Adrenergic and Cholinergic Effects of CNS Drugs Flashcards
T or F. Both adrenergic and cholinergic neurons exist within the brain
T. And they both can be impacted by drug therapy
Neurons secrete the same set of neurotransmitters from all of their synaptic termini. These transmitters include:
- 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)
Where are the majority of noradrenergic neurons (contain NE)?
the locus ceruleus (highest) and the central nucleus of amygdala (but NE is distributed widely in the brain)
What does the locus ceruleus do?
It is involved in regulating sleep and arousal and the asociated aspects of attention and viligance.
What can increased activity of the locus ceruleus cause?
increased anxiety by releasing NE in the amygdala and in other limbic areas
Stimulation of beta-adrenergic receptors in the amygdala does what?
enhances memories for stimuli encoded under strong negative emotion, that is to say, recall of stimuli predicting danger. This mechanism may contribute to PTSD
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?
it has effects upon the a4b2 constructs in the substania nigra ventral tegmental area
ACh influences what processes in the brain?
motivation, learning, and memory
NE influences what processes in the brain?
arousal, attention, vigilance, and memory. Descending NE fibers also modular afferent pain signals
T or F. Both Ach and NE are involved in regulation of arousal (wakefulness) and cognition.
T. So drugs that are antagonists for these processes will tend to produce sedation and mental clouding. Histamine is also involved in wakefulness
How do antipsychotics work?
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
What are the potential ANS AEs of antipsychotics?
loss of accommodation
dry mouth
difficulty urinating/constipation
orthostatic hypotension
impotence
ejaculation failure
What is the mechanism of the potential ANS AEs of antipsychotics?
muscarinic cholinoceptor blockade and/or
a-adrenoceptor bockade
What are the potential CNS AEs of antipsychotics?
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
What is the mechanism of the potential CNS AEs of antipsychotics?
dopamine receptor blockade
supersensitivity of dopamine receptors
muscarinic blockade
What are the potential Endocrine AEs of antipsychotics?
amenorrhea-galactorrhea
infertility
impotence
What is the mechanism of the potential Endocrine AEs of antipsychotics?
dopamine rceptor blockade resulting in hyperprolactinemia
Antipsychotics can also cause weight gain. How?
possibly combined H1 and 5HT2 blockade
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
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
What are the potential manifestations of NE transporter blockade by antidepressants?
anxiety, increased pressor effects of sympathomimetic amines, diaphoresis, tachycardia, and tremor
What are the potential manifestations of a1-adrenergic receptor blockade by antidepressants?
postural hypotension and dizziness
potentiation of the antiHTN effect of other meds
reflex tachycardia
What are the potential manifestations of muscarinic receptor blockade by antidepressants?
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
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
T.
Parkinson is commonly tx with what drug class?
anti-cholinergics
Drugs producing dopaminergic blockade (and Parkinson’s) tend to produce movement disorders like dystonia or akasthisia. How?
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
What are 3 anticholinergic drugs used in the early stages of Parkinsonism or in conjunction with dopamimetic therapy?
Benzrtopine
Diphenhydramine
Trihexyphenodyl
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
Actions within the amygdala are projected foward to other regions invovled in the consolidaiton of memory
NE release from the amygdala is critical for memory modulation. Explain its mediating factors
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
How can PTSD be tx?
B-adrenergic blockade for intrusion (re-experiencing traumatic memories)
a-adrenergic blockade for hyperarousal (insomnia, irritability or outbursts of anger, difficulty concentrating, hypervigilance)
The only two drugs approved for PTSD tx are what?
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
What peripheral drugs can enter the CNS?
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
_______ are the ‘go-to” for initial control of insomnia
1st gen antihistamines
When used to treat peripheral conditions, central AEs caused by lipophilic muscarinic antagonists can be minimized how?
by the selection of drugs with a quaternary amine structure
