Cancer Chemotherapeutic Agents
CHAPTER 4 Autonomic Agents
CHAPTER 4
Yes
Doe s AC h incre ase or de cre ase the following (in othe r words, what is the e ffe ct of parasympathe tic stimulation of the following)?
Blood pre ssure
Decreases (both arterial and venous dilation via NO) He art rate
Decreases (via M2 receptors) Salivation
Increases (via M3 receptors) Lacrimation
Increases (via M3 receptors) Swe ating
Increases (via sympathetic stimulation of muscarinic cholinergic receptors) GI se cre tions
Increases (via M3 receptors) GI motility
Increases (via M3 receptors) Miosis (constriction of pupil) Increases (via M3 receptors) Bladde r de trusor muscle tone Increases (via M3 receptors) Bladde r sphincte r tone
Decreases (in combination with increased detrusor tone this leads to increased urination also via M3receptors) Bronchodilation
Decreases (via M3 receptors)
W hat doe s AC h do to the ciliary muscle of the e ye ? Increased contraction which leads to increased accommodation How doe s AC h cause miosis?
Increased contraction of the circular muscle in the iris Doe s be thane chol have muscarinic activity?
Yes (agonist)
Doe s be thane chol have nicotinic activity?
No
Doe s AC hE have a high affinity for be thane chol?
No (zero affinity). T his gives bethanechol a long duration of action.
W hat is a clinical use for be thane chol?
Nonobstructive urinary retention as can result from denervation of the urinary sphincter in conditions such as diabetes or spinal cord injury. Bethanechol can also be used for gastroesophageal reflux disease (GERD). As a cholinergic drug, it will increase detrusor tone and GI motility.
Doe s carbachol have muscarinic activity?
Yes, it is a muscarinic agonist.
Doe s carbachol have nicotinic activity?
Yes, it is also a nicotinic agonist.
Doe s AC hE have a high affinity for carbachol?
No, the enzyme has zero affinity for carbachol.
W hat is carbachol use d for?
It is a miotic agent to reduce intraocular pressure (IOP) in emergency settings of narrow-angle and open-angle glaucoma.
Doe s pilocarpine have muscarinic activity?
Yes, it is a muscarinic agonist.
Doe s pilocarpine have nicotinic activity?
No
Doe s AC hE have a high affinity for pilocarpine ? No, the enzyme has zero affinity for pilocarpine.
W hat is pilocarpine use d for?
It is the miotic drug of choice to lower IOP in emergency settings of narrow-angle and open-angle glaucoma.
C an pilocarpine cross the blood-brain barrie r (BBB)?
Yes. Because it is a tertiary, uncharged amine.
Give e xample s of re ve rsible AC hE inhibitors:
Neostigmine; pyridostigmine; physostigmine; edrophonium; rivastigmine; donepezil; galantamine; tacrine W hat are done pe z il, galantamine , rivastigmine , and tacrine use d for?
Alzheimer-type dementia. T hey are AChE inhibitors, thereby increasing the levels of ACh in the brain.
W hat two AC hE inhibitors are quate rnary ammonium compounds and the re fore cannot cross the BBB?
1. Neostigmine 2. Pyridostigmine
As a result, these drugs will not reverse the central nervous system effects of cholinergic toxicity.
W hat short-acting AC hE inhibitor is use d to diagnose myasthe nia gravis and is also use d to diffe re ntiate myasthe nic from choline rgic crisis?
Edrophonium. T he trade name of edrophonium is T ensilon. T his test is commonly referred to as the T ensilon test.
W hich re ve rsible AC hE inhibitor is use d as an antidote in atropine ove rdose ? Physostigmine, a tertiary amine, is able to cross the BBB to act on the CNS.
Give e xample s of irre ve rsible AC hE inhibitors:
Echothiophate; isoflurophate; sarin; malathion; parathion Name an irre ve rsible AC hE inhibitor that is use d as ne rve gas:
Sarin
W hich two AC hE inhibitors are use d as inse cticide s?
1. Malathion 2. Parathion
W hat is anothe r name for the irre ve rsible AC hE inhibitors?
Organophosphates
How do organophosphate s irre ve rsibly inhibit AC hE?
T he phosphate group covalently binds to serine hydroxyl group in the active site of AChE, thereby rendering the enzyme permanently inactive.
W hat is use d to counte ract the muscarinic and C NS e ffe cts of organophosphate poisoning?
Atropine via competitive inhibition. Atropine binds the muscarinic receptors, outcompeting the increased levels of ACh thereby preventing overstimulation.
