packaged into vesicle with VMAT along with Da-Beta-Hydroxylase which converts it into NE in the vesicle and then released
Controlled by:
- Alpha2 Adrenergic Autoreceptor – activated and inhibits release of NE
- MAO
- NE Transporter
What is the monoamine hypothesis of depression? What evidence is it based on?
Depression results from decreased levels of NE/5HT
Reserpine – Anti-HTN drug that induces depression in patients by inhibiting VMAT and thereby depleting NE/Da/5HT stores
Imipramine and Iproniazid are both Tricyclices
Imipramine (and metabolie Desipramine) block 5HT and NE transporters respectively
Iproniazid blocks MAO
Both lead to elevated mood!
What are the symptoms of Serotonin Deficiency Syndrome?
Depressed mood
Anxiety and panic and phobia
Obsessions and compulsions
Food craving and bulimia
Where does Serotonin act and what are its physiologic functions? What happens in the brainstem if you have too much?
Frontal Cortex – regulates mood
Basal Ganglia – regulates compusion/obsession and movement [deficiency = Akathisia/Agitation, OCD]
Lymbic system – anxiety
Hypothalamus – Appetite/bulimia
Brainstem
- Sleep centers – too much get insomnia
- Spinal Cord – too much get sexual dysfunction
- Area Postrema – N/V
What are the important Serotonin Receptor subtypes and how do they work?
They are all GPCR (*Except for 5HT3- ion channel)
5HT1D = Autoreceptor
5HT1A + 5HT1D = presynaptic receptors that inhibit 5HT release
5HT2A, 2C, 3 = Post-Synaptic
All of these implicated in depression
Whats the difference between the 2 pre-synaptic 5HT receptors?
5HT1A = Presynaptic receptor in the Dendrite and when activated slows down AP firing
5HT1D = Classic Autoreceptor at terminal and limits release at the synapse
What are the symptoms of NE deficiency syndrome?
Impaired attention, problems concentrating, deficiencies in working memory
Slowness of information processing
Depressed mood
Psychomotor retardation, fatigue
Where does NE act and what are the physiological effects?
Pre-Frontal Cortex – Beta 1 receptors to modulate mood and depression
Frontal Cortex – Alpha 2 receptors modulate attention
Limbic system – agitation, emotion, energy levels
Cerebellum – deficiency can lead to tremor
Brainstem – Controls BP and orthostatics
Heart – Drugs can cause Tachycardia
Bladder – Urinary retention!!
What are the NE receptor subtypes to know/associated with depression?
A1, A2, B1, B2 associated with depression (out of 9 total receptor subtypes)
A2 – presynaptic auto-inhibitory for NE transmission
- On dendrite slows rate of firing and reduced excitability
- On Terminal, blocks release
B1 – postsynaptic in Pre-Frontal cortex for regulating NE action in mood
How do 5HT and NE interact with each other? What’s their relationship?
NE can control 5HT release as an Accelerator in the brainstem and a brake in the frontal cortex
Accelerator: NE neuron in LC projects to 5HT neuron in RN and activates Alpha 1 receptors on 5HT neurons to increase firing rate
Brake: NE acts on Pre-synaptic Alpha-2 Receptor on 5HT neurons in cortex to decrease release
Tricyclics (TCAs): Name them, MOA and pharmacokinetics
Amitriptyline, Desipramine, Imipramine, Nortriptyline
Block 5HT and NE reuptake transporters w/ varying affinities
- Also block Muscarinic Receptors
- Also block H1 Histamine Receptors
- Also block Alpha1 Adrenergic Receptors
- Also Block Na Channels
Lipophilic and cross BBB easily
Well absorbed and undergo first pass metab in liver by CYP2D6
***Many metabolites are pharmacologically active from demethylation or hydroxylation **
TCAs: Side Effects
CARDIAC ARRHYTHMIA – blocks NA channels in heart, slow depolarizations
Antihistamine: sedation and weight gain
Anticholinergic: N/V, anorexia, dry mouth, blurred vision, confusion, constipation, tachycardia, urinary retention
Anti-Adrengergic: orthostatic hypotensions, reflex tachycardia, drowsiness, dizziness
Classic MAOIs: name them and discuss MOA
Isocarboxazid, Phenelzine sulfate, Tranylcypromine
MOA: irreversibly bind and inhibit MAO that degrades monoamines 5HT, NE, and Tyramine (MAO-A) and dopamine (MAO-B)
Bc bound irreversibly, cleared as a comlex with MAO
