Quiz 1 Exam 3 Flashcards
What is a muscarinic agonist?
This is a drug that activates the parasympathetic nervous system as this system uses Ach that binds to muscarinic receptors on effector organs. It can also act on sweat glands controlled by the sympathetic system as they have muscarinic receptors.
What are the main sites that can be affected by muscarinic drugs?
- Parasympathetic innervated effectors organs
- Sweat glands innervated by sympathetic system
- Endothelial cells that contain muscarinic receptors but are not innervated by the parasympathetic system
What are the two categories of muscarinic drugs?
Choline esters and Natural Alkaloids
What are the 4 main muscarinic agonists categorized as choline esters?
Acetylcholine, Methacholine, Carbachol, and Bethanechol
What are the 3 main muscarinic agonists categorized as natural alkaloids?
Muscarine (don’t need to know this)
Cevimeline, Arecoline, and Pilocarpine
CAP!
Can choline esters, a category of muscarinic agonist, pass the BBB?
No because they are hydrophilic/charged.
Do natural alkaloids, like Pilocarpine, enter to BBB? Are they metabolised by acetycholinesterases?
Yes they go enter the BBB and they are not metabolized by acetylcholinesterase enzyme for breakdown.
What would be some effects to the body of a muscarinic agonist?
SLUDD and the 3Ds. Overall, it would depend on affinity for different receptors but in a general sense.
Salivation, Lacrimation, Urination, Digestion, Defecation, decrease heart rate, decrease bronchodilation, and decrease pupil size.
What are the effects of the cardiovascular system with a muscarinic agonist?
- Reduction in heart rate via M2 receptor
- Reduction in peripheral resistance via M3 receptor presence mediated by nitric oxide
What would be the response to LOW doses of acetylcholine (muscarinic agonist)?
Vasodilation and reflexive arc trigger to increase heart rate due to baroreceptors sensing decreased blood pressure.
What would be the response to HIGH doses of acetylcholine?
Bradycardia and hypotension (remember, parasympathetic does NOT innervate the vessels but muscarinic receptors are present)
What would be the effects to the respiratory system with a muscarinic agonist?
Bronchoconstriction and increased secretion via the M3. No clincial use for this.
Why is the ciliary epithelium of the eye clinically relevant?
It secretes the aqueous humor in the eye which increases with glaucoma.
What happens in the eye when a muscarinic agonist is given?
- Sphincter muscle constricts causing miosis/pupil constriction via M3
- Ciliary muscles constricts allowing for near vision and outflow of aqueous humor liquid reducing intraocular pressure via M3
The internal sphincter of the bladder is primarily controlled by which ANS route?
Sympathetic and overall functions to relax the bladder muscle (detrusor) and close sphincter to inhibit urination.
The external sphincter of the bladder is primarily controlled by which ANS route?
Parasympathetic and overall functions to constrict bladder muscle (detrusor) and open sphincter to promote urination.
What would a muscarinic agonist due to urination?
It would promote urination via M3 receptors by contracting the bladder muscle (detrusor) and opening up the external sphincter.
What would a muscarinic agonist due to secretory glands?
It would promote secretions by sweat glands, lacrimal glands, salivary glands, gastric glands, and nasopharyngeal glands.
What would a muscarinic agonist due to the GIT?
It would stimulate increased secretions and motor activity as well as relax sphincters of the GIT via M3.
What are the 6 main clinical uses of muscarinic agonists?
- Post-op urinary retention and bowl paralysis
- Xerostomia (dry mouth) for radiation to head and neck or Sjogren’s syndrome
- Glaucoma to enhance aqueous humor drainage
- Miotic agent to help with near vision
- Diagnostic tool for bronchial airway hyperactivity (methacholine inhalation)
- Antimuscarinic drug intoxication due to overdose of atropine (muscarinic antagonist) or tricyclic antidepressants
What is the drug methacoline?
This is muscarinic agonist categorized as a choline ester.
What is methacholine used for?
This muscarinic agonist is used for diagnostic testing of bronchial airway hyperreactivity.
What is the drug bethanechol?
This is a muscarinic agonist categorized as a choline ester. It is selective to the GIT and urinary tract.
What is bethanechol used for?
Bethanechol is used for post-op urinary retention and abdominal distention.
What is the drug pilocarpine?
This is a muscarinic agonist categorized as a natural alkaloid. It is selective.
What is pilocarpine used for?
Pilocarpine is used for xerostomia (dry mouth) and in Sjogren’s syndrome with reduced secretions, as well as a miotic agent and glaucoma for the eyes.