W hat age nt is use d to re activate inhibite d AC hE during organophosphate poisoning?
Pralidoxime (2-PAM). It is critical to initiate treatment with pralidoxime early along with atropine to prevent the process of aging where AChE is irreversibly inactivated by the organophosphates.
W hat are the signs and symptoms of organophosphate poisoning?
SLUDGE: salivation; lacrimation; urination; diaphoresis; GI motility (diarrhea); emesis. Basically, parasympathetic overstimulation.
Doe s atropine block nicotinic re ce ptors, muscarinic re ce ptors, or both?
It blocks muscarinic receptors.
W hat are the pharmacologic actions of atropine ?
Mydriasis; cycloplegia; tachycardia; sedation; urinary retention; constipation; dry mouth; dry eyes; decreased sweating; hallucinations; sedation; hyperthermia;
delirium; blurred vision; coma (high doses). Basically, anticholinergic/sympathetic overstimulation.
W hat class of drugs can be use d to counte ract atropine ove rdose ? AChE inhibitors
Name thre e drug classe s that may cause antimuscarinic adve rse e ffe cts:
1. Sedating/first-generation antihistamines (diphenhydramine) 2. T ricyclic antidepressants (T CAs)
3. Phenothiazines
Low-dose (<0.5-1 mg) atropine doe s what to he art rate ? Decreases heart rate (unknown paradoxical vagalmimetic effect) High-dose (>0.5-1 mg) atropine doe s what to he art rate ?
Increases heart rate (parasympatholytic effect) W hat is be lladonna?
A perennial plant also known as “ deadly nightshade” due to the toxic effects of its foliage and berries from which atropine is derived. Other toxins include scopolamine and hyoscyamine. T he name belladonna derives from the cosmetic enhancing effects of dilated pupils, blushing of the cheeks, and reddening of the lips for which the plant was originally used.
How doe s scopolamine diffe r from atropine ?
Scopolamine has a longer duration of action, more potent CNS effects, and is able to block short-term memory.
W hat is the main the rape utic indication of scopolamine ? Motion sickness
Giving drugs with anticholine rgic activity can pre cipitate an e me rge nt situation in patie nts with what me dical condition?
Patients with narrow-angle glaucoma
W hat are the signs and symptoms of acute -angle -closure glaucoma?
General distress; pain; headache; red eye; photophobia; increased IOP; visual changes; malaise; nausea; vomiting
W hat two anticholine rgic age nts are quate rnary ammonium compounds and use d for the tre atme nt of asthma and chronic obstructive pulmonary dise ase (C O PD)?
1. Ipratropium 2. T iotropium
T iotropium has a longer half-life compared to ipratropium.
Doe s ipratropium e ffe ct airway se cre tions?
No (unlike atropine, which decreases airway secretions) Name thre e ganglionic blocking age nts:
1. Hexamethonium 2. Mecamylamine 3. T rimethaphan
W hat are ganglionic blocking age nts primarily use d for?
Lowering blood pressure; blocking autonomic nervous system reflexes; smoking cessation due to blockade of central nicotine receptors W hy can ganglionic blocke rs cause a marke d postural hypote nsion?
Since sympathetic tone to the blood vessels is blocked, both arterial and venous dilation occur, lowering blood pressure. Moreover, the ganglionic blockers prevent the sympathetically mediated baroreceptor response to a sudden decrease in blood pressure, such as that occurs with a rapid change in position from sitting to standing.
Ne uromuscular blocking age nts (NMBs) can be groupe d into what two ge ne ral cate gorie s?
1. Depolarizing 2. Nondepolarizing
Do NMBs work at muscarinic or nicotinic re ce ptors?
Nicotinic receptors (remember the NMJ has nicotinic receptors).
How many subunits is the nicotinic re ce ptor made of?
Five subunits. T wo α:- and three β-subunits make up this transmembrane ligand-gated ion channel.
W hich subunit of the nicotinic re ce ptor doe s AC h bind to?
Between the two α-subunits
Binding of AC h to the nicotinic re ce ptor at the NMJ is re quire d to ope n which type of ion channe l?
Sodium channel
W hat is the most commonly use d NMB?
Succinylcholine, the only depolarizing NMB. T his is an ideal drug for endotracheal intubation due to its fast onset of action and short duration of action.
How doe s succinylcholine work at the NMJ?
It behaves as a cholinergic agonist that remains bound to the ACh receptor for a prolonged period.
W hat happe ns during e ach of the following phase s of succinylcholine activity at the NMJ?
