Pharmacology Psychotherapeutic Drugs: Antidepressants And Antimanic Drugs I-Ii

Front 1

How do antidepressants work?

Back 1

Antidepressant drugs interact with neurotransmitter systems in the central nervous system to exert their therapeutic and toxic effects, and with peripheral autonomic transmission which results in some of the adverse effects.

Front 2

What are the major pathways of neurohormonal transmission?

Back 2

Serotonergic
Adrenergic
Cholinergic

Front 3

What are the MAOIs?

Back 3

Phenelzine
Tranylcypromine
Isocarboxazid
Selegeline

Front 4

What are the serotonin reuptake inhibitors (SRIs)?

Back 4

Citalopram
Fluoxetine
Fluovaxamine
Sertraline
Paroxetine

Front 5

What are the norepinephrine/dopamine reuptake inhibitors (NDRIs)?

Back 5

Bupropion

Front 6

What are SRIs used to treat?

Back 6

Mood disorders (depresion)
Obsessive-compulsive disorder
Posttraumatic stress disorder
Anxiety disorder
Panic disorder
Bulimia

Front 7

What evidence is there for 5-HT roles in depressive disorders?

Back 7

a. 15 percent of people treated with reserpine (one of the early drugs for treatment of hypertension) get depressed. Reserpine depletes neuronal 5-HT, NE, and DA.
b. There is decreased CSF 5HIAA (5-hydroxyindoleacetic acid; serotonin metabolite that results from MAO metabolism of serotonin followed by oxidation by aldehyde dehydrogenase) in drug-free patients with depressive disorders.
c. Decreased 5-HT and 5HIAA in brain tissue of depressed patients.
d. There is a decreased number of 5-HT transporter (reuptake pumps) binding sites in brain tissue of depressed patients.
e. There is decreased plasma tryptophan (precursor of 5-HT) in patients with depressive disorders.
f. There is relapse of patients successfully treated with SRIs following tryptophan depletion.
g. There is an increased density of 5-HT2 binding sites in brain and platelets of patients with depressive disorders.
h. There is an increased density of 5-HT2 transporter binding sites in brain tissue of suicide victims.

Front 8

Describe the role of presynaptic reuptake pumps

Back 8

Presynaptic membrane sites (pumps) reuptake serotonin and catecholamines into the nerve terminals after the transmitters are released during nerve transmission in the CNS. Reuptake is the primary mechanism for termination of the neurotransmitters effects

Front 9

Describe the rate of release of serotonin in depressed patients

Back 9

The rate of release of serotonin from CNS neurons is decreased in depressed patients. (Norepinephrine will be discussed later.) The reason for a decrease in firing of serotonergic neurons and release of serotonin is not known. Therefore, there is a decrease in serotonin in the synaptic cleft.

Front 10

Explain how serotonin reuptake inhibitors work

Back 10

The class of drug known as serotonin reuptake inhibitors (fluoxetine or Prozac) inhibit this pump so that more serotonin remains in the synapse. This increases serotonergic transmission but is not the immediate mechanism for antidepressant activity (see below). (Other drugs can inhibit norepinephrine and/or dopamine pumps to also increase level of these transmitters in the synapse; to be described later.)

Front 11

Explain the time of course of SRI action

Back 11

The effect of SRIs on the pump is manifested in about one hour but clinical effects on depression may take about 4 weeks to occur. Why? The adverse side effects such as nausea, do occur early correlating with the time course of pump inhibition.

Front 12

Explain the relationship betwen uptake inhibiton and the antidepressant effect of SRIs

Back 12

Uptake inhibition is not the direct cause of the antidepressant effect of these drugs

Front 13

Describe the presynaptic 5-HT1A receptor

Back 13

On cell bodies in the midbrain raphe, control firing rate of serotonergic neurons (autoreceptors) by serotonin decreases neuronal firing, therefore, providing negative feed back. These recpetors may be responsible for the decreased rate of firing of serotonergic neurons in depressed patients because of an abnormal increased effect on serotonergic transmission. The receptors are down regulated in about 3 weeks after an SRI because of exposure to a large amount of extracellular serotonin for a long time period, resulting from inhibition of the reuptake pump (exposure to large amounts of transmitters cause down regulation of receptors through effects on genes and protein synthesis). After down regulation of these recpetors, the firing rate of the serotonergic neurons increases because they are no longer abnormally inhibited by these receptors. This is believes to be the mechanism for the therapeutic effect.