What is the drug cevimeline?
This is a synthetic muscarinic agonist. It is similar to pilocarpine and is approved for Sjogren’s syndrome.
What are the symptoms of muscarinic agonist toxicity?
Overactivation of SLUDD and the 3Ds. Include nausea, vomiting, salivation, sweating, and bronchial constriction. Reversed with a muscarinic antagonist.
Are acetylcholinesterase inhibitors direct or indirect muscarinic agonist?
AChEase inhibitors are indirect muscarinic agonists as they stop the breakdown of acetylcholine increasing its concentration.
What are the main 3 pharmacological actions of acetylcholinesterase inhibitors?
- Stimulates muscarinic receptors are effector organs
- Stimulates muscarinic receptors after depression or paralysis of autonomic ganglion (nicotinic receptors)
- Stimulation of cholinergic sites in the CNS
What are the differences among acetylcholinesterase inhibitor drugs?
They have differences in chemical and pharmacokinetics but NOT pharmacodynamics.
What are the 3 classes of acetylcholinesterase inhibitor drugs?
- Alcohols (edrophonium)
- Carbamic esters of alcohols (neostigmine)
- Organophosphates/insecticides (malathion)
What are the reversible cholinesterase inhibitors?
Physostigmine, Neostigmine, Pyridostigmine,
Rivastigmine, Tacrine, Donepezil, Galantamine (alzheimer’s)
Edrophonium
Out of these 3 reversible cholinesterase inhibitors, which one can pass the BBB and enter the brain?
Physostigmine, Neostigmine, Pyridostigmine
Physostigmine because it is not charged.
What are the two drug that are irreversible cholinesterase inhibitors?
Insecticides and nerve gases like malathion
Most of the effects between direct acting muscarinic agonists and indirect acting acetylcholinesterase inhibitors are the same. What is the effect on the cardiovascular system that is different between these two drug types?
AChEase inhibitors increase BOTH sympathetic and parasympathetic ganglia supply the heart (Ach binds at ganglion sites for both system so this makes sense). The parasympathetic effect dominantes so the heart rate and cardiac output decrease.
Additionally, AChease inhibitors no direct effect on blood vessels compared to muscarinic agonists which have receptors on blood vessels. However, moderate doses of AChease inhibitors increase vascular resistance due to activity at ganglion for sympathetic.
OVERALL, modest bradycardia, decreased cardiac output, and increases in vascular resistance causing increase in blood pressure.
Why do AChease inhibitors need to be monitored in Alzheimer’s patient with hypertension?
AChease inhibitors increased blood pressure through its actions on the ganglion at the sympathetic system.
What are the 4 main conditions that acetylcholinesterase inhibitors are used for?
- Atony of bladder and GIT
- Glaucoma
- Myasthenia gravis
- Alzheimer’s disease
What is the RX for myasthenia gravis, the autoimmune disorder causing degradation of the nicotinic m receptors at the neuromuscular junction?
Acetylcholinesterase inhibitor. This would increase the concentration of acetylcholine therefore increasing the likelihood that ACh could still bind to produce an effect.
What is the main hypothesis surrounding Alzheimer’s disease that leads to the use of what 4 AChease inhibitor drugs?
The hypothesis states that there is a loss or cholinergic transmission in the brain which can be halted with anticholinesterase inhibitors to increase the amount of ACh in the synapse. These drugs include Tacrine, Donepezil, Rivastigmine, and Galantamine
What are the symptoms of pesticide organophosphate toxicity like malathion?
Organophosphates have similar effects to muscarinic agonist as they inhibit AChEase resulting in a higher concentration of acetylcholine. Therefore the effects would include overexxageration of SLUDD +3D responses. Includes miosis, salivation, sweating, bronchoconstriction, vomiting, and diarrhea.
How is insecticide organophosphate toxicity treated?
Treated with a muscarinic agonist like atropine.
A nerve gas like sarin is also an irreversible AChEase inhibitor. How is toxicity of this drug treated?
Pralidoxime. This is an AChEase reactivator. Specifically, it prevents aging which is the formation of the covalent bond between AChEase and the nerve gas.
What drug would be used prophylactically for nerve gas exposure?
Pyridostigmine. It would prevent the actions of nerve gas if exposed but would require atropine if exposure occured.
Woman undergoes abdominal surgery and develops an absence of bowel motility, severe bloating, and difficulty urinating. Mild cholinomimetic stimulation with bethanechol or neostigmine is often effective at relieving these complications. Bethanechol or neostigmine in moderate doses have significantly different effects on which of the following?
