01/08/16 and 01/11/16 Flashcards
1
Q
Introduction: ANS
A
- Regulates function of the heart, blood vessels, GI tract, various types of smooth muscle
2
Q
Comparison of NM and Autonomic Nervous System
A
- Actions of somatic nerves are voluntary while ANS is involuntary
- Skeletal muscle needs neuronal stimulation for action; ANS show tonic activity (has spontaneous activity that is modulated by stimulation)
- 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
- There are presynaptic receptors in the ANS but not at neuromusclar junction; regulate the release of neurotransmitters
3
Q
Parasympathetic vs. Sympathetic Nervous system
A
- 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
4
Q
Adrenals and Stress
A
- 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
5
Q
Parasympathetic ganglia are generally closer to the target organ; more discrete
A
- 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
6
Q
Classification of Motor Fibers
A
- 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
7
Q
Effects of Autonomic Stimulation on Organ Function
A
- 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
- Parasympathetic:
- The sympathetic nervous system innervates all of the heart but there is very little parasympathetic innervation of the ventricles
8
Q
Autonomic Effects on Vasculature
A
- 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
9
Q
Smooth Muscle, General, Exocrine glands, sweat gland, liver, salivary gland
A
- 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.
10
Q
Pupil Constriction
A
- 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
11
Q
Lens Accommodation:
A
- 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.
12
Q
Synaptic Transmission through Autonomic Sympathetic Ganglia
A
- Stimulation of preganglionic fibers causes a complex series of events in the membrane potential of the postganglionic neuron:
- An initial large depolarization, EPSP due to the activation of the ganglionic nicotinic receptor of the postganglionic neuron by ACh.
- A small hyperpolarization (slow IPSP) due to the activity of an interneuron.
- 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.
13
Q
Synaptic Transmission through Parasympathetic Ganglia
A
- 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.
- The synthesis, storage and release of acetylcholine in preganglionic cholinergic terminals of autonomic ganglia are similar to that described for the NM junction.
- 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.
14
Q
Nicotinic Ganglionic Stimulating Drugs
A
- 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.
15
Q
Muscarinic Ganglionic Stimulating Drugs
A
- 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.
16
Q
Ganglionic Blockers
A
- 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.
17
Q
Predominant Autonomic Tone and Effects of Ganglionic Blockers
A
- 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:
- arterioles and veins-cause, ganglionic blockers cause vasodilation
- Sweat glands- Anhidrois, decreased sweating
- Effects on organs with predominantly parasympathetic tone are:
- Heart- tachycardia (excessive fast heart rate)
- eye- mydriasis, pupillary dilation and cycloplegia (paralysis of the intraocular muscle)
- Salivary gland- Xerostomia, dry mouth
- GI tract- relaxation of intestinal muscle, constipation
- 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.
18
Q
Differences between Muscarinic and Nicotinic Synapses.
A
- There are important differences between synaptic transmission at muscarinic synapses compared to nicotinic synapses.
- 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.
- 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.
- 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.
- 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.
19
Q
Muscarinic Axons and Varicosities In Heart Muscle
A
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.
20
Q
Muscarinic synapse in heart
A
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.
21
Q
Muscarinic Agonists
A
- 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.
22
Q
Cardiovascular Effects of Muscarinic Agonists
A
- 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.
23
Q
NO is Produced in Endothelial Cells of Blood Vessels
A
- 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.
24
Q
BP Changes Caused by Acetylcholine
A
- Decrease in BP-vasodilation, through NO in vascular smooth muscle which causes vasodilation
- More ACh even lower BP.
- This is blocked by a muscarinic antagonist-atropine
- 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.
28
Q
Structure of the alkaloids
A
- 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
30
Q
Structure of the Belladonna Alkaloids
A
- 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.
31
Q
*******Atropine Biphasic Effect on Heart Rate ********
A
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.
33
Q
Quaternary Derivatives of Antimuscarinic Alkaloids
A
- These drugs, which are quaternary ammonium derivatives of the anti-muscarinic alkaloids have different properties from their corresponding tertiary amine derivatives.
- They do not cross the blood brain barrier. Therefore they exhibit no CNS side effects
- 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.
35
Q
Anti-muscarinics use to induce mydriasis and cycloplegia.
A
- Ophthalmology-Go through slide. Note that the drugs differ in duration of action and the recovery time is significant. It can take days.
- 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.
- Cardiovascular System- Atropine is used to relieve bradycardia caused by excessive stimulation of vagal tone following myocardial infarction.
- 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.
- CNS- The antimuscarinics are used to prevent motion sickness and the relieve symptoms of Parkinson’s disease.
36
Q
Muscarinic Receptor Subtypes.
A
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.
- 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.
- Pirenzepine is a muscarinic antagonist used in Europe to reduce gastric secretion, it has little effect on heart rate or pupillary constriction.
- 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
