Adrenergic and Cholinergic Effects of CNS Drugs

Question 1

T or F. Both adrenergic and cholinergic neurons exist within the brain

Answer 1

T. And they both can be impacted by drug therapy

Question 2

Neurons secrete the same set of neurotransmitters from all of their synaptic termini. These transmitters include:

Answer 2

• excitatory glutamate and asparatate
• inhibitory GABA, gkycine, B-alanine, and taurine

ACh acting on nicotinci and muscarinic (M1-M5) receptors

• catecholamines: dopamine, NE, and epi acting on dopaminergic and a1, a2, b1, and b2 receptors
• serotonin (5-HT)

Question 3

Where are the majority of noradrenergic neurons (contain NE)?

Answer 3

the locus ceruleus (highest) and the central nucleus of amygdala (but NE is distributed widely in the brain)

Question 4

What does the locus ceruleus do?

Answer 4

It is involved in regulating sleep and arousal and the asociated aspects of attention and viligance.

Question 5

What can increased activity of the locus ceruleus cause?

Answer 5

increased anxiety by releasing NE in the amygdala and in other limbic areas

Question 6

Stimulation of beta-adrenergic receptors in the amygdala does what?

Answer 6

enhances memories for stimuli encoded under strong negative emotion, that is to say, recall of stimuli predicting danger. This mechanism may contribute to PTSD

Question 7

Nicotinic cholinergic receptors are found in autonomic ganglia (Nn) and in the NMJ (Nm). They are also found throughout the brain, albeit in the different permutations of the multimeric alpha/beta receptor conformation. How does nicotine act in the brain?

Answer 7

it has effects upon the a4b2 constructs in the substania nigra ventral tegmental area

Question 8

ACh influences what processes in the brain?

Answer 8

motivation, learning, and memory

Question 9

NE influences what processes in the brain?

Answer 9

arousal, attention, vigilance, and memory. Descending NE fibers also modular afferent pain signals

Question 10

T or F. Both Ach and NE are involved in regulation of arousal (wakefulness) and cognition.

Answer 10

T. So drugs that are antagonists for these processes will tend to produce sedation and mental clouding. Histamine is also involved in wakefulness

Question 11

How do antipsychotics work?

Answer 11

Atypicals dont possess uniform pharmacology or MOA but some things are:

• antagonism at dopaminergic D1-5 receptors
• agonist or antagonist at 5-HT (1A/2A) receptors
• antagonists at a-1 and (mostly) a-2 receptors
• antagonist at muscarinic receptors (clozapine, olanazapine, quetiapine)
• antagonism at H1 receptors

drug choice is based on tolerability of side effects

Question 12

What are the potential ANS AEs of antipsychotics?

Answer 12

loss of accommodation

dry mouth

difficulty urinating/constipation

orthostatic hypotension

impotence

ejaculation failure

Question 13

What is the mechanism of the potential ANS AEs of antipsychotics?

Answer 13

muscarinic cholinoceptor blockade and/or

a-adrenoceptor bockade

Question 14

What are the potential CNS AEs of antipsychotics?

Answer 14

Parkinson’s syndrome

akathisia (a state of agitation, distress, and restlessness that is an occasional side-effect of antipsychotic and antidepressant drugs.)

dystonias

Tardive dyskinesia

toxic confusional state

Question 15

What is the mechanism of the potential CNS AEs of antipsychotics?

Answer 15

dopamine receptor blockade

supersensitivity of dopamine receptors

muscarinic blockade

Question 16

What are the potential Endocrine AEs of antipsychotics?

Answer 16

amenorrhea-galactorrhea

infertility

impotence

Question 17

What is the mechanism of the potential Endocrine AEs of antipsychotics?

Answer 17

dopamine rceptor blockade resulting in hyperprolactinemia

Question 18

Antipsychotics can also cause weight gain. How?

Answer 18

possibly combined H1 and 5HT2 blockade

Question 19

Antidepressants, like antipsychotics, also produce actions at multiple receptors including muscarinic, histaminic, and a1 adrenergic receptors. Thus AEs are similar to antipsychotics and can be explained by lack of receptor specificity

Answer 19

Antidepressants typically BLOCK synaptic reuptake of NE, serotonin, and dopamine BUT they also act an antagonists at muscarinic, histaminic (H1), a1, dopaminergic (D2), and possible serotonergic (5-HT2A) receptors

Question 20

What are the potential manifestations of NE transporter blockade by antidepressants?

