Flashcards in Drugs modulating the autonomic nervous system I and II Deck (49):
what part of the nervous system is the autonomic nervous system and somatic nervous system?
peripheral nervous system leads to either the autonomic nervous sytem or the somatic nervous system. the autonomic nervous system leads to the parasympathetic nervous system and the sympathetic nervous system. The somatic nervous system has sensory and motor division.
What is the autonomic nervous sytem?
Autonomous – independent, not under conscious control of the brain.
ANS: A branch of the peripheral nervous system innervating smooth muscle tissue, glands, organs whose activity is not under conscious control.
What are the parasympathetic nerves and the sympathetic nerves?
Parasympathetic nerves originate from the medulla and sacral spinal cord – CRANIOSACRAL OUTFLOW
Sympathetic nerves originate from the thoracic and lumbar spinal cord – THORACOLUMBAR OUTFLOW
what are the Neurotransmitters released by parasympathetic and sympathetic nerves.?
ACh – acetylcholine (parasympathetic neurotransmitter)
NE - norepinephrine (sympathetic neurotransmitter)
E - epinephrine
N - nicotinic receptors
where are the sites where ACh and NE are released?
Acetylcholine is released at the following synapses:
1. Preganglionic parasympathetic nerves at their ganglia
2. Preganglionic sympathetic nerves at their ganglia and at their synpases in adrenal medulla
3. Postganglionic parasympathetic nerves at their organ / tissue receptors
4. Preganglionic sympathetic nerves at their synpases in adrenal medulla
5. Somatic motor nerves at the neuromuscular junction in the skeletal muscles
Norpeineprine is released at the following synapses:
1. Postganglionic sympathetic nerves at their organ / tissue receptors
(The postganglionic fibres of the sympathetic system innervating all sweat glands , except in the palms, and skeletal blood vessels, release Ach)
What is an important source of epi and NE in the blood?
The adrenal medulla releases epinephrine (adrenaline) (80%), and norepinephrine (20%) into the circulation when stimuated by preganglionic sympathetic nerves.
Phaeochromocytoma – a tumor of the adrenal medulla that releases large amounts of Epi and NE into the circulation. The BP and heart rate of such patients are very high.
How is synthesis of ACh carried out?
what does botulinum toxin do related to ACh?
Acetylcholine (ACh) is synthesized from choline and acetyl coenzyme A
It is stored in neuronal vesicles, and released by nerve stimulation.
Botulinum toxin blocks ACh release – causes skeletal muscle paralysis.
How is the synthesis carried out of dopamine, norepinephrine, and epinephrin?
A benzene ring with two hydroxyl groups is known as a catechol
The amine side chain
So compounds with such a structure are called catecholamines
NE, Epi and dopamine are synthesized from the amino acid tyrosine
What are the cholinergic receptor types stimulated by ACh?
nicotinic --> neuronal or non-neuronal (skeletal muscle). Neuronal (Nn) --> adrenal, immune cells, CNS, ganglia
muscarinic --> M1,M3,M5 or M2,M4
M4 and M5 are in the brain and we don't need to remember htem as much.
Where are the nicotinic receptor locations?
Nicotinic receptors are sodium ion channels.
N(M) (neuromuscular), skeletal neuromuscular junction, skeletal muscle contraction.
N(N)(ganglionic or peripheral neuronal), autonomic ganglia (parasympathetic, sympathetic, adrenal medulla), postganglionic excitation.
Central neuronal (CNS), CNS synapses (pre- and post-junctional), CNS effects
What are the adrenergic receptor types - stimulated by NE?
We only need to remember Alpha 1 and Alpha 2. Also for the beta receptors we need to know Beta 1 and Beta 2.
What is dominant tone?
The dominant tone in an organ means that the branch of ANS (parasympathetic or sympathetic) innervating that organ is dominant or more active
Drugs affecting the system which is dominant will have a more noticeable effect in that organ.
For example the parasympathetic system is more dominant in the gastrointestinal tract. So if you give a cholinergic antagonist, you will see a marked reduction in peristaltic activity and reduced GI tract secretions
What does parasympathetic stiumation do to the heart?
Parasympathetic stimulation or muscarinic agonists will decrease the heart rate and AV conduction
E.g. Methacholine, cholinesterase inhibitors
ACh --> M2 --> decrease heart rate, decrease atrioventricular conduction.
