Pharmacology Autonomic Agents
Terms
undefined, object
copy deck
- What is the major neurotransmitter of the parasympathetic autonomic nervous system
- Acetylcholine
- Where are four places where nicotinic receptors are located
-
Postsynaptic neurons in ganglia of both the parasympathetic nervous systems and sympathetic nervous systems
Neuromuscular junction
Central nervous system
Adrenal medulla - Where are three places where muscarinic receptors are located
-
Organs innervated by the PNS
Thermoregulatory sweat glands innervated by the SNS
CNS (cortex, hippocampus) - What drug inhibits transport of choline from the extracellular fluid into the cytoplasm of a cholinergic neuron
- Hemicholinium
- What enzyme catalyzes the reaction between choline and acetyl CoA to form Ach
- Choline acetyltransferase (CAT)
- The neuronal release of Ach into the synapse is inhibited by what toxin
- Botulinum toxin
- What organism produces botulinum toxin
- Clostridium botulinum (anaerobic, spore-forming, gram positive rod)
- The venom of what spider results in the release of stored Ach into the synapse
- Black widow
- What enzyme degrades Ach
- Acetylcholinesterase (AchE)
- What are the breakdown products of Ach
- Choline and acetate
- Where is AchE located
- Synaptic cleft
- What is muscarine
- Alkaloid compound found in various poisonous mushrooms
- Where is the M1 muscarinic receptor found in the body
-
Neurons
Gastric parietal cells - Where is the M2 muscarinic receptor found in the body
-
Neurons
Cardiac cells
Smooth muscle - Where is the M3 muscarinic receptor found in the body (7)
-
Neurons
Smooth muscle
Exocrine glands
Lungs
GI tract
Eye
Bladder - Where is the M4 muscarinic receptor found in the body
- Neurons
- Where is the M5 muscarinic receptor found in the body
- Neurons
- Name the type of G protein that M1 is coupled to
- Gq coupled
- Name the type of G protein that M2 is coupled to
- Gi coupled
- Name the type of G protein that M3 is coupled to
- Gq coupled
- Does the PNS innervate the vasculature
- No (however there are muscarinic receptors located on the vasculature)
- How can Ach lower blood pressure
- Ach binds to Ach receptors in the vasculature leading to increased synthesis of NO via second messenger pathways
- NO is also known as what
- Endothelial-derived relaxation factor (EDRF)
- What amino acid is a precursor to NO synthesis
- Arginine
- Does AchE have a high affinity for Ach
- Yes
- Does Ach increase or decrease blood pressure
- Decreases
- Does Ach increase or decrease heart rate
- Decreases
- Does Ach increase or decrease salivation
- Increases
- Dose Ach increase or decrease lacrimation
- Increases
- Does Ach increase or decrease sweating
- Increases
- Does Ach increase or decrease GI secretions
- Increases
- Does Ach increase or decrease GI motility
- Increases
- Does Ach increase or decrease Miosis (constriction of pupil)
- Increases
- Does Ach increase or decrease bladder detrusor muscle tone
- Increase (this lead to increased urination)
- Does Ach increase or decrease Bronchodilation
- Decrease
- What does Ach do to the ciliary muscle of the eye
- Increased contraction which leads to increased accommodation
- How does Ach cause miosis
- Increased contraction of the circular muscle in the iris
- Does bethanechol have muscarinic activity
- Yes (agonist)
- Does AchE have a high affinity for bethanecol
- No (zero affinity)
- Does bethanechol have nicotinic activity
- No
- What is bethanechol used for
- Neurogenic bladder (nonobstructive urinary retention)
- Does carbachol have muscarinic activity
- Yes (agonist)
- Does carbachol have nicotinic activity
- Yes (agonist)
- Does AchE have a high affinity for carbachol
- No (zero affinity)
- What is carbachol used for
- Miotic agent to reduce intraocular pressure (IOP)
- Does pilocarpine have muscarinic activity
- Yes (agonist)
- Does pilocarpine have nicotinic activity
- No
- Does AchE have a high affinity for pilocarpine
- No (zero affinity)
- What is pilocarpine used for
- Mitotic drug of choice to lower IOP in emergency settings of narrow-angle and open-angle glaucoma
- Can pilocarpine cross the blood-brain barrier (BBB)
- Yes (tertiary amine)
