Intro To Cns Pharmacology

Front 1

The CNS is the primary site of action of ___% of all prescription drugs.

Back 1

The CNS is the primary site of action of 20% of all prescription drugs.

Front 2

Explain the counerintuitive effects of CNS drugs...

Back 2

They can have different actions in the brain than in the body...one can dominate over the other and determine the ultimate action of the drug.

Front 3

So far all we can do is hypothesize that most CNS disorders are caused by.....

Back 3

Chemical Imbalances in the brain.

Front 4

Once a NT is released into the synapse....what are the all the things that can happen to it?

Back 4

1) It can bind to it's target receptor on the post-synaptic neuron and cause it's effect.
2) It can bind to an inhibitor autoreceptor on the presynaptic neuron that inhibits the release of more NT.
3) It can be transported back into the presynaptic terminal by plasma membrane transporters.
4) It can be metabolized by enzymes in the synapse.
5) It can diffuse away from the synapse.

Front 5

What are the monoamine NT's in the brain?

Back 5

Dopamine
Norepinephrine
Serotonin.

Front 6

What are all of the NT's in the brain?

Back 6

Monoaminess: NE, 5-HT, DA

GABA
Glutamate

ACh
Opiod Peptides
Adenosine

Front 7

Functions of Dopamine

Back 7

(Think of all the parkinson's, demantia, addiciton symptoms)

* Involuntary motor activity
* Memory and Cognition
* Motivation and Reward
* Emotional Responses
* Regulation of Prolactin Release and milk production
* Nausea and Vomiting (CTZ zone)

Front 8

Location of Dopamine Neurons on the brain.

Are the functions the same?

Back 8

1) SUBSTANTIA NIGRA/ NIGROSTRIATAL PATHWAY (D2 receptors)
--> From the Substantia Nigra to the Striatum
---> Involuntary Motor movement here.
----> D2 Blockade/Decrease: Parkinsonism/ Parkinson's Disease/ EPS
----> D2 stimulation/ Incr: Huntington's, Tourrettes, Dyskinesias

2) VENTRAL TEGMENTAL AREA/

MESOLIMBIC PATHWAY:
-->From the VTA to the Limbic System (Nucleus Accumbens/ Hippocampus)
--> Memory, Emotional Responses (Amydala and Hippo projections)
--->, Reward/Desire, Addiction (Nucleus Accumbens Projections)
--> Too much stimulation leadst o Schizophrenia (Positive Symptoms) and Addiction.

MESOCORTICAL PATHWAY
---> From the VTA to the Prefrontal Cortex.
---> Cognition, Executive Functions, Socialization, Motivation, emotional responses
----> Dysfunction can leads to psychosis and Schizophrenia (negative symptoms).

3) ARCUATE NUCLEUS of the hypothalamus/TUBERO-INFUNDIBULAR PATHWAY
-->From arcuate nucleus to the Pituitary Gland (median eminence).
--> Fcn: Tonic inhibitory control of prolactin secretion from the ANT PIT.
---> DA Blockade leads to hyperprolactinemia and galactorrhea/ amenorrhea (Gynecomastia in men.)
--> DA blockade here can also cause Acromagaly due to decr inhibition of GH.

Are the fcns the same??? NO - Each type of DA neuron is responsible for a specific action in the brain. Dysfunction in these diff areas of DA neurons leads to DIFFERENT diseases.

Front 9

Explain the different Dopamine Receptors

Back 9

BOTH ARE PRESENT ON POST-SYNAPTIC MEMBRANES

D-1 Receptors
--> Work by Increasing Cyclic AMP

D-2 Receptors
--> Work by Decreasing Cyclic AMP
---> Also present on the presynaptic membrane (inhibitory autoreceptors).

Front 10

How is Dopamine Synthesized?

Back 10

Dopamine is synthesized from Tyrosine.

* Tyrosine enters the neuron.
* Tyrosine-->DOPA via Tyrosine hydroxylase (Tyrosine hydroxylase is the rate-limiting step.)
* DOPA--> Dopamine (in the neural cytoplasm) (By DOPA decarboxylase, ADDD+, and Vit. B6)
* Dopamine - taken from cytoplasm and transported into the synaptic vesicle by a VESICULAR MONOAMINE TRANSPORTER.

(AAAD = AROMATIC AMINO ACID DECARBOXYLASE)

Front 11

How is Dopamine Metabolized?

