Functional Aspects of ANS

Question 1

What is the pre-eminent area of autonomic drug use?

Answer 1

the cardiovascular system (CV system)

Question 2

One very important aspect of autonomic drugs affecting the CV system is that what two things are linked? Why is this important?

Answer 2

One very important aspect of autonomic drugs affecting the CV system is that HR and BP are reflexively linked. If one goes up, the other often goes down as a reflexive effect. It’s important that you have to recognize if an effect is a direct effect or a reflexive effect of the drug.

Question 3

What are the divisions of the peripheral nervous system and how do they function?

Answer 3

1. Somatic NS. It control voluntary processes such as movement.
2. Autonomic NS. The ANS is not under direct conscious control and is involved in visceral function necessary to keep us alive.

Question 4

What is the major disadvantage of clinical therapy involving drugs that act upon the CNS?

Answer 4

A lack of specificity. The receptors that the drugs are acting upon are not only located on the heart or in the vasculature, but are also located in many organ systems of the body. The unwanted effects of these drugs are due to receptors in tissue other than the desired tissue.

Question 5

What are the two divisions of the ANS, their general functions, and the primary nt’s used in each? What are two other nt of the ANS?

Answer 5

1. Sympathetic→Fight or Flight→Norepinephrine (NE)
2. . Parasympathetic (PS)→Rest and Digest→Acetylcholine (ACh)
3. Dopamine is another nt that has a more limited specific function. and Epinephrine

Question 6

What is epinephrine? How is it related to Dopamine and NE?

Answer 6

It’s the circulatory arm of the SNS, and it’s released from the adrenal medulla. These three nt’s are structurally related very closely.

Question 7

How do the pretsynaptic and postynaptic neurons of the SNS and PSNS compare?

Answer 7

1. SNS→short presynaptic neuron and long postsynaptic neuron b/c the ganglia are located close to the spinal cord in the paravertebral chains.
2. PSNS→long presynaptic neuron and short postsynaptic neuron

Question 8

What are the major autonomic receptors? Are the subtypes important?

Answer 8

Major ANS receptors:
1. Cholinergic: a. Muscarinic (M1-M5) b.Nicotinic (Nn→neuronal/ganglion and Nm→muscular)
2. Adrenergic: a. Alpha (α1 and α2) b.Beta (β1, β2, and β3)
3. Dopaminergic (D1-D5)
Yes, the subtypes are important, but only up to a point. That point is that even though there are conceptual ways of differentiating drug activity in a loco-regional fashion in the body (on a specific subtype), it turns out that ANS drugs are notorious in lacking absolute specificity.

Question 9

What are the five key features of nt function that provide targets for drug therapy?

Answer 9

1. Synthesis 2. Storage 3. Release 4. Termination of action (degradation or reuptake) 5. Receptor interactions

Question 10

Why block the synthesis and storage of nt? What type of effect will you get, immediate or long-term? Why?

Answer 10

Synthesis and storage of nt’s are usually the RATE-LIMITING steps. Blocking these steps will not produce an immediate effect because this will not prevent the actions of nt’s that have already been made, but it will produce LONG-TERM effects b/c it prevents production of nt’s for future use once the ones already made have been used up.

Question 11

What type of effect will you get by blocking release of nt?

Answer 11

Rapid and effective action

Question 12

What happens when you inhibit the reuptake of nt’s? What about if you inhibit the metabolism (degradation) of nt?

Answer 12

Increased nt concentrations in the synaptic cleft results from both of these. Blocking reuptake can be selectiv or nonselective. Blocking metabolism can be reversible or irreversible.

Question 13

How could you alter the interaction between the nt and its receptors on the postsynaptic membrane? What type of effect would this have?

Answer 13

The use of receptor antagonists or agonists. This would tend to have a rapid effect.

Question 14

What is a sympathomimetic drug? What about a parasympathomimetic drug?

Answer 14

A drug that stimulates SNS function. (SNS agonist). (A drug mimicking the effects of impulses conveyed by adrenergic postganglionic fibers of the SNS.)

This would be a drug that stimulates the PSNS.

Question 15

What is a Sympatholytic drug? What about Parasympatholytic?