- Give examples of reversible AchE inhibitors
-
Neostigmine
Pyridostigmine
Physostigmine
Edrophonium
Rivastigmine, Donepezil, Galantamine, Tacrine - What are donepezil, galantamine, rivastigmine, and tacrine used for
- Alzheimer’s disease
- What two AchE inhibitors are quaternary ammonium compounds and therefore cannot cross the BBB
-
Neostigmine
Pyridostigmine - What short-acting AchE inhibitor is used to diagnose myasthenia gravis and is also used to differentiate myasthenic from cholinergic crisis
- Edrophonium
- Which reversible AchE inhibitor is used as an antidote in atropine overdose
- Physostigmine (tertiary amine therefore crosses BBB to enter CNS)
- Give examples of irreversible AchE inhibitors
-
Sarin
Malathion
Parathion
Echothiphate
Isoflurophate - Which irreversible AchE inhibitor is used as nerve gas
- Sarin
- Which two AchE inhibitors are used as insecticides
-
Malathion
Parathion - What is another name for the irreversible AchE inhibitors
- Organophosphates
- How do organophosphates irreversibly inhibit AchE
- Phosphate group covalently binds to serine hydroxyl group in the active site of AchE thereby rendering the enzyme permanently inactive
- What is used to counteract the muscarinic and CNS effects during organophosphate poisoning
- Atropine (protects muscarinic receptors, via competitive inhibition, from the increased levels of Ach thereby preventing overstimulation)
- What agent is used to reactivate inhibited AchE during organophosphate poisoning
- Pralidoxime (2-PAM)
- True or False? The effectiveness of 2-PAM in counteracting organophosphate poisoning is not time dependent
- False, 2-PAM must be given before the “aging†process of the organophosphate-AchE complex is complete
- What are the signs and symptoms of organophosphate poisoning
-
Miosis
Diarrhea
Urination
Bradycardia
Sweating
Lacrimation
Salivation
Bronchoconstriction
Peripheral nerve demyelination - Does atropine block nicotinic receptors, muscarinic receptors, or both
- Muscarinic receptors
- What are the pharmacologic actions of atropine
-
Mydriasis
Cycloplegia
Tachycardia
Sedation
Urinary retention
Constipation
Dry mouth
Dry eyes
Decreased sweating
Hallucination
Sedation
Hyperthermia
Delirium
Blurred vision
Coma (high doses) - What class of drugs can be used to counteract atropine overdose
- AchE inhibitors
- Name three drug classes, other than atropine, that may cause antimuscarinic adverse effects
-
Sedating/ first generation antihistamines (diphenhydramine)
Tricyclic antidepressants (TCAs)
Phenothizines - Low dose (<0.5 to 1 mg) atropine does what to heart rate
- Decreases heart rate (unknown paradoxical vagalmimetic effect)
- High dose(>0.5 to 1 mg) atropine does what to heart rate
- Increases heart rate (parasympatholytic effect)
- What is the half life of atropine
- 4 hours
- Name four belladonna alkaloids
-
Belladonna
Atropine
Scopolamine
Hyoscyamine - What is belladonna
- Perennial atropine-based plant; also known as “nightshadeâ€
- How does scopolamine differ from atropine (3)
-
Longer duration of action
More potent CNS effects
Able to block short-term memory - What is the main therapeutic indication of scopolamine
- Motion sickness
- Giving drugs with anticholinergic activity can precipitate an emergent situation in what type of patients
- Patients with narrow-angle glaucoma
- What are the signs and symptoms of acute angle closure glaucoma
-
General distress
Pain
Headache
Red eye
Photophobia
Increased IOP
Visual changes
Malaise
Nausea
Vomiting - What two anticholinergic agents are quaternary ammonium compounds used for the treatment of asthma and COPD
-
Ipratropium
Tiotropium - How often is tiotropium dosed
- Once daily (longer half-life vs. ipratropium)
- Does ipratropium affect airway secretions
- No (unlike atropine)
- Name three ganglionic blocking agents
-
Hexamethonium
Mecamylamine
Trimethaphan - What are ganglionic blocking agents primarily used for
-
Lowering blood pressure
Blocking autonomic nervous system reflexes - Will trimethaphan block a reflex bradycardia after a vasoconstricting agent is given
- Yes
- Will trimethaphan block a directly induced bradycardia by a muscarinic agonist
- No
- Neuromuscular blocking agents can be grouped into what two general categories
