01/08/16 and 01/11/16

Question 1

Introduction: ANS

Answer 1

• Regulates function of the heart, blood vessels, GI tract, various types of smooth muscle

Question 2

Comparison of NM and Autonomic Nervous System

Answer 2

1. Actions of somatic nerves are voluntary while ANS is involuntary
2. Skeletal muscle needs neuronal stimulation for action; ANS show tonic activity (has spontaneous activity that is modulated by stimulation)
3. Axons skeletal muscle nerves are in the spinal cord; ANS have afferent pathway to CNS controlling and integrating centers, efferent of the ANS provide all innervated structures of the body except skeletal muscle
4. There are presynaptic receptors in the ANS but not at neuromusclar junction; regulate the release of neurotransmitters

Question 3

Parasympathetic vs. Sympathetic Nervous system

Answer 3

• Difference is an anatomical distrubtuion based upon where the pre-ganglion fibers orginate
• PS preganglion: originate in the midbrain, medullar and sacral portions of the spinal cord
• S preganglion: originate from the intermdiate spinal cord
• Many organs innervated by both S and PS that act in an antagonist manner

Question 4

Adrenals and Stress

Answer 4

• Adrenal medullar part of the sympathetic nervous system and contains secretory cells that release catcholamines (epi/norepi) in response to neuronal stimulation
• Sympathetic: increased heart rate, blood pressure, pupil dilation/bronchial dilatation, increased blood sugar and shifting blood from skin and GI to skeletal muscle
• Note: Splanchnic nerve to the adrenal medulla and the similarity of the parasympathetic ganglia to chromaffin cells

Question 5

Parasympathetic ganglia are generally closer to the target organ; more discrete

Answer 5

• Dominates when you are sleeping and undergoes discharge at discrete sites
• Sympathetic ganglia innervate many targets, PS only innervate 1 organ and the ganglia are generally in the organ

Question 6

Classification of Motor Fibers

Answer 6

• Sympathetic preganglion: ACh
  
  • synapse onto ganglionic neurons that have nicotinic recetpors
• Sympathetic postganglion: Norepi
• EXCEPTION:
  
  • Postganglion to sweat glands: cholinergic and release ACh
  • Adrenal medulla releases both NE and Epi
• Parasympathetic preganglion: ACh
  
  • Form nicotinic synapses
• Parasympathetic postganglion: ACh
  
  • cholinergic synpase onto the target organ
• Motor fibers originate in the spinal axis with no intervening ganglia and at the neuromuscular junction release ACh which stimulates nicotinic receptors

Question 7

Effects of Autonomic Stimulation on Organ Function

Answer 7

• Heart:
  
  • Ionotropic: contraction strength
  • Chronotropic: rate of heart beating
  • ANS branches antagonize each other
    
    • Parasympathetic:
      
      • Slows heart by hyperpolarization and slowing of the diastolic depolarization in the sino-atrial node.
      • Reduces contractile force by shortening atrial action potential
    • Sympathetic:
      
      • Increases ehart rate by increasing the rate of diastolic depolarization
      • Increases contractile force by increasing Ca2+ influx during action potential
  • The sympathetic nervous system innervates all of the heart but there is very little parasympathetic innervation of the ventricles

Question 8

Autonomic Effects on Vasculature

Answer 8

• Only sympathetic innervation
• Sympathetic stimulation causes constriction (most of the time)
• Sympathetic stimulation can cause dialation of constriction of skeletal musle vasculature due to multiple types of adrenergic receptors

Question 9

Smooth Muscle, General, Exocrine glands, sweat gland, liver, salivary gland

Answer 9

• Parasympathetic:
  
  • Contraction or increased rhythmic activity of smooth muscle
• Sympathetic:
  
  • Relaxation or decreased rhythmic activity
• Smooth muscle in blood vessels only receives sympathetic inneravation. Sympathetic stimulation generally causes constriction of blood vessels
• Exocrine glands ( Lachrymal Glands (tear glands))
  
  • Parasympathetic activity normally stimulates secretion
  • sympathetic activity either reduces or has no effect on secretion, depending on the particular gland.
• Lungs and Respiratory System
  
  • Sympathetic stimulation causes bronchial dilation relaxation of bronchial smooth muscle.
  • Parasympathetic causes bronchial constriction.
• Sweat gland
  
  • Sympathetic stimulation causes secretion, it increase sweating.
• Liver
  
  • Sympathetic stimulates the breakdown of glycogen.
• Salivary glands
  
  • Sympathetic and parasympathetic stimulation causes secretion.
  • Parasympathetic stimulation is dominant.

