All ANS Drugs

8/10/2019 All ANS Drugs

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All ANS Drugs

ANS Neurotransmitters

Acetylcholine

Trade Name:Miochol-E Drug Class:Cholinomimetic (direct acting muscarinic & nicotinic agonist) Mechanism of Action:

o The endogenous agonist for muscarinic and nicotinic receptors.o Acetylcholine is the primary neurotransmitter responsible for neurotransmission at:

1.All autonomic ganglia (sympathetic & parasympathetic)(nicotinic)2.All post-ganglionic parasympathetic neurons(e.g. vagal innervation of

the heart)(muscarinic)3. Post-ganglionic motor neurons(which innervate skeletal

muscle)(nicotinic)4. Sympathetic postganglionic neurons that innervate sweat glands

(muscarinic)5. Preganglionic sympathetic nerves that innervate the adrenal medulla

(nicotinic), resulting in the release of epinephrine and norepinephrine into thesystemic circulation.

o Muscarinic receptorsmediate their responses by G-proteinso Nicotinic receptorsmediate their responses by opening a cationic ion channel that

is an intrinsic component of the nicotinic-receptor-channel complex Indications:

o

To produce miosis (reduction of size) of the iris in seconds after delivery tothe lens in cataract surgery, and in other types of eye surgery where rapidmiosis is required (e.g. in penetrating keratoplasty, iridectomy and other anteriorsegment eye surgery). Direct application of acetylcholine to the iris will cause rapidmiosis of short duration (by acting as a muscarinic agonist). Topical ocularinstillation of acetylcholine to the intact eye causes no discernible response ascholinesterase destroys the molecule more rapidly than it can penetrate the cornea.

Side Effects:o Rare when applied only to the eyeo If given i.v. - acetylcholine will produce a dose-dependent reduction of

blood pressure & associated changes in heart rate.

Note: following administration of an i.v. bolus, acetylcholine willstimulate muscarinic receptors located on the vascular endothelium,resulting in the release of nitric oxide. Nitric oxide will relax arterialsmooth muscle, resulting in a fall in arterial blood pressure. The fallin arterial pressure will in turn produce an associated baroreceptormediated increase in heart rate. If the baroreceptor reflex is blockedby either a ganglionic blocker or a beta blocker, then acetylcholine'sdirect effect on the SA node to reduce heart rate can typically beobserved.

Pharmacokinetics:o

After release from the nerve ending, acetylcholine is rapidly inactivated by theenzyme acetylcholinesterase by hydrolysis to acetic acid and choline.

Notes:


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o When released from nerve terminals, its actions are primarily (75%)terminated by neuronal reuptake

o Diffusion and degredation by extracellualr COMT contribute to a lesser extent. Whengiven as an i.v. bolus, redistribution (and associated fall in concentration) alsocontributes to the decrease in effect as a function of time

Drug Interactions:o Halogenated anesthetics (e.g. halothane) increase cardiac automatic irritability and

therefore seem to sensitize the myocardium to the action of intravenouslyadministered epinephrine or norepinephrine, resulting in an increased incidence ofcardiac arrhythmias

o Norepinephrine should be used with extreme caution in patients receivingmonoamine oxidase inhibitors (MAOI) or tricyclic antidepressants, because severe,prolonged hypertension may result

Notes:o Another synonym for noreinephrine is levarterenol. The British name for

norepinephrine is noradrenaline. References:

o Biaggioni I, Robertson D (2012):Adrenoceptor Agonists & Sympathomimetic Drugs(Chapter 9). In: Basic & Clinical Pharmacology.12e. Katzung BG, Masters SB, Trevor

AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)o rxlist.com (Levophed )

Keywords

Epinephrine

Trade Name:generic, Adrenalin, Epipen Drug Class:Catecholamine, Sympathomimetic Mechanism of Action:

o Epinephrine stimulates both 1 & 2 and 1 & 2 receptor subtypesonsympathetic effector cells.

o When given i.v. it is a very potent vasoconstrictor and cardiac stimulant. The rise in systolic blood pressure results from a 1 mediated increase in

heart rate and ventricular contractility The rise in diastolic pressure results from stimulation of 1 and 2 receptor

mediated vasoconstriction in many vascular beds Epinephrine also stimulates 2 receptors present in skeletal muscle blood

vessels, resulting in their dilation

At low doses, at which 2 receptor stimulation predominatesover receptor stimulation, total peripheral resistance anddiastolic pressure may fall

Under physiological conditions, epinephrine released from the adrenal

gland functions as a hormone and, via activation of 2 receptors,contributes to increased blood flow during exercise.