Answer 20

anxiety, increased pressor effects of sympathomimetic amines, diaphoresis, tachycardia, and tremor

Question 21

What are the potential manifestations of a1-adrenergic receptor blockade by antidepressants?

Answer 21

postural hypotension and dizziness

potentiation of the antiHTN effect of other meds

reflex tachycardia

Question 22

What are the potential manifestations of muscarinic receptor blockade by antidepressants?

Answer 22

blurred vision

central effects: emmory and cognitive impairment, delirium in severe cases

GI effects: decreased salivation, dry mouth, decreased peristalsis, constipation

precipitation of narrow-angle glaucoma

sinus tachycardia

urinary hesitancy and retention

Question 23

T or F. Since antidepressants cirucalte widely in the vasculature, many of the anti-muscarinic effects are produced not in the CNS, but through actions directly within peripheral organs

Answer 23

T.

Question 24

Parkinson is commonly tx with what drug class?

Answer 24

anti-cholinergics

Question 25

Drugs producing dopaminergic blockade (and Parkinson's) tend to produce movement disorders like dystonia or akasthisia. How?

Answer 25

the net activity of striatal GABA neurons is determined by the relative balance of inhibitory D1 and D2 dopaminergic neruons from the substantia nigra (which are inhibitory) and excitatory muscarinic neurons. In Parkinson, the dopaminergic nerusons degenerate, leading to muscarinic cholinergically-mediated excitiation of the GABAergic neurons and to the associated motor-dysfunction Thus, tx of Parkinson involves augmentation of the dopaminergic signaling by administration of drugs like L-dope and/or inhibiton of muscarinic cholinergic activity

Question 26

What are 3 anticholinergic drugs used in the early stages of Parkinsonism or in conjunction with dopamimetic therapy?

Answer 26

Benzrtopine Diphenhydramine Trihexyphenodyl

Question 27

The amygdala is important in the interface between memories and emotions. Neuronal activity within the amygdala is subject to many external influences, both from other areas of the brain like the nucleus of the solitary tract or the locus ceruleus, and by glucocorticoids

Answer 27

Actions within the amygdala are projected foward to other regions invovled in the consolidaiton of memory

Question 28

NE release from the amygdala is critical for memory modulation. Explain its mediating factors

Answer 28

E released from the adrenal medulla activates receptors on the ascending vagus projecting to the NTS, which sends NA projections to the amygdala to promote NE release (blocked by opiod peptides), as well as to the locus coeruleus, which also sends NA prohections to the amygdala to promote NE release (GABA inhibits) Corticosterone released from the adrenal cortex activates glucocorticoid receptors in the NTS to promote NE release in the amygdala Glutamater and Ach activation from the nucleus basalis also promotes it and histamine modulates this process

Question 29

How can PTSD be tx?

Answer 29

B-adrenergic blockade for intrusion (re-experiencing traumatic memories) a-adrenergic blockade for hyperarousal (insomnia, irritability or outbursts of anger, difficulty concentrating, hypervigilance)

Question 30

The only two drugs approved for PTSD tx are what?

Answer 30

paroxetine and sertraline NOTE: there is interest in using prazosin (an a1 blocker) with propranolol (non-specific BB). Use of these drugs would be part of a script-driven trauma imagery viewing, to recalibrate the emotioms aroused by memory recall

Question 31

What peripheral drugs can enter the CNS?

Answer 31

BBs vary my lipophilicity- more lipohilic, like propanolol, produce any of a varierty of CNS effects including dizziness, confusion, lethargy, fatigue, memory issues, insomnia, etc. 1st gene H1 blockers (more lipophilic, like diphenhydramine, produces both H1 blockade centrally (sedation and confusion) and strong antocholinergic action centrally and peripherally leading to xerostomia, convulsions, tachycardia, blurred vision, constipation, etc. Lipophilic muscarinic antagonists produce central effects

Question 32

\_\_\_\_\_\_\_ are the 'go-to" for initial control of insomnia

Answer 32

1st gen antihistamines

Question 33

When used to treat peripheral conditions, central AEs caused by lipophilic muscarinic antagonists can be minimized how?

Answer 33

by the selection of drugs with a quaternary amine structure

Question 34

Answer 34