Phase I
T he receptor becomes depolarized and transient fasciculations are observed as various motor units depolarize.
Phase II
T he receptor becomes resistant to depolarization and a flaccid paralysis ensues.
W hat are the two main use s of succinylcholine ?
1. It is used for facilitation of endotracheal intubation via relaxation of pharyngeal and laryngeal muscles.
2. It is used as an adjunct during electroconvulsive shock therapy to prevent prolonged full body convulsions which would result in muscle breakdown. A tourniquet is placed on a lower extremity to prevent the drug from reaching this location so that the seizure is visible in a localized area and the rest of the body is spared.
Is succinylcholine short or long acting?
It is short acting with a duration of 4-8 minutes because of rapid hydrolysis by plasma cholinesterase.
W hat are the adve rse e ffe cts of succinylcholine ?
Malignant hyperthermia; apnea; hypertension; hyperkalemia W hat are the signs and symptoms of malignant hype rthe rmia?
Muscular rigidity; increased oxygen consumption; increased carbon dioxide production (usually the first sign detected during surgery); tachycardia; hyperthermia is a late finding
How is malignant hype rthe rmia tre ate d?
With dantrolene
W hat is the me chanism of action of dantrole ne ?
It inhibits calcium release from the sarcoplasmic reticulum of muscle cells, thereby relaxing muscle tone and reducing heat production.
Succinylcholine may have a prolonge d half-life in what type of patie nts?
Patients with a genetic deficiency or altered form of plasma cholinesterase W hat is the me chanism of action of nonde polariz ing NMBs?
Competitive antagonists of ACh at the NMJ
W hich drug is the prototype of the nonde polariz ing NMBs?
T ubocurarine
W hat antidote is use d in tubocurarine ove rdose ?
AChE inhibitor (increases ACh concentration which competes with tubocurarine at ACh receptors at the NMJ) List in orde r, from first to last, the muscle s that are paralyz e d by nonde polariz ing NMBs:
1. Small muscles of the face and eye 2. Fingers
3. Limbs, neck, trunk 4. Intercostals 5. Diaphragm
W hich antimicrobial class of drugs may act in syne rgy with nonde polariz ing NMBs by inhibiting re le ase of AC h from ne rve e ndings by compe ting with calcium ions, the re by incre asing ne uromuscular blockade ?
Aminoglycosides (most likely to occur with high doses; patients with hypocalcemia, hypomagnesemia, or neuromuscular disorders) Give e xample s of nonde polariz ing NMBs:
T ubocurarine; atracurium; mivacurium; rocuronium; vecuronium; pancuronium; pipercuronium
W hat is the only nonde polariz ing NMB that doe s not re quire dosage re duction in patie nts with re nal failure ? Atracurium, which excreted in bile, not in urine
W hat nonde polariz ing NMB has the most rapid onse t of action?
Rocuronium. T hink: ROcuronium—Rapid Onset In what situations are nonde polariz ing NMBs use d?
Adjunct to general anesthesia to facilitate endotracheal intubation and to relax skeletal muscles during surgery; to facilitate mechanical ventilation in ICU patients
ADRENERGIC AGENTS
W hat are the major ne urotransmitte rs of the SNS?
Epinephrine; norepinephrine; dopamine
W hat amino acid is the pre cursor to dopamine , e pine phrine , and nore pine phrine ? T yrosine
W hat are the ste ps, in orde r, to the synthe sis of e pine phrine starting from tyrosine ?
Tyrosine is 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.
W hat two e nz yme s me taboliz e nore pine phrine ?
1. Monoamine oxidase (MAO)
2. Catechol-O-methyltransferase (COMT )
W hat is the me chanism of action of re se rpine ?
It inhibits the transport of norepinephrine from the neuronal cytoplasm into the synaptic vesicles.
W hat are the common side e ffe cts of re se rpine ? Depression; sedation
W hat bre akdown products of nore pine phrine are e xcre te d in the urine and can be me asure d to he lp diagnose phe ochromocytoma?
Vanillylmandelic acid (VMA); metanephrine; normetanephrine W hat are the two major classe s of adre ne rgic re ce ptors?
1. α-Receptors
2. β-Receptors
W hat ne urotransmitte rs are me taboliz e d by MAO type A?
Norepinephrine; epinephrine; serotonin; tyramine; dopamine W hat ne urotransmitte rs doe s MAO type B me taboliz e ?
Dopamine. Dopamine is metabolized by both the A and B type of the enzyme.
How doe s cocaine incre ase nore pine phrine le ve ls in the synaptic cle ft?