Muscarinic receptor blockers will increase the heart rate and AV conduction
What does sympathetic do to the heart?
Sympathetic stimulation or β1 agonists will increase the heart rate, AV conduction and contractility
NE, Epi --> B1 (mostly), B2 --> increase heart rate, increase atrioventricular conduction, increased contractility.
β1 receptor blockers will decrease the heart rate, AV conduction and contractility (when sympathetic activity is increased)
Clinical relevance: hypertension, cardiac arrythmias, congestive heart failure, angina pectoris, myocardial infarction etc.
What does sympathetic do to the blood vessels?
Sympathetic stimulation or α1 agonists will cause vessel contraction and increase blood pressure
NE, Epi --> alpha 1 --> contraction, increased vascular resistance, increased blood pressure.
α1 receptor blockers will cause vasodilation, decrease peripheral resistance and BP
Blood vessels don't have what type of innervation?
Note: Blood vessels do NOT have cholinergic innervation (no parasympathetic innervation)
What do muscarinic agonists do to blood vessels? what about blockers?
Muscarinic agonists will cause vasodilation and decrease the blood pressure
ACh Muscarinic agonist --> M3 on the endothelium --> vasodilation.
Muscarinic receptor blockers – little or no effect
(this occurs because of the release of nitric oxide release)
Note: Skeletal muscle, pulmonary, abdominal viscera, renal and coronary vessels have β2 receptors which cause VASODILATION and decrease vessel resistance. E.g. epinephrine will dilate these vessels, NE will not (little β2 activity)
What is the dominant tone in the kidney?
sympathetic. There is no cholinergic innervation of the kidney.
What does sympathetic stimulation do to the kidney? What does the blocker do?
Sympathetic stimulation or β1 agonists will increase the secretion of renin (which will increase angiotensin and blood pressure)
β1 receptor blockers will decrease the secretion of renin (which will decrease angiotensin and reduce blood pressure)
What does the alpha 1 receptor stiumation do in the kidney?
α1 receptor stimulation decrease the secretion of renin, but the β1 effect predominates
Clinical relevance: hypertension, congestive heart failure
What does the parasympathetic do in the urinary bladder? What does the blocker do?
Parasympathetic stimulation or muscarinic agonists will contract the detrusor muscle (and relax the sphincter) to empty the bladder
E.g. Methacholine, cholinesterase inhibitors (used clinically)
ACh --> M3 (mostly), M2 --> detrusor contraction, sphincter relaxation
Muscarinic blockers will relax the detrusor muscle (and contract he sphincter) to prevent bladder emptying
Clinical relevance: urinary incontinence, urinary retention, benign prostatic hypertrophy
What does sympathetic do in the urinary bladder? what does the blocker do?
Sympathetic stimulation or β2 agonists will relax the detrusor muscle (but the parasympathetic effect dominates), and α1 agonists will contract the sphincter to prevent bladder emptying
NE, Epi --> a1 --> contract the sphincter
α1 blockers will relax the sphincter to allow bladder emptying (used clinically)
What does parasympathetic do in the tracheal and bronchial smooth muscle?
Parasympathetic stimulation or muscarinic agonists will contract the bronchial muscle and increase bronchial gland secretions
ACh --> M2,M3 --> contract the bronchial smooth muscle, increase secretions.
Clinical relevance: Asthma, COPD
Muscarinic blockers will relax the bronchial muscle and decrease bronchial gland secretions
E.g. Ipratropium (used clinically)
What does sympathetic do in the tracheal and bronchial smooth muscle?
Sympathetic stimulation or β2 receptor agonists agonists will RELAX the bronchial muscle
E.g. Albuterol, epinephrine
Albuterol, Epinephrine --> B2 --> RELAX the bronchial smooth muscle
Non-selective β blockers (e.g. to treat hypertension) and β2 blockers will contract the bronchial muscle
E.g. propranolol (not given to asthmatics)
What will the parasympathetic system do in the gastrointestinal tract smooth muscle?
Parasympathetic stimulation or muscarinic agonists will contract the GI muscle, stimulate PERISTALSIS, relax sphincters and ↑ intestinal gland secretions
E.g. Bethanechol, AChE inhibitors
Clinical relevance: Diarrhea, irritable bowel syndrome, gastric atony, paralytic ileus, peptic ulcer
ACh --> M3,M2 --> Contract the GI smooth muscle (stimulate peristalsis), increase secretions (M1 will increase HCl secretion in stomach)
Muscarinic blockers will inhibit PERISTALSIS and intestinal gland secretions
E.g. Dicyclomine, neostigmine
What will the sympathetic stimulation do to the gastrointestinal tract smooth muscle?