Question 10

Pupil Constriction

Answer 10

• Parasympathetic:
  
  • cause miosis (pupilary constriction) by stimulating contraction of the iris sphincter muscle
• Sympathetic:
  
  • causes mydriasis (pupilary dilation) by cuasing contractino of the dilator muscle

Question 11

Lens Accommodation:

Answer 11

• Parasympathetic activity
  
  • stimulates contraction of the ciliary muscle causing increased curvature of lens for near vision.
• Sympathetic activity
  
  • causes relaxation of the ciliary muscle, decreasing curvature for far vision.
• Synaptic Transmission through Autonomic Ganglion
  
  • There are a family of drugs that affect synaptic transmission in autonomic ganglia.

Question 12

Synaptic Transmission through Autonomic Sympathetic Ganglia

Answer 12

• Stimulation of preganglionic fibers causes a complex series of events in the membrane potential of the postganglionic neuron:

1. An initial large depolarization, EPSP due to the activation of the ganglionic nicotinic receptor of the postganglionic neuron by ACh.
2. A small hyperpolarization (slow IPSP) due to the activity of an interneuron.
3. A slow or late EPSP due to activation of mACh on the postganglionic neuron. The fast EPSP is responsible for transmission through the ganglion

• The IPSP and the late EPSP serve to modulate synaptic transmission The late, slower EPSP is due to Ach activation of muscarinic receptors.

Question 13

Synaptic Transmission through Parasympathetic Ganglia

Answer 13

• Less is know about synaptic transmission through the parasympathetic ganglia. Studies with amphibian heart suggest the presence of a fast EPSP due to activation of nACh-R and a slow IPSP due to activation of mACh-R.
• Thus the main pathway for synaptic transmission through ganglia, in each case, uses ACh as the released neurotransmitter activating nicotinic receptors postsynaptically.
• There are similarities between synaptic transmission through autonomic ganglia and at the NM junctions.

1. The synthesis, storage and release of acetylcholine in preganglionic cholinergic terminals of autonomic ganglia are similar to that described for the NM junction.
2. The nerve terminal contains many synaptic vesicles which release acetylcholine upon stimulation.

• Ganglionic Drugs
  
  • There are two classes of ganglionic stimulating drugs, nicotinic drugs and muscarinic drugs.

Question 14

Nicotinic Ganglionic Stimulating Drugs

Answer 14

• Nicotinic Drugs include Nicotine, DMPP, and TMA. These drugs are agonists which activate and then subsequently desensitize the nicotinic ACh-R in ganglionic synapses.
• Low concentrations of the drugs stimulate n-ACh-R in sympathetic and parasympathetic ganglia and in the adrenal medulla. Higher concentrations cause blockade of both types of ganglia. Their effects are very broad and unpredictable and the drugs are not used clinically.
• However, because of the widespread consumption of nicotine in tobacco, it is important to understand nicotine pharmacology. At low doses, nicotine has sympathomimetic cardiovascular effects which include increased inotropic and chronotropic effects, parasympathetic GI effects increases GI motility. Nicotine is lipid soluble and can cause complex central effects including stimulation of respiration, and at very high doses convulsions.
• Nicotine is a highly addicting drug and abrupt stopping of smoking can cause headaches, tremor, visual disorders, irritability etc. One solution is the availability of nicotine-containing gum or nicotine patches to reduce withdrawal effects. Nursing women or people with cardiovascular conditions should not use nicotine.