It inhibits the reuptake of neurotransmitter back into the presynaptic neuron.
How do amphe tamine , e phe drine , and tyramine incre ase nore pine phrine le ve ls?
T hey act as indirect sympathomimetic agents by entering the presynaptic neuron releasing stored norepinephrine into the synaptic cleft.
W he re are α1-re ce ptors found?
Vascular smooth muscle; papillary dilator muscle; pilomotor smooth muscle; prostate; heart W he re are α2-re ce ptors found?
Postsynaptic CNS adrenoceptors; pancreatic β-cells; platelets; adrenergic and cholinergic nerve terminals; vascular smooth muscle; fat cells W he re are β1-re ce ptors found?
Heart; juxtaglomerular cells W he re are β2-re ce ptors found?
Respiratory, uterine, and vascular smooth muscle; skeletal muscle; liver W he re are D1-re ce ptors found?
Smooth muscle
W he re are D2-re ce ptors found?
Nerve endings
C ompare and contrast the local ve rsus the syste mic e ffe cts of α2-re ce ptor activation.
Local infusion of an α2-agonist will activate the α2-receptors in the vasculature, causing vasoconstriction. Systemic administration will activate the central α2 -receptors in the locus ceruleus which inhibits norepinephrine release and sympathetic activation. T he central effects overwhelm the local effects leading to decreased blood pressure.
Give e xample s of α2-re ce ptor agonists:
Clonidine; α-methyldopa; guanabenz; guanfacine; dexmedetomidine W hat are the the rape utic indications of clonidine ?
Hypertension; severe pain; heroin withdrawal; nicotine withdrawal; ethanol dependence; clozapine-induced sialorrhea; prevention of migraines W hat is de xme de tomidine use d for?
Sedation of intubated and mechanically ventilated patients; prolongation of spinal anesthesia
W ith drugs that activate both α- and β-re ce ptors, which re ce ptors are ge ne rally activate d first (which re ce ptors are more se nsitive )?
β-Receptors
Activation of what re ce ptor type in the e ye will le ad to contraction of the radial muscle and subse que ntly le ad to mydriasis?
α1-Receptor
For e ach of the following re ce ptor type s, name the type of G-prote in it is couple d to:
α1 Gq α2 Gi β1,β2,D1 Gs
Name the major e ffe cts me diate d by e ach of the following re ce ptor type s:
α1
Mydriasis; vasoconstriction → increased blood pressure; decreased urination; increased glycogenolysis; decreased renin release; ejaculation α2
Inhibition of norepinephrine release (central effect); inhibition of insulin release; platelet aggregation β1
Increased heart rate; increased conduction velocity; increased force of heart contraction; increased renin release β2
Vasodilation; bronchodilation; relaxation of uterine, respiratory, and vascular smooth muscle; increased insulin secretion; increased potassium uptake; increased glycogenolysis
Pe riphe ral
Vasodilation of coronary, renal, and mesenteric vasculature; increased glomerular filtration rate (GFR); increased renal blood flow (RBF); increased sodium excretion
W ill α2-re ce ptor activation in the pancre as cause insulin se cre tion to incre ase or de cre ase ? It will cause insulin secretion to decrease.
W ill β2-re ce ptor activation in the pancre as cause insulin se cre tion to incre ase or de cre ase ? It will cause insulin secretion to increase.
W hich re ce ptor type doe s e pine phrine pre fe re ntially bind to at low dose s?
β-Receptors (vasodilation in vasculature)
W hich re ce ptor type doe s e pine phrine pre fe re ntially bind to at high dose s?
α-Receptors (vasoconstriction in vasculature)
W hat is the drug of choice in patie nts with type 1 (imme diate ) hype rse nsitivity re actions?
Epinephrine
W hat is the dose of e pine phrine give n for anaphylaxis?
0.1-0.5 mg. Note: T he EpiPen (epinephrine auto-injector) that many patients with a history of anaphylaxis carry is 0.3 mg.
W hat is the conce ntration of e pine phrine use d for anaphylaxis?
1:1000
W hat is the conce ntration of e pine phrine use d for advance d cardiac life support (AC LS) protocol?
1:10,000
W hy is e pine phrine ofte n give n in combination with local ane sthe tics?
Epinephrine causes a vasoconstriction, thereby inhibiting the local anesthetics redistribution away from its site of action, so it increases the duration of local anesthesia.
W hat is the conce ntration of e pine phrine whe n give n in combination with local ane sthe tics?