Sympathetic stimulation or β and α agonists will relax the GI muscle, inhibit PERISTALSIS, α1 will contract sphincters and α2 will inhibit intestinal gland secretions
Adrenergic agonists --> B2, B1, a1, a2 --> RELAX the GI smooth muscle (inhibit peristalsis), inhibit secretions, contract sphincters
Adrenergic blockers will not have noticeable effects on the GI tract because the sympathetic tone is not dominant
What will parasympathetic do to the salivary and parotid glands?
Parasympathetic stimulation or muscarinic agonists will stimulate salivary gland secretions
E.g. Bethanechol, AChE inhibitors
ACh --> M3, M2 --> stimulate salivary and mucus secretions
Muscarinic blockers will inhibit salivary gland and mucus secretions
What will sympathetic stimulation do to the salivary and parotid glands?
Sympathetic stimulation or α1 agonists will stimulate salivary gland secretions
Adrenergic agonists --> a1 --> stimulate salivary secretions mildly.
What will sympathetic stimulation of the liver do?
Sympathetic stimulation or β2 receptor agonists agonists will cause glycogenolysis and gluconeogenesis (increase plasma glucose in response to hypoglycemia)
Epinephrine --> B2 --> glycogenolysis, gluconeogenesis
β2 and non-selective β receptor blockers will prevent glycogenolysis and gluconeogenesis (will NOT ALLOW plasma glucose to increase in response to hypoglycemia)
Clinical relevance: Type 1 diabetic patients on insulin
Note: If plasma glucose decreases, e.g. in patients taking insulin, the sympathetic stimulation of liver releases glucose and corrects hypoglycemia, and reduces the risk of hypoglycemic coma.
β2 blockers prevent this response and the patient is at higher risk of hypoglycemic coma
How will the sympathetic stimulation of the uterus change things?
Sympathetic stimulation or β2 receptor agonists agonists will cause RELAXATION of uterine smooth muscle
Epinephrine --> B2 --> relaxation
Clinical relevance: Prevent premature labour
How will parasympathetic stimulation change the pupillary muscles, ciliary muscles?
Dominant tone: parasympathetic
Parasympathetic stimulation or muscarinic agonists will cause contraction of circular (sphincter) fibres of the iris and miosis (narrowing of pupil)
Muscarinic M3, M2 receptors on ciliary muscles will cause spasm of accomodation
M3, M2 receptors on lacrimal glands will cause lacrimation
Muscarinic receptor blockers will cause mydriasis (dilation of pupil), impair accomodation and decrease lacrimation
Clinical relevance: Glaucoma, retinal examination
What will the sympathetic system do to the pupillary muscles, and ciliary muscles
Sympathetic stimulation or α1 receptor agonists will cause mydriasis (dilation of pupil)
Adrenergic receptor blockers will have little or no effect (symp[athetic tone is not dominant)
How is glaucoma characterized?
Glaucoma is characterized by an increase in intraocular pressure
↑ production of aqueous humor
↓ outflow (drainage) of aqueous humor
The aqueous humor is produced by secretion from the ciliary processes and flows from the posterior chamber through the pupil into the anterior chamber and leaves the eyes primarily by the trabecular meshwork and canal of Schlemm. From here it drains into episcleral venous plexus and systemic circulation. This pathway accounts for 80 – 95% of outflow and is the target for cholinergic drugs.
Muscarinic - (M3, M2) contraction causes opening of trabecular meshwork and drainage of aq. humor - reduces intraocular pressure
Muscarinic - contraction relaxes fibres holding the lens which becomes more spherical (focuses on near objects – “spasm of accomodation”)
Muscarinic - contraction causes miosis (narrowing of pupil)
α2-receptor agonists (e.g. alpraclonidine, brimonidine) reduce aqueous production (presynaptic action - reduce NE release and its effects; postsynaptic action – reduce aqueous production by reducing cAMP)
β2 receptors on ciliary epithelium and blood vessels – stimulation increases blood flow and aq. humor secretion – β2 antagonists (e.g. timolol) reduce blood flow and decrease aq. humor secretion and pressure
β2 receptors - relax the ciliary muscles and increase tension of fibres holding the lens which becomes more flat (focuses on far objects – blurring of near vision)
What drugs can mimick the effect of the parasympathetic system?