Answer 15

An SNS antagonist that blocks/inhibits SNS function (SNS antagonist). (antiadrenergic drug that opposes the effects of impulses conveyed by adrenergic postganglionic fibers of SNS).

That would be a drug that blocks/inhibits PSNS function.

Question 16

Describe the selectivity of drugs that act on the ANS? What is the result of this?

Answer 16

They are never absolutely selective for one receptor system/subtype, so there are often global unwanted effects of autonomic drugs (such as CV effects that may result when trying to treat urinary incontinence)

Question 17

What is meant when an autonomic drug is said to be relatively selective?

Answer 17

At therapuetic/clinical levels, it shows a strong preference toward a certain receptor system (but not absolute). However, if the dose is increased, the drug may have activity in other receptor systems.

Question 18

What is the fundamental difference between the methods of inactivation (termination of action) of ACh and NE?

Answer 18

ACh→degradation

NE→reuptake into the presynaptic terminal

Question 19

Where is ACh the primary nt?

Answer 19

ACh is the primary nt in all autonomic ganglia (pre and postganglionic neuronal synapse) and at the synapses between PS postganglionic neurons and their effector cells.

Question 20

Describe the synthesis of ACh in cholinergic nerve terminals? What drug blocks the synthesis of ACh?

Answer 20

ACh is synthesized in the nerve terminal by the enzyme Choline acetyl transferase (ChAT) from acetyl CoA and Choline, which has to be transported into the cell by CHT (choline transporter is the rate-limiting step).
Hemicholiniums are experimental drugs that can inhibit choline transport into the cell.

Question 21

How is newly synthesized ACh stored in vesicles? What drug inhibits the storage of ACh?

Answer 21

ACh is actively transported into its vesicles for storage by VAT (vesicle-associated transporter).
This process can be inhibited by another research drug, Vesamicol.

Question 22

What is required in order to release nt (ie ACh)?

Answer 22

Calcium influx into cells required in order to connect the depolarization of the membrane with the release of the nt.

Question 23

How does calcium entry into the cell result in the release of nt? What proteins are involved?

Answer 23

Calcium entry triggers and interaction between VAMPs (vesicle-associated membrane proteins) and SNAPs (synaptosome-associated proteins) that allows docking and fusion of the vesicle containing nt with the synaptic end plate membrane, releasing its contents into the synaptic cleft.

Question 24

What two types of drugs can inhibit the release of nt into the synaptic cleft?

Answer 24

1. CCBs→prevent influx of calcium thru calcium channels
2. Botulinium toxin (Botox)→ inhibits the function of VAMPs and SNAPs, preventing the binding and release vesicle contents. It’s a very long-acting drug.

Question 25

How is the action of ACh in the synapse terminated?

Answer 25

The action is normally terminated by the rapid metabolism/degradation of ACh to acetate and choline by the enzyme ACETLYCHOLINESTERASE (cleaves off an ester) in the synaptic cleft. The products are then recycled (not excreted)

Question 26

What happens to the action of ACh if acetylcholinesterase is inhibited? What is an example of a substance that can inhibit it?

Answer 26

Inhibition as therapeutic or adverse effect of many drugs increases the duration of ACh activity in the synapse, thus improving ACh activity.
Serine Nerve Gas does this and leads to potentially fatal cholinergic excess, which is treated by drugs that reactivate acetylcholinesterase.

Question 27

What two types of receptors can be found on the presynaptic membrane? What is their purpose?

Answer 27

1. Autoreceptors
2. Heteroreceptors
   These are involved in the regulating the presynaptic release of neurotransmitter.

Question 28

What do presynaptic autoreceptors do?

Answer 28

They recognize/bind to the primary nt (ligand being releases from that synapse) (ie a muscarinic receptor for ACh). Usually autoreceptors are inhibitory→ when activated by ligand, it inhibits further release of nt.

Question 29

What do heteroreceptors do?

Answer 29

Heteroreceptors bind to cotransmitters released from the vesicle into the synaptic cleft with the primary nt or to substances (usually of the opposing system (PS or symp) released from other nerve terminals. This results in the inhibition of this PS terminal while sympathetic terminal are activated and vice versa. Therefore, Cholinergic PS terminal often have heteroreceptors that bind NE and vice versa.