- Depolarizing and nondepolarizing
- Do neuromuscular blockers (NMBs) work at muscarinic or nicotinic receptors
- Nicotinic (NMJ has nicotinic receptors)
- How many subunits is the nicotinic receptor made of
- Five
- Which subunit of the nicotinic receptor does Ach bind to
- Alpha subunit (nicotinic receptors have two alpha subunits)
- Binding of Ach to the nicotinic receptor at the NMJ is required to open which type of ion channel
- Sodium channel
- What is the most commonly used NMB
- Succinylcholine (depolarizing NMB)
- How does succinylcholine work at the NMJ
- Behaves as a cholinergic agonist that remains bound to the Ach receptor for a prolonged period
- What happens during phase I of succinylcholine activity at the NMJ
- Receptors become depolarized and transient fasciculations are observed
- What happens during phase II of succinylcholine activity at the NMJ
- Receptor becomes resistant to depolarization and a flaccid paralysis ensues
- What are the main uses of succinylcholine
-
Endotracheal intubation
Adjunct during electroconvulsive shock therapy - Is succinylcholine short or long acting
- Short acting (duration 4-8 minutes) because of rapid hydrolysis by cholinesterase
- Where is the enzyme (cholinesterase) that metabolizes succinylcholine found
- Plasma
- What are the adverse effects of succinylcholine
-
Malignant hyperthermia
Apnea
Hypertension
Hyperkalemia - What are the signs and symptoms of malignant hyperthermia
-
Sudden onset of hyperthermia
Tachycardia
Tachypnea
Sweating
Cyanosis
Muscle rigidity - How is malignant hyperthermia treated
-
Rapid cooling of patient
Dantrolene - What is the mechanism of action of dantrolene
- Inhibits calcium release from the sarcoplasmic reticulum of muscle cells thereby relaxing muscle tone and reducing heat production
- Succinylcholine may have a prolonged half-life in what type of patients
- Patients with a genetic deficiency or altered form of plasma cholinesterase
- What is the mechanism of action of nondepolarizing NMBs
- Competitive antagonists of Ach at the NMJ
- Which drug is the prototype of the nondepolarizing NMBs
- Tubocurarine
- What antidote is used in tubocurarine overdose
- AchE inhibitor (increases Ach concentration which competes with tubocurarine at the NMJ)
- List in order, from first to last, the muscles that are paralyzed by nondepolarizing NMBs
- Small muscles of the face and eye; fingers; limbs, neck, trunk; intercostals; diaphragm
- Which antimicrobial class of drugs may act in synergy with nondepolarizing NMBs by inhibiting release of Ach from nerve endings by competing with calcium ions, thereby increasing neuromuscular blockade
- Aminoglycosides (most likely to occur with high doses; patients with hypocalcemia, hypomagnesemia, or neuromuscular disorders)
- Give examples of nondepolarizing NMBs
-
Tubocurarine
Atracurium
Rocuronium
Mivacurium, Vecuronium, Pancuronium, Pipercuronium - What is the only nondepolarizing NMB that does not require dosage reduction in patients with renal failure
- Atracurium
- What nondepolarizing NMB has the most rapid onset of action
- Rocuronium
- In what situations are nondepolarizing NMBs used
-
Adjunct to general anesthesia to facilitate endotracheal intubation and to relax skeletal muscles during surgery
Facilitate mechanical ventilation in ICU patients - What are the two major neurotransmitters of the SNS
- Epinephrine; norepinephrine
- What amino acid is the precursor to dopamine, norepinephrine, and epinephrine
- Tyrosine
- What are the steps, in order, to the synthesis of epinephrine starting from tyrosine
-
Tyrosine converted into DOPA by tyrosine hydroxylase (rate limiting step);
DOPA is converted into dopamine by DOPA decarboxylase;
Dopamine is converted into norepinephrine by dopamine β-hydroxylase;
Norepinephrine is converted into epinephrine by methylation in the adrenal medulla - What is the mechanism of action of fuanethidine and bretylium
- Inhibits the release of norepinephrine into the synapse
- What two enzymes metabolize norepinephrine
- Monoamine oxidase (MAO); catechol-O-methyltransferase (COMT)
- What is the mechanism of action of reserpine
