Lecture 8: Autonomic Pharmacology

Question 1

What is the NT and receptors for the Parasympathetics?

Answer 1

NT: ACh

Receptors: nAChR and mAChR

Question 2

What is the NT and receptors for the Sympathetics?

Answer 2

NT: NE>Epi (DA); ACh

Receptors: α,β, (D), nAChR, mAChR

Question 3

Dopamine is the precursor to NE and Epi, where does it exert its actions?

Answer 3

Acts on the CNS and renal vascular smooth muscle

Question 4

All preganglionic autonomic fibers use what NT?

Answer 4

ACh (cholinergic)

Question 5

All post-ganglionic parasympathetics utilize what NT?

Answer 5

ACh

Question 6

What are the 3 cholinergic receptors that are GPCR, G_q/11; what cascade results from activation of these receptors?

Answer 6

• M1
• M3
• M5

* All activate PLC; IP3; DAG cascase

Question 7

What are the 2 cholinergic receptors that are GPCR, G_i/o; what is the cascade that occurs upon activation of these receptors?

Answer 7

• M2
• M4

* Inhibition of adenylyl cyclase (AC); decreased cAMP, activation of K+ channels

Question 8

What is the location of M1-M5 cholinergic receptors?

Answer 8

M1: CNS, ganglia

M2: Heart, nerves, smooth muscle

M3: Glands, smooth muscle, endothelium

M4: CNS

M5: CNS

Question 9

What kind of receptor is the Alpha 1 and what are its agonists?

Answer 9

• Gq; increased PLC; IP3; DAG; Ca²⁺
• Epi ≥ NE

Question 10

Activation of the β3 receptor primarily causes what and where are they found; which agonist preferentially acts on this receptor?

Answer 10

• Found in adipose tissue
• Activation results in lipolysis
• NE is the agonist

Question 11

The β2 receptor responds best to what agonist and where are these receptors found?

Answer 11

• Epi >> NE
• Smooth muscle (vascular, bronchial, GI, GU), skeletal muscle
• Relaxaton and Glycogenolysis; uptake of K+

Question 12

What does stimulation of the alpha-1 receptor do to smooth muscle, vascular smooth muscle, and glandular smooth muscle (rules to live by)?

Answer 12

• Stimulate contraction of all smooth muscle
• Vascular smooth muscle - vasoconstriction
• Glandular smooth muscle - secretion

Question 13

What does stimulation of the beta-2 receptor do to smooth muscle (rules to live by)?

Answer 13

Relax smooth muscle - vasodilation

Question 14

What does stimulation of the Muscarinic receptors do to smooth muscle (rules to live by)?

Answer 14

• Contract smooth muscle
• ACh and muscarinic agonists given IV cause vasodilation due to release of nitric oxide (NO)

Question 15

ACh and muscarinic agonists given IV will cause what?

Answer 15

• You get contraction of smooth muscle
• BUT, also get vasodilation due to the release of nitric oxide (NO)

Question 16

What are 5 effects of the parasympathetics?

Answer 16

1) Salivation, lacrimation
2) Pupil constriction (myosis)
3) Decrease in HR
4) Urination, defecation
5) Increased secretion and motility

*Cholinergic

Question 17

What are 5 effects of the sympathetics?

Answer 17

1) Cutaneous vasodilation
2) Pupil dilation (mydriasis)
3) Increase in HR
4) Reduction/elimination of the desire to urinate
5) Decreased secretion and motility

*Adrenergic

Question 18

In general activation of alpha-2 receptors results in what?

Answer 18

• Vascular smooth muscle contraction
• Decreased insulin secretion
• Decreased release of NE (pre-synaptic α2 receptors)

Question 19

β1 receptors are mainly found where and activation causes?

Answer 19

• Mainly found in the myocardium
• Increased force and rate of heart contraction and AV nodal conduction velocity

Question 20

β2 receptors are mainly found where and activation causes?

Answer 20

• Mainly found on smooth muscle and most other sites
• Activation causes: vascular, bronchial, genitourinary, and GI smooth muscle RELAXATION

Question 21

In a patient with an overactive parasympathetic NS presenting with worsening urinary incontinence what is the drug of choice?

Answer 21

• mAChR antagonist
• Will cause relaxation and inhibit bladder contraction

Question 22

How is activation of the mAChR’s able to cause trigone and sphincter relaxation?

Answer 22

• Normally associated with contraction of smooth muscle
• BUT, also leads to vasodilation due to release of nitric oxide (NO)

Question 23

What are adverse effects that may be seen after treatment with a non-selective mAChR antagonist?

Answer 23

Constipation, dry mouth/eyes, dizziness, and blurred vision

Question 24

Why does the administration of non-selective mAChR antagonists lead to blurred vision?

Answer 24

• Contraction of the ciliary muscle of eye is PNS mediated (cholinergic)
• Loss of contraction of ciliary muscle = lens stays flat = decreased abillity to focus and loss of near vision

Question 25

A patient presents with worsening COPD, what type of drug is best in this situation?

Answer 25

- A mAChR antagonist - Will block the contraction of the bronchial smooth muscle

Question 26

Tiotropium is an inhaled (mAChR antagonist), what is a common side effect of this drug?