Parasympathetic effects can be mimicked by:
Muscarinic receptor agonists (carbachol, pilocarpine)
Acetylcholinesterase (or anticholinesterase) inhibitors (these drugs delay the breakdown of ACh and prolong its action) (e.g. Neostigmine)
What drugs can mimick the blocking of the effect of the parasympathetic system?
Parasympathetic effects can be blocked by:
Muscarinic receptor antagonists (e.g. Atropine)
Skeletal neuromuscular junction blockers (e.g. D-tubocurarine)
What are the muscarinic receptor agonists?
- Choline esters
Bethanechol (methacholine and bethanechol are selective for muscarinic receptors)
Carbachol (Bethanechol and carbachol are relatively resistant to hydrolysis by AChE, prolonging their action as compared with ACh).
- Plant alkaloids
What are the therapeutic uses of parasympathomimetics?
Generally speaking cholinergic agonists are used to
1. Reduce intraocular pressure in glaucoma: e.g. pilocarpine eye drops (better tolerated than anticholinesterases) – cause contraction of ciliary muscle and open up trabecular meshwork to facilitate outflow of aqueous . They do not affect aqueous production. Also used in In narrow angle glaucoma to cause miosis (pupillary constriction) and facilitate drainage of aqueous humor
2. Increase the motility (peristalsis) of the gastrointestinal (GI) tract: e.g. Bethanechol is used in certain cases of postoperative abdominal distension, gastric atony, gastroparesis, congenital megacolon, postoperative ileus (hypomotility)
3. Increase motility of the urinary tract (bladder contractions): e.g. Bethanechol is used in urinary retention (postoperative and postpartum), hypotonic bladder
4. To increase salivary secretions: To treat xerostomia (dry mouth) – following head and neck irradiation or associated with Sjögren’s syndrome (an autoimmune disorder in women in whom salivary and lacrimal secretions are reduced)- pilocarpine is given orally (can cause excessive sweating)
What does cholinesterase inhibitor do? What does acetlycholinesterase do?
- Remember: ACh released at the synapse acts for a few milliseconds before it is metabolized in the synapse (The whole ACh molecule is not taken up back into the presynaptic neuron like NE, therefore we do not have clinically used uptake blockers for ACh)
- The enzyme is acetylcholinesterase (AChE)
- It is present in the synaptic cleft on the outer membrane of the postjunctional cell (neuron or effector organ)
- Hydrolysis of ACh is one of the fastest known enzymatic reactions - approx. 104 molecules of ACh / second by a single enzyme molecule
- These drugs (also called acetylcholinesterase inhibitors) increase the duration of action of the released ACh at the synapse (indirectly acting parasympathomimetics)
- Potentiated responses due to stimulation of muscarinic and skeletal neuromuscular nicotinic receptors are seen
What are the two types of cholinesterase (ChE) enzymes?
- There are two types of cholinesterase (ChE) enzymes :
butyrylcholinesterase (BuChE, also called plasma or pseudoChE)
- BuChE is located at non-neuronal sites, mainly in the plasma and liver
metabolizes certain drugs, including some local anesthetics, and succinylcholine (a muscle relaxant)
- Most enzyme inhibitors used clinically do not discriminate between the two types of ChEs
What is a cholinesterase inhibitor and when is reversible inhibition and irreversible inhibition used?
- Acetylcholinesterase (AChE) hydrolyzes ACh and the enzyme becomes acetylated. It becomes deacetylated very rapidly (recovers enzyme activity very fast). This is its normal cycle.
- Reversible inhibition of the enzyme (used therapeutically): A reversible AChE inhibitor such as neostigmine causes carbamylation of the enzyme. Hydrolysis of carbamylated enzyme occurs slowly (3-4 h), causing reversible inhibition of the enzyme (it slowly recovers enzyme activity).
- Irreversible inhibition of the enzyme (poisoning) (this is used for pesticides) : An irreversible AChE inhibitor (e.g. diisopropyl flurophosphate) causes phosphorylation of the enzyme. Dephosphorylation and recovery (if it occurs at all) takes several hours. After some hours the phosphorylated enzyme loses a chemical group (“aging”) and the drug-enzyme complex forms a new chemical with no enzyme activity. Note: An oxime such as 2-PAM, if administered before aging occurs, can bind to and release the phosphate moiety attached to the enzyme; this process reverses the enzyme inhibition
How are reversible ChE inhibitors used as drugs?