Back 11

* Dopamine is metabolized in the synapse by COMT into 3-methyl DOPA. This is then taken back up into the presynaptic neuron by Plasma membrane transporters to recycle DA.

* Dopamine is also metabolized in the synapse MAO-B.

Front 12

Explain how the metabolism of DA can sometimes interfere with treatment for Parkinson's disease.

Back 12

Dopamine is metabolized by COMT to 3-O-methyl DOPA. This is inactive, but, it is a substrate for the AA plasma membrane transporter that transports neutral AA’s into the brain. This is how L-dopa gets in the brain…so…this 3-o-methyl dopa competes with L-dopa to get into the brain…if you have too much. L-dopa will not work.

Front 13

What are the cerebral tracts for NE?

Back 13

LOCUS COERULEUS/ LATERAL TEGMENTAL AREA-----> HIPPOCAMPUS, THALAMUS, CORTICES, AMYGDALA, HYPOTHALAMUS (basically the whole brain).

Causes
* Arousal
* Attention
* Affect (Mood)
* Appetite

Dysruptions in signalling cause ANXIETY AND DEPRESSION.

Front 14

How is NE synthesized?

Back 14

NE is synthesized from Tyrosine

* Tyrosine enters the neuron.
* Tyrosine-->DOPA via Tyrosine hydroxylase (Tyrosine hydroxylase is the rate-limiting step.)
* DOPA--> Dopamine (in the neural cytoplasm) (By DOPA decarboxylase, ADD+, and Vit. B6)
* Dopamine - taken from cytoplasm and transported into the synaptic vesicle by a VESICULAR MONOAMINE TRANSPORTER.
* In the vesicle, the enzyme Dopamine Beta Hydroxylase turn DA into NE.

(AAAD = AROMATIC AMINO ACID DECARBOXYLASE)

Front 15

How is Norepinephrine metabolized?

Back 15

* NE is metabolized in the synapse by COMT into inactive metabolite. These are then taken up into the presynaptic cell to be recycled by Plasma Membrane Transporters.

* Once back in the presynaptic neuron, these metabolites are then metabolized FURTHER INTO DOMA (dihydromandelic acid) by MAO-A.

* DOMA then leaves the neuron and in the plasma..is metabolized FURTHER by COMT (again) into VMA (vanilmandelic acid). This is an inactive byproduct.

Front 16

What are all the things that can happen to NE once it is released by the synapse?

Back 16

1) Binds to Alpha and beta receptors on post-synaptic membrane (effect)

2) is metabolized by COMT and then metabolites are taken back up into the presynaptic neuron by plasma membrane transporters and metabolized further by MAO-A into DOMA. DOMA then leaves the neuron and is metabolized further by COMT into VMA.

3) BInds to alpha2 (inhibitory autoreceptors) on presynaptic membrane.

4) Diffuses away

Front 17

What is the cerebral pathway for Serotonin?

What effects does it cause?

Blockage or Dysruption of the pathway causes??

Back 17

RAPHE NUCLEI---> AMYGDALA, HIPPOCAMPUS, HYPOTHALAMUS, SEPTUM, CTZ (the whole brain)

Effects:
* Affect (Mood)
* Anxiety/ Depression
* Appetite
* Sleep
* Emesis

*Dysfunction or blockage of these receptors leads to anxiety and depression.

Front 18

How is serotonin synthesized?

Back 18

Serotonin is synthesized from Tryptophan.

* Tryptophan enters the neuron and is converted to 5-OH Tryptophan by Tryptophan hydroxylase.
* 5-OH Tryptophan is converted to Serotonin (5-HT) by AAAD+ & Vit. B6.

* Serotonin then enters the vesicle via vesicular monoamine transporters.

Front 19

HOw is melatonin synthesized?

Back 19

In the pineal gland, serotonin is converted to melatonin.

Front 20

How is serotonin metabolized?

Back 20

* Serotonin is taken back up into the neuron by the Plasma Membrane Transporter.
* Inside the neuron, it is metabolized by MAO-A into 5-HIAA (5-hydroxy-indole acetic acid).
* 5-HIAA is then released into the plasma. This can be used as a marker for carcinoid syndrome/tumors.

Front 21

T/F COMT metabolizes serotonin.

Back 21

False

Front 22

Explain everything that happens to serotonin when it is released from the neuron.