Question 15

Muscarinic Ganglionic Stimulating Drugs

Answer 15

• These drugs stimulate muscarinic receptors and they include muscarine, pilocarpine leading tp stimulation of sympathetic nervous system via the late EPSP.
• However, these effects are usually masked by the direct muscarinic effects on the cardiovascular system.
• One experimental drug, McN-A-343, acts preferentially to stimulate mACh-R in the sympathetic ganglia and in the adrenal medulla compared to heart or vascular smooth muscle. This is because there are subclasses of mACh receptors and drugs which are relatively specific for these subclasses.

Question 16

Ganglionic Blockers

Answer 16

• Pentolinium, hexamethonium, and triethyl ammonium (TEA) and related drugs act as competitive antagonists and block ganglionic transmission by blocking nicotinic ACh-R without a change in the membrane potential of the ganglionic cells. Hexamethonium is the six-carbon analogue of the depolarizing neuromuscular junction blocker, decamethonium 10.
• Hexamethonium is a weak NM junction blocker but a stronger blocker at autonomic ganglia. The ganglionic blockers inhibit both parasympathetic as well as sympathetic ganglia.

Question 17

Predominant Autonomic Tone and Effects of Ganglionic Blockers

Answer 17

• The actual pharmacological effect of the ganglionic blockers depends upon whether the predominant autonomic tone in the untreated individual is parasympathetic or sympathetic.
• The effects on organs with predominantly sympathetic tone are:
  
  1. arterioles and veins-cause, ganglionic blockers cause vasodilation
  2. Sweat glands- Anhidrois, decreased sweating
• Effects on organs with predominantly parasympathetic tone are:
  
  1. Heart- tachycardia (excessive fast heart rate)
  2. eye- mydriasis, pupillary dilation and cycloplegia (paralysis of the intraocular muscle)
  3. Salivary gland- Xerostomia, dry mouth
  4. GI tract- relaxation of intestinal muscle, constipation
  5. Bladder- difficulty in voiding the bladder
• Ganglionic blockers were used as hypotensive agents but they are not used now except in emergency treatment or to produce controlled hypotension during surgical procedures.
• The hypotensive effects are due to the dilation of most arteries and veins in the skin and viscera causing a decrease in total systemic vascular resistance.
• The side effects are due to their effects on other organ systems mentioned above, visual problems, constipation etc.

Question 18

Differences between Muscarinic and Nicotinic Synapses.

Answer 18

• There are important differences between synaptic transmission at muscarinic synapses compared to nicotinic synapses.

1. At the NM junction there is a highly specialized structure with a highly differentiated nerve terminal, there are discrete terminals; in the ANS the muscarinic receptors are more spread out. They are found at various varicosities.
2. At the NM the synapse gap is very small 20 nm to 50 nm…..Consequently the time for diffusion is very short.
   
   • At Muscarinic synapses the distance is generally larger, 20 nm to 2 μm.
3. At the NM the receptors are highly localized and concentrated at the synapse. At the muscarinic junctions, receptors are distributed throughout the target tissue to give uniform responses.
4. The response at the NM junction is very fast… less than a 100 μsec. At muscarinic synapses the response is slow, slower than 100 msec.

Question 19

Muscarinic Axons and Varicosities In Heart Muscle

Answer 19

This slide shows muscarinic synapses, the varicosities in the heart. You can see the axon and the varicosities, points where synapses occur throughout the heart muscle. ACh is released throughout the target organ. You have this general wide distribution because you would not want part of the heart beating at a different rate than the other.

Question 20

Muscarinic synapse in heart

Answer 20

In contrast to the NM junction, the muscarinic synapses are not concentrated or have specialized folds, the synapses are spread along the target organ, uniformly. The distance between the nerve and target organ is much greater than at the NM junction. You don’t see a highly specialized postsynaptic localized structure on the heart muscle.