Question 30

Why are the anticholinergic drugs (vesamicol, hemicholinium, botox, etc) not very useful for systemic therapy?

Answer 30

B/c their effects are not sufficiently selective, as cholinergic transmission is involved in all ANS ganglia and the ganglia between PS postganglionic neurons and their effector tissues.

Question 31

What are contransmitters? What is the purpose of cotransmitters? What are the cotransmitters released with ACh in cholinergic synapses?

Answer 31

The vesicles of both cholinergic and adrenergic neurons contain other substances in the vesicles called cotransmitters in addition to the primary transmitter.
They modulate synaptic transmission. In some cases, they provide a faster or slower action to supplement or modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals to help localize the response.
Cholinergic→Substance P and ATP

Question 32

What are the two divisions of cholinergic receptors? How do they function? Specific example?

Answer 32

1. Metabotropic→function thru a 2nd messenger system→Muscarinic
2. Ionotropic→function thru ion channels→ Nicotinic

Question 33

Describe the muscarinic receptors for ACh? What are the two types? How do they work and what are their key effectors?

Answer 33

They are metabotropic GPCR’s.

a. M1, M3, M5→ Gq→activated PLC→DAG and IP3→IP3 increases intracellular [Ca2+], the key effector
b. M2, M4→Gi(Go)→inhibitor response→inhibits the production of cAMP by AC and opens up K+ channels (key effector)→decreased neuronal activity as membrane becomes less electrically active

Question 34

Describe the nicotinic receptors of ACh?

Answer 34

Ionototropic ion channels, predominantly for Na+ and Ca2+→leads to increase in intracellular Ca2+, which often stimulates the release of Ca2+ from w/in the neuronal terminal further amplifying the effect

Question 35

Whereas endogenous ACh is susceptible to breakdown by AChesterase, what two clinical drug forms of ACh agonists are not broken down by AChesterase? What does this result in?

Answer 35

Carbachol Chloride and Bethanechol Chloride;
This improves the longevity of the drug, and in circumstances where there is perhaps a problem w/ AChesterase, these drugs will not be impacted.

Question 36

What is the primary nt at most sympathetic postganglionic neuron-effector cell synapses?

Answer 36

NE in most circumstances, but Dopamine and ACh occur occasionally

Question 37

Describe the synthesis of Dopamine and NE? What is the rate limiting step? What drug blocks this rate-limiting step?

Answer 37

Tyrosine is transported into the cell→it is converted to DOPA by Tyrosine Hydroxylase (rate-limiting step)→Dopamine→NE.
Dopamine is transported into the vesicle by VMAT where it is converted into NE.
Tyrosine Hydrooxylase is inhibited by METYROSINE.

Question 38

What drug can interfere with the storage of NE? What does this result in?

Answer 38

Reserpine (which is clinically available) inhibits VMAT (vesicular monoamine transporter) which transports dopamine into the vesicles, resulting in depletion of nt stores.

Question 39

Describe the termination of action of NE and catecholamines in general?

Answer 39

The action of NE is terminated by a) reuptake (major) and b) diffusion out of the synapse (minor).
It’s taken back up into the presynaptic terminal by NET (aka Uptake-1), where it can be broken down or repackaged into vesicles.

Question 40

What are some drugs that interfere with NE/catecholamine reuptake?

Answer 40

Cocaine and tricyclic antidepressants, leading to an exaggerated response to NE b/c it persists for longer in the synaptic cleft.

Question 41

What is the main problem leading to adverse effects with autonomic drugs?

Answer 41

There is no such thing as ABSOLUTE specificity w/ autonomic drugs. Although they may be relatively specific at clinical doses, if the dose is pushed higher, these drugs tend to give rise to effects on other receptor systems.

Question 42

What receptors does NE act on? What about epinephrine (E)? What does this lead to?

Answer 42

NE acts on alpha1 and alpha2 equally, but shows a relative specificity to Beta1 over Beta2.
E acts on alpha1 and 2 equally, as well as Beta1 and 2 equally.
During fight-or-flight sympathetic response, E can bind to B2R’s in skel muscle vessels, causing vasodilation and increasing the blood supply.

Question 43

Where are Beta1 adrenergic receptors (B1R’s) located? What about B2R’s?