Back 22

1) Binds to 5-HT receptors on post-synaptic membrane for an effect
---> 5-HT3 (Na/K Channel)
---> All others: G-protein coupled
2) Binds to 5-HT1 inhibitor autoreceptors on the presynaptic membrane. (Cause of depression..too many autoreceptors).
3) Reenters the presynaptic neuron via SERT plasma membrane transporters (where it is metabolized by MAO-A into 5-HIAA). This is the site of action of SSRI's.
4) Diffuses away

Front 23

How do you test for carcinoid syndrome?

Back 23

Get a blood sample and look for 5-HIAA (a serotonin metabolite)..marker for carcinoid tumors

Front 24

What is Ramelton?

Back 24

Melatonin 1 &2 Agonist.

Used to tx insomnia.

Front 25

What is the Acetylcholine Pathway?

Back 25

BASAL FOREBRAIN/ PEDUNCULOPONTINE NUCLEUS---> AMYGDALA, HIPPOCAMPUS, THALAMUS, CORTICES, CTZ (most of the brain).

Effects:
* Emotion (Limbic System)
* Memory/ Cognition (Hippocampus)
* Extrapyramidal Movement (Striatal Interneurons)
* Emesis (CTZ Vomiting Center).

Dysruption/ Blockade causes:
---> Alzheimers Disease (hippocampal degeneration)
---> Parkinsonism (Increased ACh to striatum).
---> Psychosis
---> Emesis

Front 26

What causes Alzheimers Disease and how can you tx it?

Back 26

Cholinergic Degeneration of the Hippocampus.

Can treat it by increasing ACh.
---> Donepazil (Aricept)...an Achesterase Inhibitor.

Front 27

How is ACh synthesized?

Back 27

ACh is synthesized from Choline and Acetyl CoA in the neuron.

Choline + Acetyl CoA ---> ACh via the enzyme Choline aceytyltransferase.

* ACh then goes into the vesicle via a vesicle transporter.

Front 28

How ACh Metabolized?

Back 28

ACh is metabolized in the plasma by by Achesterase into Acetic Acid and Choline.

Choline is then taken back up into the presynaptic neuron via a choline transporter...this is the rate limiting step in ACh synthesis.

Front 29

What are all the actions of ACh once it is released into the synapse?

Back 29

1) Binds to post-synaptic cholinergic receptors for effect
---> Nicotinic: (Na/K Channel)
---> Muscarinic (G-protein coupled)
2) Is metabolized by AChesterase into Acetic Acid and Choline. Choline is taken up into the presynaptic neuron for recycling.
3) Diffuses away.

Front 30

What 2 NT's work together in balance to maintain overall brain excitation level?

Back 30

GABA (major inhibitory NT the brain, ubiquitous)

Glutamate (major excitatory NT in the brain, ubiquitous).

Front 31

Dysruption in the balance b/n GABA and Glutamate in the brain can result in....

Back 31

TOO GLUTAMATE/ DECR GABA
* Seizures/ Epilepsy

INCR GABA/DECR GLUTAMATE
* Lethargy

Front 32

___% of neurons in the brain are glutamatergic.

Back 32

70%!!

Front 33

Endogenous opiod peptides (______) are involved in what functions in the brain?

Back 33

Endogenous opiod peptides (Endorphins Enkephalins) are involved in:

Motivation
Emotion
Pain and Stress response
Control of Food Intake.

Front 34

HOw does Caffeine work?

Back 34

Caffeine's stimulatory effects are due in part to antagonism of adenosine receptors causing increased dopamine and glutamate activity.

(Adenosine suppresses arousal).

Front 35

Where is the vomiting center of the brain.

Back 35

At the base of the brain.

VOMITING CENTER: Dorsal Lateral Reticular Formation

CTZ ZONE: Area Postrema, 4th Ventricle

Front 36

What Four Pathways that Stimulate the Vomiting Center of the Brain (Dorsal Lateral Reticular Formation)??

What receptors are involved for each pathway??

Back 36

1) Labyrinth Apparatus in Ear (motion) goes to the CEREBELLUM, to the vomiting center.
---> H1 and M1 receptors!!!