- Inhibits the transport of norepinephrine from the neuronal cytoplasm into the synaptic vesicles
- What are the common side effects of reserpine
-
Depression
Sedation - What breakdown products of norepinephrine are excreted in the urine and can be measured to help diagnose pheochromocytoma
-
Vanillylmandelic acid (VMA)
Metanephrine
Normetanephrine - How does cocaine increase norepinephrine levels in the synaptic cleft
- Inhibits reuptake of neurotransmitter back into the presynaptic neuron
- What are the two major classes of adrenergic receptors
- α-receptors; β-receptors
- What drug can inhibit tyrosine hydroxylase
- Methyl-p-tyrosine; feedback inhibition by norepinephrine
- What neurotransmitters are metabolized by MAO type A
-
Norepinephrine
Serotonin
Tyramine - What neurotransmitters does MAO type B metabolize
- Dopamine
- How do amphetamine, ephedrine, and tyramine increase norepinephrine levels
- Act as indirect sympathomimetic agents by displacing norepinephrine from the mobile storage pool (drug enters presynaptic nerve terminal and displaces stored norepinephrine)
- Where are α2-receptors found
-
Presynaptic neurons
Pancreatic β cells - What happens when α2-receptors are activated
- Inhibits the release of norepinephrine from synaptic vesicles
- Give examples of α2-receptor agonists
-
Clonidine
Dexmedetomidine
α-methyldopa; guanabenz; guanfacine; - What are the therapeutic indications (7) of clonidine
-
Hypertension
Severe pain
Heroin withdrawal
Nicotine withdrawal
Ethanol dependence
Clozapine-induced sialorrhea
Prevention of migraines - What is dexmedetomidine used for
- Sedation of intubated and mechanically ventilated patients
- With drugs that activate both α and β-receptors, which receptors are generally activated first (which receptors are more sensitive)
- β-receptors
- Activation of what receptor type in the eye will lead to contraction of the radial muscle and subsequently lead to mydriasis
- α1-receptor
- Name the G-protein associated with α1 receptors
- Gq
- Name the G-protein associated with α2 receptors
- Gi
- Name the G-protein associated with β1, β2, and D1 receptors
- Gs
- Name the major effects mediated by α1 receptors (7)
-
Mydriasis
Vasoconstriction
Increased blood pressure
Increased glycogenolysis
Decreased renin release
Decreased urination
Ejaculation - Name the major effects mediated by α2 receptors (3)
-
Inhibition of norepinephrine release
Inhibition of insulin release
Platelet aggregation - Name the major effects mediated by β1 receptors (4)
-
Increased heart rate
Increased conduction velocity
Increased force of heart contraction
Increased renin release - Name the major effects mediated by β2 receptors (5)
-
Vasodilation
Bronchodilation
Increased insulin secretion
Increased glycogenolysis
Relaxation of uterine smooth muscle - Name the major effects mediated by peripheral D1 receptors (4)
-
Vasodilation of coronary, renal, and mesenteric vasculature
Increased GFR
Increased renal blood flow
Increased sodium excretion - α2-receptor activation in the pancreas will cause insulin secretion to increase or decrease
- Decrease
- β2-receptor activation in the pancreas will cause insulin secretion to increase or decrease
- Increase
- Which receptor type does epinephrine preferentially bind to at low doses
- β-receptors (vasodilation in vasculature)
- Which receptor type does epinephrine preferentially bind to at high doses
- α-receptors (vasoconstriction in vasculature)
- What is the drug of choice in patients with type 1 hypersensitivity reactions
- Epinephrine
- Why is epinephrine often given in combination with local anesthetics
- Epinephrine causes a vasoconstriction thereby inhibiting the local anesthetics redistribution away from its site of action (increases the duration of local anesthesis)
- What is the concentration of epinephrine when given in combination with local anesthetics
- 1:100,000
- State whether peripheral vascular resistance increases or decreases with low dose epinephrine
- Decreases
- State whether systolic blood pressure increases or decreases with low dose epinephrine
- Increases
- State whether diastolic blood pressure increases or decreases with low dose epinephrine
- Decreases