Answer 43

Two lungs and one heart:
B1R are the predominant ones in the heart, while B2R’s are predominant in the lungs and are also present in skeletal muscle blood vessels.

Question 44

How do E and NE affect the pulse pressure differently?

Answer 44

E widens the pulse pressure (PP) via B2R stimulation (vasodilation), while NE does not widen the PP.

Question 45

Describe the method thru which stimulation of an a1 adrenergic receptor occurs? What about a2R’s?

Answer 45

They are both metabotrpic receptor systems. a1R’s are linked to a Gq protein which leads to increased intracellular calcium.
a2R’s are linked to Gi proteins that inhibit AC, and have an overall inhibitory effect on the cell.

Question 46

Describe the method thru which BetaR stimulation occurs?

Answer 46

B-R’s are also metabotropic receptors, and they are linked to Gs proteins.

Question 47

How does cardiac contraction change in response to E or NE?

Answer 47

E/NE bind to B-R’s on cardiac myocytes, increasing the force of contraction, as this results in the release of Ca2+ from the SR (via RyR) following the influx of Ca2+ thru calcium membrane channels.

Question 48

How does ACh affect cardiac muscle function?

Answer 48

It binds the M2 receptor which activates the inhibitory Gi protein, which inhibits the release of Ca2+ from the SR, and tends to inhibit CV function.

Question 49

What is the Ryanodine receptor? How is it related to malignant hypothermia?

Answer 49

RyR is the receptor on the SR that gets activated and allows Ca2+ to enter the cytoplasm. Some drugs produce a condition known as malignant hypothermia (increase in heat), due to a defect in the RyR caused by these drugs in patients with a genetic predisposition. To treat these patients, give Dantroline.

Question 50

How is Ca2+ important in smooth muscle tone? What drugs has this led to?

Answer 50

Ca2+ is important in smooth contraction, as its entry into the cytoplasm from the cell exterior leads to contraction (no SR Ca2+).
This led to development of CCB’s which prevent Ca2+ entry and therefore prevent contraction, so the muscle relaxes and BP decreases.

Question 51

What type of drug causes relaxation of bronchial smooth muscle in the tx of asthma?

Answer 51

B2 agonists

Question 52

What are the 2 most important enzymes regarding the biosynthetic and degradative pathways of catecholamines (Dopamine, NE, and E)? Why?

Answer 52

Monoamine Oxidase (MAO) and COMT (catechol-O-methyltransferase).
There are drugs deliberately administered to inhibit those enzymes and the metabolic pathways they are involved in.

Question 53

What is pheochromocytoma and how is it diagnosed?

Answer 53

It is a tumor of the adrenal gland that leads to excessive catecholamine secretion, making the patients massively hypertensive and massively affected by SNS stimulation.
Dx→ look at the urinary levels of 2 metabolic products of the catecholamine synth/degrad pathways: Metanephrine and VMA (vanllyl mandelic acid)

Question 54

In what disease do you want increase CNS/brain levels of dopamine? Why cant you just treat with dopamine? What do you give instead? What is the problem with that? How do you deal with the problem?

Answer 54

Parkinsons disease (PD). Can’t just give dopamine b/c it can’t cross the BBB, so instead give a precursor called L-DOPA. Unfortunately, L-DOPA can be metabolized in the periphery to Dopamine, and you don’t want that b/c it will stimulate the CV system. So, we administer inhibitors of L-DOPA metabolism in the periphery, MAOi’s (monamine oxidase inhibitors), to ensure that maximal levels of L-DOPA get across the BBB

Question 55

Why aren’t MAOi’s used much anymore?

Answer 55

MAO has a very important role in the GI system in breaking down Tyramine, which you do not want to get into the presynaptic terminals, where it can cause an expulsion of NE and an increases in SNS activity.
These tyramines are in most common foods, so restricting these foods in patients on MAOi’s is very difficult to do.

Question 56

What is the potential problem of drugs acting on GPCRs?

Answer 56

Desensitization (long-term effect) of the GPCRs due to long-term use of the drug, which reduces the effectiveness of the drug. So, you have to increase dosage to maintain effectiveness.

Question 57

How does desensitization of GPCR’s due to long-term with drugs acting on them occur?