A. Gastric secretory cells
B. Vascular Endothelium
C. Salivary glands
D. Sweat glands
E. Ureteral tubes
B. Vascular Endothelium. Bethanechol is a muscarinic agonist and therefore can bind to muscarinic receptors present on vascular endothelium and induce dilation leading to hypotension. Neostigmine has little direct effect on blood pressure itselg but it is an AChEase inhibitor that works at all sites where acetylcholine is present include the sympathetic ganglion. This means at moderate doses, it will increase vascular resistance via sympathetic activation causing vasocontriction leading to hypertension.
A crop duster pilot has been accidently exposed to high concentrations of a highly toxic organophosphate insecticide. It untreated, the cause of death due to exposure would probably be…
A. Cardiac arrythmia
B. GIT bleeding
C. Heart failure
D. Hypotension
E. Respiratory failure
E. Respiratory failure. A nicotinic sites like in the ganglion, high doses initially stimulate then and then lead to depression and paralysis at autonomic ganglion. This would include both sympathetic and parasympathetic ganglion. Since the parasypathetic is the primary control of the lungs, that effector organ would eventually shut down if not treated.
A man has been diagnosed with dysautonomis (chronic idopathic autonomic insuffiencey). You are considering different therapies for his disease. Pyridostigmine and neostigmine may cause which of the following in this patient?
A. Bronchodilation
B. Cycloplegia
C. Diarrhea
D. Irreversible inhibition of acetylcholinesterase
E. Reduced gastric acid secretion
C. Diarrhea. Since pyridostigmine and neostigmine and AChEase inhibitors, they mostly act similar to muscarinic agonist as they increase the concentration of acetylcholine. Therefore it would induce the SLUDD + 3D responses like defecation which would include diarrhea. It would not induce bronchodilation it would induce bronchoconstriction. These are reversible inhibitors of AChEase and they also would increase GIT secretions.
Parasympathetic nerve stimulation and a low infusion of bethanechol will each…
A. Cause ganglion cell depolarization
B. Cause skeletal muscle end plate depolarization
C. Cause vasodilation
D. Increase bladder tone
E. Increase heart rate
D. Increase bladder tone. This also means to contract the bladder (detrusor) muscle. Bethanechol is a muscarinic agonist and the parasympathetic system is controls release of urine. It is possible for bethanechol to cause vasodilation but parasympathetic nerve stimulation would not do this as it does not actually innervate that vascular endothelium as it is under full control by the sympathetic system.
Actions and clincial uses of muscarinic cholinoceptor agonists include which one of the following?
A. Bronchodilation (treatment of asthma)
B. Miosis (treatment of glaucoma)
C. Decreased GIT motility (treatment of diarrhea)
D. Decreased neuromuscular transmission and relaxation of skeletal muscle (during surgical anesthesia)
E. Vasoconstriction
B. Miosis (treatment of glaucoma). Muscarinic agonist cause vasodilation via binding to M3 receptors on vascular endothelium.
What are the 4 main ganglionic blocker drugs?
- Mecamylamine
- Trimethaphan
- D- Tubocucarine
- Succinylcholine
- Hexamethonium
What are ganglionic blocking drugs?
These are nicotinic antagonist as at the ganglion there are nicotinic n receptors. If we block the ganglion, we are blocking the nicotinic n receptors there.
What areas are effected by ganglionic blocking drugs?
As ganglionic blocking drugs are nicotinic antagonists, these would effect the parasympathetic system at the ganglion, it would effect the sympathetic system at the ganglion, and it would effect the neuromuscular junction where nicotinic m receptors are present.
What is the MOA of mecamylamine?
This is a ganglion blocker (nicotinic antagonist) that is a nondepolarizing, noncompetitive antagonist of ACh receptors in the brain and muscles.
What is the MOA of trimethophan?
This is a ganglion blocker (nicotinic antagonist) that is a nondepolarizing, competitive antagonist of the nicotinic acetylcholine receptors.
What is the MOA of hexamethonium?
This a long-acting ganglion blocker (nicotinic antagonist) that is nondepolarizing, mixed action antagonist of Ach receptors.
What are the two types of MOAs for ganglionic blockers?
- Depolarizing blockade
- Non-depolarizing blockade includes competitive, non-competitive, and mixed antagonists.
Which ganglionic blocker discussed is the only one that can cross the BBB?
Mecamylamine
What is the effect to the eye when a ganglion blocker is introduced?