1:100,000
State whe the r e ach of the following cardiovascular e ffe cts incre ase s or de cre ase s with low-dose e pine phrine : Pe riphe ral vascular re sistance
Decreases
Systolic blood pre ssure Increases
Diastolic blood pre ssure Decreases
Pulse pre ssure Increases
W hat re ce ptors are activate d by isoprote re nol?
β1 = β2
W hat re ce ptors are activate d by dopamine ? D > β > α
W hat re ce ptors are activate d by dobutamine ? β1 > β2
W hat re ce ptors are activate d by phe nyle phrine ? α1 > α2
Doe s nore pine phrine activate β2-re ce ptors?
No
Activation of dopamine re ce ptors will cause what type of re sponse in the me se nte ric and re nal vasculature ? Vasodilation
W hat is dopamine me taboliz e d to?
Homovanillic acid (HVA) W hat is dobutamine use d for?
Increases cardiac output in congestive heart failure (CHF) without affecting RBF (unlike dopamine) Tyramine is a bre akdown product of which amino acid?
T yrosine
W he re is tyramine found?
Examples of foods and beverages which contain tyramine include: beer, ale, robust red wines, chianti, vermouth, homemade breads, cheese, sour cream, bananas, red plums, figs, raisins, avocados, fava beans, Italian broad beans, green bean pods, eggplant, pickled herring, liver, dry sausages, canned meats, salami, yogurt, soup cubes, commercial gravies, chocolate, and soy sauce.
W hat e nz yme is re sponsible for the bre akdown of tyramine ? MAO type A
W hat can pote ntially happe n if a patie nt on a monoamine oxidase inhibitor (MAO I) consume s large amount of fe rme nte d che e se ? Hypertensive crisis due to tyramine in the cheese which leads to the release of norepinephrine from storage vesicles in presynaptic neurons W hat is phe nyle phrine and pse udoe phe drine use d to tre at?
Nasal congestion
W hat are mixe d action adre ne rgic agonists?
Substances that release stored norepinephrine from nerve terminals and also directly stimulate α- and β-receptors W hat are some e xample s of mixe d action adre ne rgic agonists?
Ephedrine; pseudoephedrine; metaraminol
W hich drug is a nonse le ctive , compe titive antagonist at both α1- and α2-re ce ptors?
Phentolamine
W hich drug is a nonse le ctive , irre ve rsible antagonist at both α1- and α2-re ce ptors?
Phenoxybenzamine
W hat are phe ntolamine and phe noxybe nz amine mainly use d for?
To achieve α-receptor blockade before surgical removal of pheochromocytoma, to achieve perioperative blood pressure control, and to prevent intraoperative hypertension from release of catecholamines during surgical manipulation
W hat is the me chanism of action of praz osin?
Selective α1-antagonist
W hat are praz osin, te raz osin, and doxaz osin use d to tre at?
Benign prostatic hyperplasia (BPH); hypertension Doe s the “H” in BPH stand for hype rtrophy or hype rplasia?
Hyperplasia, though hypertrophy is still sometimes erroneously used. T here is an actual increase in the number of prostatic cells in BPH. T he cells do not simply increase in volume as do, for example, skeletal or cardiac muscle cells in response to increased used.
This drug is a se le ctive α1A-re ce ptor antagonist, use d in the tre atme nt of BPH, and has le ss cardiovascular side e ffe cts ve rsus traditional α1 -antagonists.
T amsulosin
W hat advantage s do se le ctive α1-antagonists have ove r nonse le ctive α-antagonists?
Less reflex tachycardia
W hat C NS pre junctional α2-re ce ptor antagonist is use d to tre at postural hypote nsion and e re ctile dysfunction (impote nce )?
Yohimbine
W hat C NS pre junctional α2-re ce ptor antagonist is use d to tre at de pre ssion?
Mirtazapine
Give e xample s of β1-se le ctive antagonists:
Acebutolol; atenolol; bisoprolol; betaxolol; esmolol; metoprolol Give e xample s of nonse le ctive β-antagonists:
Propranolol; timolol; pindolol; nadolol Give e xample s of mixe d-a (Xj/P ntagonists:
Carvedilol; labetalol
W hat is the name of a β-antagonist that also blocks potassium channe ls and is use d as an antiarrhythmic?
Sotalol
W hat is intrinsic sympathomime tic activity (ISA)?
Drugs act as partial agonists and only work when there is increased sympathetic drive such as with exercise; less bradycardia; less effects on lipid metabolism W hich two β-antagonists have ISA?
1. Acebutolol 2. Pindolol