The nicotinic receptors at the NM junction and in ganglionic synapses are ligand-gated ion channels that acts fast, 100 μsec, the muscarinic receptors act slower., about 1000 times slower. This is because the muscarinic receptors themselves are not ion channels but they are coupled to second messengers, e.g. Ca2+ or cAMP that in turn can regulate the activity of ion channels.

Question 21

Muscarinic Agonists

Answer 21

• These drugs mimic the effects of parasympathetic nerve stimulation, mimic ACh. Two classes of muscarinic agonists, the first are the choline esters. The second group is the cholinomimetic alkaloids.
• The choline esters include acetylcholine, carbachol, methacholine and bethanecol. They are all able to act as agonists at the muscarinic receptors, they differ in their susceptibility to hydrolysis by choline esterases, and their cross-reactivity with nicotinic receptors:
• While Ach is very susceptible to hydrolysis by choline esterase, methacholine is less susceptible to hydrolysis.
• Carbachol has high nicotinic activity, methacholine has little nicotinic activity and bethanechol (two spellings bethanechol, bethanecol) has none.
• Because there are subclasses of muscarinic receptors with different tissue distribution, the response of different systems to these drugs vary.
• Carbachol and bethanecol are relatively effective at muscarinic receptors in the GI tract and poorer agonists for the cardiovascular system.

Question 22

Cardiovascular Effects of Muscarinic Agonists

Answer 22

• Some of the cardiovascular effects of these drugs are predictable and some are not. If one administers acetylcholine or methacholine IV one gets;
• Vasodilation of all vascular beds. How come? I told you earlier that there is no parasympathetic innervation of vascular smooth muscle. mACh-R in most smooth muscle causes contraction but not in vascular smooth muscle? Why??
• All the blood vessels have muscarinic receptors which cause vasodilation even though there is no parasympathetic innervation. Remember blood vessels have sympathetic tone and sympathetic innervation but no parasympathetic innervation.

Question 23

NO is Produced in Endothelial Cells of Blood Vessels

Answer 23

• The mACh-R is not on the vascular smooth muscle, but on the endothelial cells which release “endothelial derived relaxing factors” e.g. nitric oxide. NO diffuses into the smooth muscle cells and acts on the smooth muscle to cause vasodilation.
• M3-R →Ca2+ increase →activation of NO Synthase→NO
• Nitric oxide activates guanylyl cyclase in vascular smooth muscle to produce cGMP which relaxes vascular smooth muscle.
• The organ nitrates which would include nitroglycerin, amyl nitrate are anti-anginal drugs that release NO which in turn lowers blood pressure by causing vasodilation.
• The discovery of NO led to a Nobel Prize in medicine.

Question 24

BP Changes Caused by Acetylcholine

Answer 24

1. 1. Decrease in BP-vasodilation, through NO in vascular smooth muscle which causes vasodilation
2. More ACh even lower BP.
3. This is blocked by a muscarinic antagonist-atropine
4. If atropine is present- go to really higher Ach instead of a decrease in BP, we get a pressor response. Why??

• When you block the muscarinic receptors, ACh acting in the adrenal medulla, it stimulates nicotinic ganglionic receptors and causes release of catecholamines, vasoconstriction and an increase in BP.

Question 25

Effects of Acetylcholine on the Heart

Answer 25

• Ach causes decreased blood pressure, as just described. This leads to an autonomic reflex causing an increase in sympathetic tone and reflex tachycardia. The heart tries to accommodate for the large decrease in peripheral resistance.
• One needs very high doses of Ach to overcome this reflex sympathetic tone. So the effects are dose dependent.
• At very high concentrations of ACh you start to see a reduction in heart rate. Why?
• The heart does have cholinergic innervation which deceases the beating rate (negative chronotropic effect) activation of mACh-R in the pacemaker region of the SA node increases K+ permeability, decreases the rate of diastolic depolarization delaying the onset of an action potential and causes a longer interval between beats.