Ganglion blockers are nicotinic antagonists. The predominant tone of the eye is parasympathetic. Blocking this results in the sympathetic taking over resulting in loss of near vision (cycloplegia) therefore far vision is induced. However, pupil size is not really effected but could result in moderate dilation (mydriasis).
**
What is the effect on the genitourinary tract with a ganglionic blocker?
The predominant tone of the bladder is controlled by the parasympathic system. When inhibited, this would result in difficulty urinating due to sympathetic takeover. Additionally, both erection and ejaculation would be impacted and impaired as an erection is controlled by the parasympathetic and ejaculation is controlled by the sympathetic.
What happens in the cardiovascular system, both blood vessels and the heart, when a ganglionic blocker is introduced?
Ganglionic blockers are nicotinic antagonists. The blood vessels are dominated by the sympathetic system. Therefore addition of a ganglionic blocker would result in loss of tone resultin in vasodilation leading to hypotension. The heart is dominated by the parasympathetic so loss of this would result in tachycardia.
What is the effect of a ganglionic blocker on the GIT?
As the GIT is dominated by the parasympathetic system, blocking this would result in decreased tone, motility, and secretions.
What is the main effect to skeletal muscle neuromuscular junctions with the use of neuromuscular blocking agents like succinylcholine and d-tubocurarine?
Even though succinylcholine is a depolarizing non-competitive agent and d-tubocurarine is a non-depolarizing competitive agent at Nm receptors, they both block the action of acetylcholine at the nicotinic m receptors at the neuromuscular junctions causing paralysis.
What are the two clinically used ganglionic blocker drugs and what are they used for?
- Mecamylamine- Blocks central nicotinic receptors as it can cross BBB and may be an adjuct therapy with transdermal nicotine patches for smoking cessation
- Trimethaphan- Treatment of hypertensive crises and dissecting aortic aneurism as it procudes controlled hypotension
What is the treatment for toxicities of non-depolarizing competitive ganglion blockers (nicotinic antagonist) like trimethaphan and D-tubocurariene?
AChEase inhibitor like neostigmine. This would increase ACh concentrations to displace the blocker. It would be given with atropine (muscarinic antagonist) to reduce excess acetylcholine on muscarinic receptors producing intense SLUDD + 3D response.
What is the one non-depolarizing competitive nueromuscular blocking agent (nicotinic m receptor antagonist)?
D-tubocurarine
**
What would be the effects to salivary and sweat glands with a ganglionic blocker?
Ganglionic blockers are nicotinic antagonists. Salivary glands are controlled by the parasympathetic while sweat glands are controlled by sympathetic. When these ganglion are blocked, salivary glands stop secreting and it results in xerostomia (dry mouth). It also results in decreased sweat secretions which results in anhidrosis (no sweat secretions).
What is the prototype antinicotinic (nictonic antagonist) agent?
Curare
What is the one depolarizing, non-competitive neuromuscular blocking agent (nicotinic m receptor antagonist)?
Succinylcholine
What enzyme is succinylcholine metabolized by ?
Pseudocholinesterase as it is more resistant to degradation by acetylcholinesterase.
What were the main 3 non-selective alpha adrenergic agonists discussed?
Oxymetazoline, Epi, and NE
(Note: Epi and NE also act on Beta but we will get to that later)
What were the main 2 alpha-1 agonists discussed?
Phenylephrine and Midodrine
What were the 3 alpha-2 agonists discussed in class?
Apraclonidine, Brimonidine, and clonidine
We know that alpha-1 receptors are located in the vasculature, but what receptor controls the blood vessels in the eyes?
a2A
What adrenergic receptors can be targeted in the eye for glaucoma?
a2
B1 and B2
What adrenergic receptor in the nose can be acted on to induce nasal decongestion?
a1
It is known that most alpha-2 receptors act as those presynaptic receptors in the nerve terminals. However, some can act on blood vessels in the _______ to induce blood vessel __________.
Eye
Contraction
What is the difference between direct and indirect adrenergic agonists?
Direct agonists will bind directly to receptors and induce transmitter release while indirect agonists block the reuptake of NE or Epi.
Alpha adrenergic receptors have the highest affinity for what?
Epi then NE then isoproterenol (b1, b2, b3 agonist)
If Isoproterenol binds, it is a _______ receptor.
Beta
Beta adrenergic receptors have the highest affinity for what?
Isoproterenol then EPI then NE
What often happens to receptors after taking a drug for a period of time?