- State whether pulse pressure increases or decreases with low dose epinephrine
- Increases
- What receptors are activated by isoproterenol
- β1=β2
- What receptors are activated by dopamine
- D>β>α
- What receptors are activated by dobutamine
- β1>β2
- What receptors are activated by phenylephrine
- α1>α2
- What receptors are activated by methoxamine
- α1>α2
- Does norepinephrine activate β2 receptors
- No
- Activation of dopamine receptors will cause what type of response in the mesenteric and renal vasculature
- Vasodilation
- What is dopamine metabolized to
- Homovanillic acid (HVA)
- What is dobutamine used for
- Increases cardiac output in congestive heart failure without affecting RBF (unlike dopamine)
- Tyramine is a breakdown product of which amino acid
- Tyrosine
- Where is tyramine found
-
Cheeses (aged)
Alcoholic beverages
Fish
Chocolates
Red wines
Processed meats (fermented, aged, and pickled foods) - What enzyme is responsible for the breakdown of tyramine
- MAO type A
- What can potentially happen if a patient on a MAOI consumes large amounts of fermented cheese
- Hypertensive crisis
- What are phenylephrine and pseudoephedrine used to treat
- Nasal congestion
- What are mixed action adrenergic agonists
-
Substances that release stored norepinephrine from nerve terminals
Directly stimulate α and β receptors - What are some examples of mixed action adrenergic agonists
-
Ephedrine
Metaraminol - Which drug is a nonselective, competitive antagonist at both α1 and α2 receptors
- Phentolamine
- Which drug is a nonselective, irreversible antagonist at both α1 and α2 receptors
- Phenoxybenzamine
- What are phentolamine and phenoxybenzamine mainly used for
- Pheochromocytoma
- What is the mechanism of action of prazosin
- Selective α1 antagonist
- What are prazosin, terazosin, and doxazosin used to treat
-
Benign prostatic hypertrophy
Hypertension - What is alfuzosin used to treat
- BPH
- This drug is a selective α1A receptor antagonist, used in the treatment of BPH, and has less cardiovascular side effects vs. traditional α1 antagonists
- Tamsulosin
- What advantage do selective α1 antagonists have over nonselective α antagonists
- Less reflex tachycardia
- What CNS prejunctional α2 receptor antagonist is used to treat postural hypotension and impotence
- Yohimbine
- What CNS prejunctional α2 receptor antagonist is used to treat depression
- Mirtazapine
- Give examples (6) of β1 selective antagonists
-
Acebutolol
Atenolol
Bisoprolol
Betaxolol
Exmolol
Metoprolol - Give examples (4) of nonselective β antagonists
-
Propranolol (angina pectoris)
Pindolol (ISA)
Sotalol (anti-arrythmic)
Timolol
Nadolol - Give two examples of mixed α2/β antagonists
-
Carvedilol
Labetalol - What is the name of a β antagonist that also blocks potassium channels and is used as an antiarrhythmic
- Sotalol
- Which two β antagonists have intrinsic sympathomimetic activity (ISA)
-
Acebutolol
Pindolol - What is ISA
-
Drugs act as partial agonists and only work when there is increased sympathetic drive such as with exercise
This results in less bradycardia and less effects on lipid metabolism - What happens to exercise tolerance in patients being treated with β-blockers
- Decreased exercise tolerance
- What are the main therapeutic indications (6) of β-blockers
-
Angina
Arrhythmias
Hypertension
CHF (not all β-blockers)
Thyrotoxicosis
Glaucoma (ophthalmic formulations) - What are some noncardiovascular uses of propranolol
-
Migraine prophylaxis
Performance anxiety (stage fright) - β-blockers can inhibit the majority of effects caused by thyrotoxicosis except for what sign
- Diaphoresis
- β-blockers can inhibit the majority of effects caused by hypoglycemia except for what sign
- Diaphoresis
- What does propranolol do to serum triglycerides
- Increases serum triglycerides
- What does propranolol do to serum LDL
- Increases serum LDL
- Why does propranolol cause vivid dreams
- Crosses the BBB
- Why should β-blockers be tapered down instead of abruptly discontinued
- Chronic therapy leads to upregulation of β-receptors; therefore, abrupt discontinuation may lead to life-threatening cardiovascular rebound effects (tachycardia; hypertension; arrhythmias; death)