Question 26

Pharmacology of Choline Esters

Answer 26

• GI Effects - All of the choline esterases cause increases in tone contractile force, and peristalsis and secretory activity of the GI system. Carbachol and bethanechol can give GI effects with minimal cardiovascular effects.
• Other Effects-
• Bethanecholamine also stimulate the urinary tract.
• The choline esters increase secretion from all exocrine glands, cause bronchial constriction and produces constriction of the pupils.
• Because these drugs do not cross the blood-brain barrier they do not have significant CNS effects.

Question 27

Therapeutic Uses of the Choline Esters

Answer 27

1. Methacholine was used in the past to control, tachycardia but not now because of side effects.
2. Bethanechol is used as a GI tract stimulant to relieve a variety of conditions and to relieve urinary tract retention when there is no physical obstruction so that catherization can be avoided.
3. ACh is used to produce brief periods of miosis during extraction of cataracts. Methacholine, bethanecol, and carbachol are used in treatment of glaucoma to cause miosis which enhances drainage of aqueous humor.
4. Methacholine is also used for diagnosis of belladonna ( a muscarinic antagonist) poisoning, and for diagnosis of bronchial hyperactivity (i.e. Supersensitivity to bronco constriction in patients with asthma).

Question 28

Structure of the alkaloids

Answer 28

• Muscarine, arecoline, pilocarpine are natural alkaloids.
• Oxotremorine and aceclidine are synthetic.
• Pilocarpine, muscarine and Oxotremorine are relatively specific for m-ACh-R while arecoline can activate nicotinic receptors.
• Pharmacological activities mimic those of the choline esters. Unlike the choline esters, these drugs are not charged and can have effects in the CNS. Eg., Oxotremorine can cause Parkinson like tremors.
• Therapeutic Uses
  
  • The main therapeutic use of these drugs, only pilocarpine) is for the treatment of glaucoma

Question 29

Mushrooms

Answer 29

Toxicology- Somme toxic mushrooms, eg of the Amanita class, contain muscarine. Ingestion produces a number of symptoms due to over stimulation of autonomic organs, salivation, diarrhea, bradycardia and CNS effects. Atropine is used as an antidote for muscarine poisoning.

Question 30

Structure of the Belladonna Alkaloids

Answer 30

• Belladonna (poison, night shade) is mixture of atropine and scopolamine.
• Belladonna means beautiful woman in Italian. Italian women used to put night shade in their eyes to dilate their pupils making their eyes look more attractive…hence the name belladonna alkloids. Anticholinergics cause mydriasis (excessive dilation of the pupil)
• These are very specific competitive drugs for reversible inhibition of mACH-R. They block the parasympathetic stimulation of target organs.
• These drugs are rapidly absorbed through the GI tract and slowly absorbed through the eyes or skin.

Question 31

*******Atropine Biphasic Effect on Heart Rate ********

Answer 31

Low doses cause a slight reduction in heart rate. This due to blockade of presynaptic inhibitory muscarinic receptors on the postganglionic parasympathetic nerve terminals. In other words, the presynaptic terminal of parasympathetic ganglia have muscarinic receptors which are coupled to inhibition of adenylyl cyclase through Gi. Since they depress signaling through parasympathetic innervation to the heart, when activated these presynaptic muscarinic receptors actually increase heart rate. The low concentrations of atropine, by blocking these receptors, decrease heart rate. At higher concentrations you get the expected result, an increase in heart rate by atropine blocking of inhibitory muscarinic receptors in heart.

Question 32

Pharmacology of the Anticholinergics

Answer 32

• High doses give the expected result which is tachycardia.
• Circulation- Anticholinergics block vasodilation due to cholinergic agonists, e.g. vasodilation caused by administration of carbachol.
• However, Anticholinergics have little effect in untreated individuals. Why? Because, blood vessels have primarily sympathetic tone with no cholinergic innervation.
• Eye - Anticholinergics cause mydriasis (excessive dilation of the pupil) and cycloplegia (paralysis of the intraocular muscles) which can last for 1 to 2 wks. Belladonna was used by Italian women to dilate their pupils to make them look more attractive……belladonna means pretty woman.
• GI Tract- Anticholinergics inhibit tone and motility of the stomach and intestine and also inhibit gastric secretion.
• Salivary and Sweat Glands-Anticholinergics inhibit secretion by these glands.
• Toxicity- Atropine and scopolamine are lipid soluble and cross the blood-brain barrier. At clinical doses atropine acts as a mild CNS stimulant. Higher doses cause hallucinations and delirium followed by depression. Therapeutic doses of scopolamine cause drowsiness, tachycardia, hallucination, delirium and urinary retention. Anticholinesterases, eg physostigmine can be used as an antidote.