2 stimulation will cause bronchodilation in the lung and activate

glycogenolysis in the liver Indications:

1. a drug of choice for treatment of acute anaphylactic reactions(hypersensitivity

reactions to drugs, animal serums and other allergens)2. a secondary drug for treatment of acute asthmatic attacksto relieve

bronchospasm (selective beta-2 agonists such as albuterol are considered 1st linedrugs for this indication, since they have fewer side effects)
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3. treatment and prophylaxis of cardiac arrestand attacks of transitoryatrioventricular (A-V) heart blockwith syncopal seizures (Stokes-AdamsSyndrome).

4. combined with many local anestheticsto reduce the systemic absorption ofanesthetic, and increase their duration of action.

Contraindications:o Epinephrine should be used cautiously in patients with hyperthyroidism,

hypertension and cardiac arrhythmias Side Effects:

o Transient and minor side effects of: Anxiety

Tachycardia

Headache Fear and palpitations occur with systemic therapeutic doses Adverse effects such as cardiac arrhythmias and excessive rise in blood

pressure may also occur with therapeutic doses or inadvertent overdosage Side effects are more likely to be observed in hyperthyroid individuals

Pharmacokinetics:

o Route of administration depends on the indication for its use. It can be given i.v.,s.c., i.m., via an endotracheal tube, or direct injection into the left ventricle.

o Relatively short duration of action compared to beta-2 selective agonists.o The popular inhalational OTC formulation (Primatene Mist ) containing

chlorofluorohydrocarbons was discontinued on Dec 31, 2011 due to legal restrictionson the use of environmental pollutants known to damage the ozone layer. A moreenvironmentally friendly formulation is likely to be approved in the near future.

Drug Interactions:o All vasopressors should be used cautiously in patients taking monoamine oxidase

(MAO) inhibitors.

Notes:o The British name for epinephrine is adrenaline

References:o Biaggioni I, Robertson D (2012):Adrenoceptor Agonists & Sympathomimetic Drugs

(Chapter 9). In: Basic & Clinical Pharmacology.12e. Katzung BG, Masters SB, TrevorAJ (Editors).

o Boushey HA (2012):Drugs Used in Asthma (Chapter 20). In: Basic and ClinicalPharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors); McGraw-Hill (AccessMedicine).

o rxlist.com -epinephrine (Adrenalin )

Keywords

Dopamine

Trade Names:generic, intropin Drug Class:Sympathomimetic, Catecholamine Mechanism of Action:

o Dopamine is the immediate metabolic precursor of norepinephrine.o At LOW DOSES it selectively activates D1 receptorsin several vascular beds

(e.g. kidney) resulting in vasodilation. The D1 mediated effect to increase renalblood flow may be of clinical significance (e.g. in the treatment of shock).

Activation of presynaptic D2 receptors may suppress norepinephrine release.o At INTERMEDIATE DOSES dopamine activates 1 receptorsin the heart.
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o At HIGH DOSES dopamine activates receptorsleading tovasoconstriction, including the renal vascular bed.High doses of dopaminemay mimic the actions of epinephrine.

o Dopamine is also a neurotransmitter in certain areas of the central nervous system,especially in the nigrostriatal tract, and in a few peripheral sympathetic nerves.

Indications:o For the correction of hemodynamic imbalances present in shock due to

myocardial infarction, trauma, endotoxic septicemia, open-heart surgery,renal failure, and chronic cardiac decompensation as in congestive failure

Contraindications:o Dopamine should not be used in patients with pheochromocytoma or patients with

uncorrected tachyarrhythmias or ventricular fibrillation. Side Effects:

o Cardiac arrhythmiaso Dyspneao Nauseao Vomitingo Headache

Pharmacokinetics:

o Dopamines onset of action occurs within five minutes of intravenous administration,and with dopamines plasma half-life of about two minutes, the duration of action isless than ten minutes. However, if monoamine oxidase (MAO) inhibitors are present,the duration may increase to one hour.