Front 14

Describe the 5-HT1D receptor

Back 14

On presynaptic axon terminal also controls serotonin release from presynaptic part of cleft. If this receptor is stimulated it also reduces the release of 5HT from the nerve terminal. Some drugs used to treat migraine (sumatriptan) bind to this receptor site to stimulate it and thus inhibit serotonin release. Therefore, it might be predicted that SRIs reduce serotonin release through this receptor by an immediate effect.

Front 15

Describe the postsynaptic 5-HT1A receptor

Back 15

Controls firing rate of the serotonin system. Serotonin neurons go directly to the prefrontal cortex without synapsing at any other connections so these 5HT1A receptors are far away from the cell bodies. These receptors may be involved in anxiety; depression; aggregation; panic attack; OC behavior. Inhibition of the reuptake pump and increased serotonin in the synaptic cleft results in increased post-synaptic stimulation of these recpetors. The immediate effect may cause some patients to feel anxious, and many of the symptoms decreased abouve may occur ase adverse drug effects, that occur during the early period of treatment (hours and days). Eventually these side effects diminish and disappear as the post synaptic receptors also down regulate.

Front 16

Describe the 5HT2A receptors

Back 16

Postsynaptic

When stimulated by 5-HT release from presynaptic terminal causes increased firing of post synaptic cell. Stimulation responsible for depression; anxiety; psychosis; hallucinations; sleep disorders (insomnia), and decreased sexual function. LSD binding to these receptors is responsible for hallucinations, psychosis, and possibly mood disorders.

Front 17

Describe 5HT2C receptors

Back 17

Postsynaptic

involved in anxiety aggression; depression; sensory information; nociception; appetite stimulation; and weight gain.

Front 18

Describe 5HT3 receptors

Back 18

Postsynaptic

in brain (area postrema) and in gut. SRIs cause nausea and diarrhea through the stimulatory effect of serotonin on these receptors. Specific 5HT3 blockers are used to treat nausea and vomiting by blocking these receptors at both central and peripheral locations and slowing bowel contraction in irritable bowel syndrome.

Front 19

Describe 5HT4 receptors

Back 19

Postsynaptic

In brain and in bladder and intestinal smooth muscle; activation of these receptors and causes increased ACh release and enhances smooth muscle contraction in bladder and intestines (diarrhea)

Front 20

What is the relationship between noradrenergic and dopaminergic systems in depression?

Back 20

There is a decrease in function of noradrenergic and dopaminergic systems in depression and may also be involved in the pathophysiological mechanisms.

Front 21

What occurs with dopamine deficiency?

Back 21

Decrased ability to experience pleasure
Decreased motivation
Apathy
Decreased attention
Cognitive slowing

Front 22

What occurs with norepinephrine deficiency?

Back 22

Depression
Lethargy
Decreased alertness

Front 23

What are the side effects resulting from too much serotonin in the synaptic cleft resulting from inhibition of uptake pumps and therefore, excessive stimulation of post synaptic receptors

Back 23

-Sexual dysfunction
-GI Upset
-Sleep disturbance
-Suppression of dopamine neurotransmitters which may result in
-Decreased ability to experience pleasure
-Apathy and decreased motivation
-Decreased attention
-Cognitive slowing

Front 24

What are the side effects resulting from too much noradrenergic in the synaptic cleft resulting from inhibition of uptake pumps and therefore, excessive stimulation of post synaptic receptors

Back 24

-Tremor
-Tachycardia

Front 25

What are the side effects resulting from too much dopaminergic in the synaptic cleft resulting from inhibition of uptake pumps and therefore, excessive stimulation of post synaptic receptors

Back 25

-Psychomotor activation
-Aggravation of psychosis

Front 26

What are the effects of histamine (H1) blockade?

Back 26

Sedation
Hypotension
Weight gain

Front 27

What are the effects of muscarinic blockade?

Back 27

Dry mouth
Blurred vision
Sinus tachcardia
Constipation
Urinary retention
Memory impairment

Front 28

What are the effects of alpha1-adrenergic blockade?

Back 28

-Orthostatic hypotension
-Dizziness
-Reflex tachycardia

Front 29

What are the effects of dopamine (D2) blockade?

Back 29

-EPS
-Galactorrhea
-Sexual dysfunction

Front 30

What are the tricyclic drugs?

Back 30

Amitriptyline
Desipramine
Imipramine
Nortriptyline

Front 31

What are the monocyclic drugs?

Back 31

Bupropion

Front 32

What are the phenylpiperazines?

Back 32

Trazodone
Nefazodone