2) Cerebral Cortex

3) 5-HT3 receptors in Stomach and Small Intestines via Vagal and SNS afferents to the SOLITARY TRACT NUCLEUS (STN). (to the vomiting center).
---> 5-HT3 Receptors in the GI tract.
---> STN receptors include: 5HT3, D2, M1, H1

4) The CTZ zone (Area Postrema, 4th Ventricle)...this zones sits ON the BBB...that means that anything outside OR inside the brain can stimulate it. ...then the vomiting center. (CTZ zone can also stimulate the STN)
--> Receptors Include: M1, D2, 5-HT3, NK1

Front 37

How does chemo cause nausea?

Back 37

Via stimulation of the 5-HT3 receptors.

Front 38

Serotonin Receptors are Located Where?

Back 38

5HT3: CTZ zone, Solitary Tract Nucleus, GI Tract

Front 39

What Drugs are Blood Borne Emetics...is...stimulate the CTZ zone of the brain and/ or the 5HT3 receptors of the GI tract?

Back 39

* CYTOTOXIC DRUGS (Chemo, etc)..via 5HT3 of CTZ and GI tract
* OPIODS
* CHOLINOMIMETRICS (bind to M1 receptors in CTZ zone.
* L-DOPA (via D2 of CTZ)
* BROMOCRIPTINE (via D2 of CTZ)
* APOMORPHINE

Front 40

M1 receptors are located where in the brain? (for nausea)

Back 40

Cerebellum

CTZ zone

Solitary Tract Nucleus

Front 41

H1 Receptors are located where in the brain?

Back 41

Cerebrellum

Solitary Tract Nucleus

CTZ

Front 42

Where are neurokinin receptors located in the brain?

Back 42

In the CTZ zone (NK1).

Front 43

How does reglan stop nausea?

Back 43

Increases LES tone.
Blocks D2 receptors in the CTZ and STN

DO NOT GIVE TO PARKINSON'S PTS.

Front 44

How does Scopolamine treat Nausea? Motion Sickness?

Back 44

Scopoloamine is an antimuscarinic and crosses the BBB.

So it blocks M1 receptors in the Cerebellum..preventing motion sickness and nausea.

It also blocks M1 receptors in the CTZ zone and the STN of the brain..further preventing nausea.

Front 45

How do opiods cause nausea?

Back 45

4 diff mechanisms:

1) Cause dopamine release, which acts on CTZ

2) Acts in the stomach and SI via serotonin release

3) Act on labyrinth apparatus in the ear (unknown mechanism). To decrease labyrinth apparatus effects (give an antihistamine).

4)Opiods can also cause constipation and N.V via vagal and sympathetic afferents. (serotonin release). If the opoid is causing constipation, first line tx is metaclopramide.

Front 46

Meclizine

Back 46

Histamine-1 Receptor Antagonist
Muscarinic Antagonist
* Crosses BBB. Blocks H1 receptors in the Cerebellum and STN.

USE
* Motion Sickness
* Postop N/V

SE
* Causes less drowsiness than dimenhydrinate
* Antimusc SE...dry mouth, mydriasis, etc.

Front 47

Dimenhydrinate (Dramamine)

Back 47

A combination of Diphenhydramine and 8-chlorotheophylline (a stimulant).

--> This pvts sleepiness but allows tx of motion sickness.

Diphenhydramine is a Histamine-1 Antagonist and anti-musc that pvts motion sickness and nausea but also has a SE of sedation.

Front 48

Describe the BBB

Back 48

Has TIGHT, OVERLAPPING cell junctions formed by astrocyte end feet and endothelial cells.

These allow only lipophilic things to passively diffuse across.

Front 49

What things can passively diffuse across the BBB?

What things require facilitated transport?

Back 49

Only lipophilic, hydrophobic, or unionized molecules can passively diffuse across the BBB. Degree of ionization at body pH depends on the pKa of the compound.

L-Dopa crosses the BBB via facilitated transport via neutral AA transporters...GLUTAMINE also uses this and can compete with L-Dopa here. (So does 3-O-methyl DOPA..a metabolite of DA).

Front 50

T/F L-Dopa crosses the BBB via passive diffusion.

Back 50

False.

Uses Facilitated Transport via Neutral AA transporters. Competes with glutamine and 3-methyl DOPA.

Front 51

How does Mannitol affect the BBB?

Back 51

Causes a hypertonic systemic blood that somehow disrupts the tight junctions..

Front 52

What pathophysiologies cause disruption in the BBB?

Back 52

* Meningitis
* HTN
* Brain Trauma
* Seizures...this allow K to enter the brain...which can worsen the seizure.
* Edema