Answer 26

- Decreased mucus production - You are blocking a parasympathetic receptor, remember, the PNS is responsible for **rest and digest!**

Question 27

A patient has a positive fractionated free metanephrine test and a 24-hour urine specimen supports this dx; what is the patients condition?

Answer 27

- Pheochromocytoma - An endocrine tumor that secretes catecholamines

Question 28

The patient with a pheochromocytoma presents with headache, increased perspiration, palpitations, and a significantly increased BP, what drug should be used to decrease the BP?

Answer 28

**Alpha-1 antagonist**

Question 29

The patient with a pheochromocytoma presents with headache, increased perspiration, palpitations, and a significantly increased BP, an antagonist of which receptor will most likely reduce her HR?

Answer 29

**Beta-1 receptor antagonist**

Question 30

The patient with a pheochromocytoma presents with headache, increased perspiration, palpitations, and a significantly increased BP,after administration of a beta-receptor selective antagonist (propranolol) what do you expect to happen and why?

Answer 30

- Worsening of HTN - This is known as **unopposed alpha stimulation** - Since the pheochromocytoma is secreting catecholamines, you must block both the alpha and beta receptors. - Only blocking the beta receptor will slow down the heart rate, but the BP will likely increase due to catecholamines acting on the alpha-1 receptor.

Question 31

How does Clonodine work and what are the affects in a patient with a pheochromocytoma?

Answer 31

- A centrally-acting **alpha-2** receptor **agonist** - Activates central **pre-synaptic** alpha-2 receptors and **suppresses** the release of **catecholamines** - Has **NO EFFECT** on patient with pheochromocytoma

Question 32

A patient who presents with symptoms of an overactive sympathetic nervous system (i.e., pupils fixed/dilated, increased HR, delirium, cutaneous vasodilation, and high fever), how can you account for the high fever?

Answer 32

- Inhibition of mAChR's - The sympathetic NS uses ACh to induce sweating in an attempt to decrease body temperature - If this receptor is inhibited you will see an increase in body temperature

Question 33

A patient who presents with symptoms of an overactive sympathetic nervous system (i.e., pupils fixed/dilated, increased HR, delirium, cutaneous vasodilation, and high fever), marked cutaneous vasodilation is noted upon PE, which agent is most appropriate to use in this situation?

Answer 33

- Acetylcholinesterae inhibitor - We want to block the enzyme that breaks down ACh since we need more ACh in this patient

Question 34

What drugs would be used in a patient with Atony of the Bladder (AKA inability to urinate due to lack of muscle tone)?

Answer 34

- Direct-acting cholinergic agonist - Indirect-acting cholinergic agonist \*Will lead to smooth muscle contraction, by acting on the mAChR's

Question 35

What is the receptor for the parasympathetics found on cardiac muscle?

Answer 35

mAChR **M2**

Question 36

If a patient is exhibitng CNS symptoms and you want to give a drug to correct this, what is an important characteristic of the drug that needs to be considered?

Answer 36

The drug needs to be **uncharged,** so that it can cross the **BBB**

Question 37

What is Myasthenia Gravis and what drug is given to treat?

Answer 37

- Autoimmune disease where antibodies are made that affect nAChR's in skeletal muscle - We give an **AChE inhibitor**, which **increases ACh**, and helps to activate the reduced number of receptors!

Question 38

A 29 yo male presents to the ED unconcious w/ nonreactive, pinpoint-sized pupils, massive oral foaming, and muscle fasciculation. His pants are wet with urine and feces. What receptor family is most likely involved in his presenting symptoms? A. Adrenergic B. Cholinergic C. GABA D. Glutamate E. Opioid

Answer 38

B) Cholinergic \*These presenting symptoms are clearly parasympathetic mediated

Question 39

A 29 yo male presents to the ED unconcious w/ nonreactive, pinpoint-sized pupils, massive oral foaming, and muscle fasciculation. His pants are wet with urine and feces. An agent from which drug class was most likely ingested? A) AChE inhibitor B) Beta-blocker C) Centrally acting alpha-2 receptor agonist D) mAChR agonist E) mAChR antagonist

Answer 39

A) AChE inhibitor \*The muscle fasciculations are the key symptom here. There are no mAChR's on skeletal muscle

Question 40

If a patient presents with symptoms indicative of overactive parasympathetic NS with muscle fasciculations, you need to think about an overdose of what; what kind of drug is given in this situation?

Answer 40

- Need to think about ingestion of an AChE inhibitor - We give mAChR antagonists (atropine) to these patients, which will help manage all the sx's, except for the muscle fasciulations. - We don't give a drug that is a nAChR antagonist

Question 41

A 46 yo female presents complaining of dry eyes and a dry mouth. Her sx's have been present for the past 6 months and have progressively worsened. She saw an opthamologist 3 months ago and has been using artifical tears with little relief. She often has to wake up in the night to drink water and frequenly has to drink to help her swallow food. She experiences the feeling of grit or sand in her eyes on a daily basis? Which agent is most appropriate in this situation? A) AChE inhibitor B) AChE regenerator C) Charged mAChR antagonist D) mAChR agonist E) Uncharged mAChR antagonist

Answer 41

D) mAChR agonist - A **pure** **mAChR** will be more selective towards the effects we want in this patient - An AChE inhibitor would help too, but would also be producing unwanted side effects since it acts at the nAChR's as well.