Question 33

Quaternary Derivatives of Antimuscarinic Alkaloids

Answer 33

• These drugs, which are quaternary ammonium derivatives of the anti-muscarinic alkaloids have different properties from their corresponding tertiary amine derivatives.

1. They do not cross the blood brain barrier. Therefore they exhibit no CNS side effects
2. They have substantial nicotinic blocking activity and can have side effects due to ganglionic and neuromuscular blockade. They are more slowly absorbed through the GI and have more prolonged activity there.

Question 34

Therapeutic Uses of the Anti-Muscarinics

Answer 34

Preanesthtic medication- Atropine and scopolamine reduce excessive salivation and bronchial secretion and dilate bronchial passages. Scopolamine has an additional effect, it is a tranquilizer.

Question 35

Anti-muscarinics use to induce mydriasis and cycloplegia.

Answer 35

2. Ophthalmology-Go through slide. Note that the drugs differ in duration of action and the recovery time is significant. It can take days.
3. GI- Antimuscarinic have been used to relieve symptoms of peptic ulcer by decreasing motility and gastric secretion. They also inhibit intestinal tone or motility in mild dysentery or conditions of the irritated lower bowl.
4. Cardiovascular System- Atropine is used to relieve bradycardia caused by excessive stimulation of vagal tone following myocardial infarction.
5. Respiratory Tract- Belladonna alkaloids and other antagonists decrease secretion in the upper and lower respiratory tract. They are used in cold and hay fever medications.

Ipratropium, a quaternary ammonium antagonist is used for asthma. Inhalation of ipratropium produces bronchodilation but does not inhibit bronchial secretions nor does it show anticholinergic actions.

6. CNS- The antimuscarinics are used to prevent motion sickness and the relieve symptoms of Parkinson’s disease.

Question 36

Muscarinic Receptor Subtypes.

Answer 36

There are at least five distinct mACh-R, designated M1-M-5. These receptors show different tissue distribution and therefore offer the opportunity for more specific drug effects.

1. McN-A-343 activates mACh-R in the sympathetic ganglia and in the adrenal medulla but has little effect on mACh-R in heart and the vasculature.
2. Pirenzepine is a muscarinic antagonist used in Europe to reduce gastric secretion, it has little effect on heart rate or pupillary constriction.
3. Subtype Distribution
   a. M1 is main mACh-R in sympathetic ganglia and it is preferentially activated by McN-A-343.

b. M2 is the main subtype in heart, it is coupled to inhibition of cAMP levels.

• M1-Ca2+ mobilization and PKC activation
• M2-Inhibition of adenylyl cyclases through Gi
• M3
• M4-Inhibition of AC M5

Question 37

Anticholineesterases in the Autonomic Nervous System

Answer 37

• AChE terminates the action of acetylcholine at autonomic junctions in the same way it does so at the NMJ. Thus inhibitors AChE have cholinometric effects at both nicotinic and muscarinic synapses. Physostigmine and the organophosphate drugs are absorbed from the GI, whereas the quaternary ammonium compounds, eg neostigmine and echothiophate are not readily absorbed.
• Uses
  
  • Ophthalmology- AChE inhibitors are used in the treatment of primary and congenital glaucoma to cause miosis and increase drainage.
  • GI- Anti-AChE increase GI and urinary tract motility. Neostigmine is used for treatment of ileum and atony of the urinary bladder.
  • Atropine intoxication. The peripheral and central effects of atropine poisoning, or atropine-like side effects of the tricyclic anti-depressants) are reversed by physostigmine.