Answer 57

Interactions of the GPCR with the exogenous ligands are somewhat different than with the endogenous ligand in terms of duration and extent. This causes β-arrestin proteins to accumulate around the GPCRs, and cause endocytosis of the receptors, reducing their availability at the surface.

Question 58

What is tachyphylaxis?

Answer 58

Loss of drug activity/effectiveness in a relatively short period of time; could be due to different mechanisms such as a change in metabolism/elimination of the drug (pharmacokinetic mechanisms), mutated receptor (like in tumors), etc.

Question 59

What is meant by the term off-target effects of autonomic drugs?

Answer 59

There are autonomic receptors all over the body, and because of the lack of specificity of autonomic drugs, you see unwanted effects in other organ systems (lungs, sex organs, liver, pancreas, fat cells) that are entirely predictable.

Question 60

There are α1 and β2-R’s in the liver, that are important for what?

Answer 60

They stimulate glycogenolysis and gluconeogenesis in response to hypoglycemia.

Question 61

By what two mechanisms do BB’s cause hypoglycemic episodes in diabetics?

Answer 61

a) The nonspecifc BBs block one of the receptors responsible for production of glucose (β2’s)
b) Their effects on the CV system also masks the signs of hypoglycemia that tell the patient their blood glc is getting low, such as tachycardia, tremor, and nervousness.
So, avoid them in diabetics or use β1-selective BB’s.

Question 62

How do β receptors affect insulin secretion and sensitivity? What about α-R’s?

Answer 62

β2 activation on pancreatic β cells increases insulin secretion. β-R activation on target cells increases insulin receptor sensitivity.
α2-R activation on pancreatic β cells decreases insulin secretion.

Question 63

How do BBs affect insulin sensitivity? What about 3rd generation vasodilating BBs?

Answer 63

BBs typically decrease insulin receptor sensitivity.

3rd generation vasodilating BBs increase insulin sensitivity in patients with insulin resistance.

Question 64

What is the role of β receptors in fat cells?

Answer 64

They mediate activation of HSL (hormone sensitive lipase) in fat cells, leading to release of free fatty acids into the circulation, which is an important source of energy for exercising muscle.

Question 65

What is the effect of non-selective BBs on serum lipid levels?

Answer 65

Because they block β-mediated HSL activation, they decrease HDL and increase triglycerides with little effect on LDL and total cholesterol.

Question 66

What are the adverse/beneficial effects of α1-blockers that result from the distribution of α-R’s in various organ systems? (4)

Answer 66

1. Blockade produces ORTHOSTATIC HYPOTENSION, as α1’s are involved in vascular tone. (the MAJOR adverse effect)
2. α1’s are involved in urethral tone, so blockade relieves symptoms of BPH.
3. α1’s are involved in ejaculation, so blockade can cause sexual dysfunction
4. Blockade can cause perisistent priapism as α1’s are involves in contractile state of penile arteries.

Question 67

What is a side effect of promethazine (an anti-histamine)?

Answer 67

Orthostatic Hypotension (blocks α1’s)

Question 68

What is unusual about peripheral cholinergic effects? How do these effects occur?

Answer 68

There is NO direct PS/cholinergic innervation of blood vessels, but there are muscarinic receptors. So, exogenous muscarinic agonists promote the release of NO, which relaxes VSM and causes vasodilation.

Question 69

Why is there a potential adverse interaction/contraindication b/t Nitrovasodilators (release NO) and Sildenafil (viagra)?

Answer 69

These two drugs act on opposite ends of the same process. Nitrates activate GC and increase cGMP levels, while sildenafil inhibits PDE, the enzyme that degrades cGMP. So, you get massive amounts of cGMP, which leads to massive vascular relaxation and a massive drop in BP (~60/30).

Question 70

Why do drugs acting on the cholinergic system impact cognition?

Answer 70

Cholinergic and GABAergic pathways are intimately connected in the brain, and drugs affecting the cholinergic system can interplay and cause cognition, attention or arousal problems.

Question 71

In the context of the cholinergic system, why is there a problem with drug-induced reduction in cognition in the elderly?

Answer 71

There are numerous drugs that have anticholinergic side effects. As the elderly take large numbers of medications, they are more likely to take a drug that acts centrally or can enter the CNS and act on the cholinergic system and affect cognition.