Drug Interactions:o Patients who have been treated with MAO inhibitors within two to three weeks prior

to the administration of dopamine HCl should receive initial doses of 1/10th normalo Tricyclic antidepressants may potentiate the pressor response to adrenergic agentso Cardiac effects of dopamine are antagonized by beta-adrenergic blocking agentso

Haloperidol and haloperidol-like drugs suppress the dopaminergic renal andmesenteric vasodilation induced at low rates of dopamine infusion

References:o Biaggioni I, Robertson D (2012):Adrenoceptor Agonists & Sympathomimetic Drugs

(Chapter 9). In: Basic & Clinical Pharmacology.12e. Katzung BG, Masters SB, TrevorAJ (Editors).

o rxlist.com (Dopamine)

Keywords

Cholinomimetic Agents

Pilocarpine

Trade Names:generic, Salagen, Isopto Carpine

Drug Class:Muscarinic cholinomimetic (tertiary alkaloid), muscarinic agonist

Mechanism of Action:o A cholinergic parasympathomimetic agent exerting a broad spectrum of

pharmacologic effects with predominant muscarinic action

Indications:o Treatment of dry mouth(Salagen ) resulting from salivary gland hypofunction

caused by: Radiotherapy for cancer of the head and neck
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Sjgrens syndrome,an autoimmune disorder where immune cells attack and

destroy the glands that produce tears and salivao Treatment of glaucoma(Open-Angle & Acute Angle-Closure)(Isopto Carpine )

eye drops containing pilocarpine cause contraction of the ciliary muscle which

opens the trabecular meshwork spaces to increase the outflow of aqueoushumor through the canal of Schlemm, thereby lowering intra-ocular pressure.

pilocarpine drops also cause miosis by causing contraction of the iris sphincter

muscle. This can be beneficial as well in lowering intraocular pressure incertain types of angle-closure glaucoma (rxlist.com)

Contraindications:o Uncontrolled asthmao Known hypersensitivity to pilocarpineo When miosis is undesirable

Side Effects:o The most frequent adverse experiences are a consequence of the expected

pharmacologic effects of pilocarpine & include sweating, flushing, increasedurinary frequency.

Pharmacokinetics:

o Well absorbed from most sites of administrationo Crosses the blood brain barrier(its a tertiary amine)

Drug Interactions:

o Administered with caution to patients taking beta blockers because of the possibilityof cardiac conduction disturbances

Notes:o Pilocarpine is a natural alkaloid

References:o Pappano AJ (2012)Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs

(Chapter 7). In: Basic & Clinical Pharmacology.12e. Katzung BG, Masters SB, Trevor

AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)o rxlist.com - Isopto Carpine o rxlist.com - Salagen

Keywords

Bethanechol

Trade Names:generic, Urecholine Drug Class:Muscarinic Cholinomimetic

Mechanism of Action:o It increases the tone of the detrusor urinae muscle, usually producing a contraction

sufficiently strong to initiate micturition and empty the bladdero It stimulates gastric motility, increases gastric tone, and often restores impaired

rhythmic peristalsiso Because of the selective action of bethanechol, nicotinic symptoms of

cholinergicstimulation are usually absent or minimal Indications:

o Treatment of acute postoperative & postpartum nonobstructive urinaryretention

o

Neurogenic atony of the urinary bladder with retention. Contraindications:

o Hypersensitivity to bethanechol chloride tablets,o Hyperthyroidism
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o Peptic ulcero Latent or active bronchial asthma,o Pronounced bradycardia or hypotensiono Vasomotor instabilityo Coronary artery diseaseo Epilepsyo Parkinsonism

Side Effects:o Early signs of overdosage are abdominal discomfort, salivation, flushing of the skin

(hot feeling), sweating, nausea and vomiting (SLUDE-like symptoms).o Atropine is a specific antidote

Pharmacokinetics:o Bethanechol chloride does not cross the blood-brain barrier because of its charged

quaternary amine moiety.o The metabolic fate and mode of excretion of the drug have not been elucidated.o Administer orally or s.c.; do not give by i.v. injection due to the risk of hypotension

& bradycardia Drug Interactions:

o Special care is required if this drug is given to patients receiving ganglion blockingcompounds because a critical fall in blood pressure may occur. Usually, severeabdominal symptoms appear before there is such a fall in the blood pressure.

References:

o Pappano AJ (2012)Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs(Chapter 7). In: Basic & Clinical Pharmacology.12e. Katzung BG, Masters SB, Trevor

AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)o rxlist.com (Bethanechol)

Keywords

Nicotine

Trade Names:Nicotrol Inhaler Drug Class:Nicotinic Cholinomimetic Mechanism of Action:

o Binds stereo-selectively to nicotinic-cholinergic receptors at the autonomicganglia, in the adrenal medulla, at neuromuscular junctions, and in the brain

o Two types of central nervous system effects are believed to be the basis of nicotinespositively reinforcing properties:

A stimulating effect is exerted mainly in the cortex via the locusceruleus

A reward effect is exerted in the limbic system

At low doses the stimulant effects predominate while at high doses the

reward effects predominateo The cardiovascular effects of nicotine include peripheral vasoconstriction,

tachycardia, and elevated blood pressure Indications:

o Aid to smoking cessationfor the relief of nicotine withdrawal symptoms Contraindications:

o

Known hypersensitivity or allergy to nicotine or to menthol Side Effects:

o Nauseao Abdominal pain
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o Vomiting, diarrhea,o Diaphoresis (profuse sweating)o Flushingo Dizzinesso Disturbed hearing and vision,o Confusiono Weakness

o

Palpitationso Altered respirationo Hypotension

Pharmacokinetics:o Nicotine is well absorbed through the skin

Major drug Interactions:o May alter the pharmacokinetics of certain concomitant medications, such as tricyclic

antidepressants and theophylline. Doses of these and perhaps other medicationsmay need to be adjusted in patients who successfully quit smoking.

Notes:

o Acute tolerance (a reduction in response for a given dose) develops rapidly (lessthan 1 hour), but not at the same rate for different physiologic effects (skintemperature, heart rate, subjective effects)

o Withdrawal symptoms such as cigarette craving can be reduced in most individualsby plasma nicotine levels lower than those from smoking

o Withdrawal from nicotine in addicted individuals can be characterized by craving,nervousness, restlessness, irritability, mood lability, anxiety, drowsiness, sleepdisturbances, impaired concentration, increased appetite, minor somatic complaints(headache, myalgia, constipation, fatigue), and weight gain

References:o Luscher C (2012)Drugs of Abuse (Chapter 32). In: Basic & Clinical Pharmacology.

12e. Katzung BG, Masters SB, Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)


AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)o rxlist.com(Nicotrol )

Keywords

Carbamate Cholinesterase InhibitorsPhysostigmine

Trade Names:generic

Drug Class:Reversible Carbamate Anticholinesterase

Mechanism of Action:o A reversible anticholinesterase which effectively increases the concentration of

acetylcholine at the sites of cholinergic transmission Indications:

o

To reverse the anticholinergic effects upon the CNS & peripheral nervoussystemthat are caused by numerous drugs & plants capable of producingthe anticholinergic syndrome(see Notes)

Contraindications:
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o Physostigmine should not be used in the presence of asthma, gangrene, diabetes,cardiovascular disease, mechanical obstruction of the intestine or urogenital tract orany vagotonic state, and in patients receiving choline esters and depolarizingneuromuscular blocking agents (decamethonium, succinyicholine)

Side Effects:o nausea, vomiting, and salivationo Appropriate antidote is atropine sulfate

Pharmacokinetics:o Physostigmine contains a tertiary amine and easily penetrates the blood brain

barrier, while an anticholinesterase, such as neostigmine, which has a quatenaryammonium ion is not capable of crossing the barrier

Notes:o Pralidoxime (2-PAM) & other oximes should not be used to counteract the toxicity

caused by carbamate type anticholinesterases. Oximes are effective againstorganophosphate anticholinesterases only.

o SOME DRUGS WHICH PRODUCE THE ANTICHOLINERGIC SYNDROME: Amitriptyline,Amoxapine, Anisotropine, Atropine, Benztropine, Biperiden, Carbinoxamine,Clidinium, Cyclobenzaprine, Desipramine, Doxepin, Homatropine, Hyoscine,Hyoscyamine, Hyoscyamus, Imipramine, Lorazepam, Maprotiline, Mepenzolate,Nortriptyline, Propantheline, Protriptyline, Scopolamine, Trimipramine

o SOME PLANTS THAT PRODUCE THE ANTICHOLINERGIC SYNDROME: BlackHenbane, Deadly Night Shade, Devils Apple, Jimson Weed, Loco Seeds or Weeds,Matrimony Vine, Night Blooming Jessamine, Stinkweed


(Chapter 7). In: Basic & Clinical Pharmacology.12e. Katzung BG, Masters SB, TrevorAJ (Editors). McGraw-Hill / Lange. (Access-Medicine)

o rxlist.com (Physostigmine)

Keywords

Neostigmine

Trade Names:generic, Prostigmin Drug Class:Carbamate Anticholinesterase, Cholinomimetic Mechanism of Action:

o Inhibits the hydrolysis of acetylcholine by competing with acetylcholine forattachment to acetylcholinesterase at sites of cholinergic transmission

o

It enhances cholinergic action by facilitating the transmission of impulses acrossneuromuscular junctions

o It also has a direct cholinomimetic effect on skeletal muscle and possibly onautonomic ganglion cells

o Because it contains a quaternary ammonium group it does not cross the blood-brain barrier

Indications:o For symptomatic treatment of myasthenia graviso Its greatest usefulness is in prolonged therapy where no difficulty in swallowing is

present

o

In acute myasthenic crisis where difficulty in breathing and swallowing is present,the parenteral form (neostigmine methylsulfate) should be used. The patient can betransferred to the oral form as soon as it can be tolerated.