Desensitization occurs in part to phosphorylation and internalization of receptors. The receptors are out of homeostasis due to overstimulation and internalize those receptors to stop being activated.
It is know that a2 is the big presynaptic receptor. However, drugs can act on the presynaptic brake to reduce blood pressure. Which drug does this?
Clonidine
How does clonidine reduce blood pressure even though it is an a2 receptor agonist?
Clonidine activates presynaptic a2 receptors which acts like a break to inhibit the release of NE in the synapse. This inhibition of NE release stops it from reaching circulation to produce hypertension.
It appears that increasing substituents on the amine group for sympathomimetic drugs increases it affinity for the _______ receptor.
Beta. Example of this is isoproterenol as it has a fairly large group attached to the amine.
It appears the removing hydroxyl (OH) groups from the ring structure of sympathomimetic drugs increases the selectivity for _______ receptors.
Alpha. It also decreases potency but makes it no longer a substrate for metabolism by COMT.
What are the effects of an a1 agonist like phenylephrine or midodrine on the cardiovascular system?
Phenylephrine and midodrine will cause vasoconstriction in the vasculature leading to hypertension. In response with the reflex arc, the heart rate will decrease. These drugs have no direct action on the heart. The decrease in heart rate is solely due to the body noticing the hypertension.
What is the one exception to a1 agonist induced hypertension not inducing the reflex arc to decrease heart rate?
Heart transplant
How do beta receptor agonists influence the cardiovascular system?
- B1 (only in heart) agonists increase pacemaker activity (chronotropic), dromotropic (conduction velocity), and contractility (inotropic) to overall INCREASE HEART RATE
- B2 (vasculature of skeletal muscle) agonists cause vasodilation leading to decrease in mean arterial pressure. DECREASE BLOOD PRESSURE
What happens to the cardiovascular system when a non-selective adrenergic agonist is given that acts on both beta and alpha receptors like EPI?
Both the heart rate will increase via beta1 and blood pressure will increase via alpha1 receptors.
If an a1 agonist like phenylephrine or midodrine is added as well as a ganglionic blocker like mecamylamine or trimethaphan, what would be the cardiovascular response?
The phenylephrine and midodrine would still act on the a1 receptor to induce vasoconstriction however, because the ganglionic blockers like mecamylamine and trimethaphan block the reflex arc between the spinal cord and parasympathetic (sympathetic too but parasympathetic decreases HR), there would be no changes in the heart rate.
What would be the result of adding phenylephrine to the eyes?
Phenylephrine is an alpha-1 agonist and pupil size is controlled by the alpha-1 receptor. This would result in pupil dilation (mydriasis).
What structure/drug do bath salts look like?
Bath salts have a similar structure to amphetamines. Amphetamines stimulate NE release from the synapse.
What receptor controls constricts the internal sphincter of the bladder
The a1 receptor constricts and inhibits urination in the bladder.
Review Question.
A. Atropine
B. Epinephrine
C. Isoproterenol
D. Phenylephrine
E. Physostigmine
B. Epinephrine. It causes increases to blood pressure through a1 activation and increase heart rate and output via beta1.
What happens to blood pressure if epinephrine is administered after phentolamine has been given?
Since alpha antagonist turn epinephrine from a pressor into a depressor, the addition of EPI will bring down the blood pressure while the heart rate mildly increases due to epinephrine acting on beta-1 in the heart and via reflexes.
What happens to the heart and blood pressure when giving a non-selective beta blocker like propranolol in response to EPI?
Contractile force and heart rate would decrease while the blood pressure would increase in response to unopposed alpha receptor mediated vasoconstriction.
A new drug was given to animals. A large dose of EPI was given before and after the agent was given for comparison. Which of the following agents does the new drug closely resemble?
A. Atenolol
B. Atropine
C. Labetalol
D. Phenoxybenzamine
E. Propranolol
C. Labetalol
Labetalol is a mixed acting beta antagonist that blockers b1, b2, and a1. It decreases blood pressure by blocking epi causing vasoconstriction leading to vasodilation. It decreases heart rate and cardiac output too.
What part of the eye produces aqueous humor?
Ciliary epithelium (portion of the ciliary body)
Once the aqueous humor is produced, it is secreted into the ______ _________ where it flows through the pupil into the ________ ________.
Posterior chamber
Anterior chamber
What are the two main ways that the aqueous humor exits the eye?
Trabecular meshwork into Schlemm’s canal and uveoscleral outflow
When saying a glaucoma is closed or open angle, what is this angle between?
Iris and cornea angle