- These drugs will increase cholinergic activity where it is lacking or decreased. E.g. to increase motility of GI tract, urinary bladder, to treat symptoms of Alzheimer’s disease, to improve skeletal muscle contraction etc.
- Edrophonium has a very short duration of action (approx. 10 min). Used mainly for diagnosis.
- Neostigmine, physostigmine, pyridostigmine
- Donepezil and tacrine have higher affinities and partition into lipids. Used for Alzheimer's disease (Also rivastigmine and galantamine)
What are the therapeutic uses of ChE inhibitors?
- The sites of action of anti-ChE agents of therapeutic importance are the
CNS – Alzheimer’s disease
Eye - Glaucoma
Intestine – Postoperative ileus, congenital megacolon (in which there is atony of smooth muscle). ChE inhibitors also relax sphincters to facilitate peristaltic movement.
Urinary bladder – Atony of smooth muscle (urinary retention)
Neuromuscular junction of skeletal muscle – reversal of paralysis of competitive neuromuscular blockers
Diagnosis and treatment of myasthenia gravis
Other actions are of toxicological consequence
How are ChE Inhibitors used in the eye?
Eye – can be used to treat glaucoma, but they can cause cataracts with long-term use - used only in aphakic patients (i.e., those lacking a lens) or in those cases in which other agents are ineffective. These drugs and muscarinic agonists have many side effects so not much used
topical application to conjunctiva causes miosis (narrowing of pupils)
Ciliary muscle contraction – lens focuses on near objects, but far vision is blurred
Aqueous humor outflow is facilitated and intraocular pressure falls
E.g. Physostigmine, echothiophate, isofluorophate, demecarium
How are ChE inhibitors used for skeletal muscle neuromuscular junction?
Skeletal muscle neuromuscular junction - activate nicotinic receptors
low doses of ChE inhibitors tend to increase the force of contraction
Used to treat patients with myasthenia gravis, who have weakness of skeletal muscles
Pyridostigmine (MESTINON) – duration of action 3-6 h
Neostigmine (shorter acting), ambenonium (longer acting)
Neuromuscular junction – Intermediate doses of ChE inhibitors can cause muscle fasciculations and fibrillations due to desynchronized depolarizations from multiple receptor stimulation.
High doses cause persistent depolarization blockade and muscle paralysis
Anti-ChE agents will reverse the antagonism created by competitive neuromuscular blockers such as d-tubocurarine, but they will add to the depolarization and paralysis caused by succinylcholine and make it worse
How are ChE inhibitors used in the cardiovascular system
Cardiovascular system - The effects of ChE inhibitors are complicated by opposing effects resulting from the activation of both sympathetic and parasympathetic ganglia
ChE inhibitors decrease heart rate and cardiac output but have little effect on ventricular contraction (because parasympathetic tone dominates in the heart)
Blood pressure - moderate doses of ChE inhibitors have little effect (because few blood vessels receive cholinergic innervation), but high doses decrease blood pressure
How does botulinum toxin work?
A toxin released by the bacteria Clostridium botulinum
Botulinum toxin blocks ACh release.
It is used to paralyze skeletal muscle in cases of excessive involuntary skeletal muscle tone
Clinical uses (BOTOX®): strabismus (unaligned lines of vision between a pair of eyes), blepharospasm (contracted eyelid), hemifacial spasm
Cosmetic use: to remove facial wrinkles
What are the 2 muscarinic cholinergic receptros blockers?
- Belladonna alkaloids
- Semisynthetic and synthetic
Wat are the effects of muscarinic receptor antagonists?
Eye - pupillary dilation (mydriasis) and a paralysis of the accommodation reflex (cycloplegia), resulting in blurred vision
Relax smooth muscle in the bronchi, the GI tract, and the urinary bladder
Inhibit the secretion of substances from various exocrine glands, including sweat, salivary, lacrimal, and mucosal glands of the trachea and GI tract
In moderate to high doses - muscarinic receptor antagonists block the effects of ACh on the heart - ↑ heart rate
Atropine and scopolamine - interfere with short-term memory and, in moderately high doses, cause delirium, excitement, agitation, and toxic psychosis