Contraindications:
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o Patients with known hypersensitivity to the drugo Contraindicated in patients with peritonitis or mechanical obstruction of the intestinal

or urinary tract Side Effects:

o Generally due to an exaggeration of pharmacological effects of which salivation andfasiculation are the most common

o Bowel cramps and diarrhea may also occur

o

For a more complete list, see therxlist.comreference Pharmacokinetics:

o Neostigmine bromide is poorly absorbed from the gastrointestinal tract following oraladministration

o As a rule, 15 mg of neostigmine bromide given orally is equivalent to 0.5 mg ofneostigmine methylsulfate given parenterally

Major drug Interactions:o Certain aminoglycoside antibiotics, especially neomycin, streptomycin and

kanamycin, have a mild but definite nondepolarizing blocking action which mayaccentuate neuromuscular block. These antibiotics should be used in the myasthenicpatient only where definitely indicated.

References:


AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)o rxlist.com (Prostigmin )

Keywords

Pyridostigmine

Trade Names:Mestinon, Regonol Drug Class:carbamate cholinesterase inhibitor (reversible) Mechanism of Action:

o Inhibits the destruction of acetylcholine by cholinesterase Indications:

o Treatment of myasthenia graviso Prophylaxis against poisoning by Soman nerve gas(which otherwise produces

rapid irreversible aging) Pyridostigmine is needed for adequate protection against soman. If personnel

take pyridostigmine in advance of exposure, soman will be prevented from

binding to AChE because the AChE binding sites are occupied bypyridostigmine, and so aging cannot take place.

The armed forces estimate that during a chemical attack, many personnel

may be exposed to 5 times the lethal dose (LD) of soman, so a protectiveratio (that raises the LD) by at least 5 times is needed. Addition ofpyridostigmine allows the protective ratio to exceed 5 for soman (according tostudies in monkeys).

Clinical trials (pyridostigmine is clinically used in myasthenia gravis) indicate

that pyridostigmine is well-tolerated at the doses intended for military use. Pyridostigmine should be started (oral tablets) at least several hours

before exposure to soman (8 hours in advance is preferred), anddiscontinued upon exposure to the nerve gas, at which point atropine andpralidoxime are given at the first indication of exposure.
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Pyridostigmine pretreatment does not confer an advantage against

sarin, based on studies in animals; personnel have enough time to takeoxime after exposure to this nerve agent before aging takes place,reactivating the AChE molecule. Indeed, soman is the only nerve agent forwhich PB is known to be necessary to produce an adequate protective ratio.

Contraindications:o Mechanical intestinal or urinary obstruction

o

Particular caution should be used in its administration to patients with bronchialasthma

Side Effects:o SLUDE. With overdose it can produce muscarinic & nicotinic symptoms

Muscarinic: nausea, vomiting, diarrhea, abdominal cramps, increased

peristalsis, increased salivation, increased bronchial secretions, miosis anddiaphoresis

Nicotinic side effects are comprised chiefly of muscle cramps, fasiculation andweakness

Overdosage may result in cholinergic crisis, a state characterized by

increasing muscle weakness which, through involvement of the muscles ofrespiration, may lead to death

Pharmacokinetics:

o Oral administration. The size and frequency of the dosage should be adjusted to theneeds of the individual patient.

o Pyridostigmine is mainly excreted unchanged by the kidneyo Pyridostigmine is a quaternary amine(permanently charged) and does not readily

cross the blood brain barrier Notes:

o Chemically related to neostigmine, but has a longer duration of action andless GI effects


(Chapter 7). In: Basic & Clinical Pharmacology.12e. Katzung BG, Masters SB, TrevorAJ (Editors). McGraw-Hill / Lange. (Access-Medicine)

o rxlist.compyridostigmine (Mestinon )o fda.gov(Prophylactic use against poisoning by Soman nerve gas)

Keywords

Quaternary Alcohol CholinesteraseInhibitors

Edrophonium

Trade Names:generic, Enlon Plus, Tensilon

Drug Class:Anticholinesterase (quaternary alcohol subtype) Mechanism of Action:

o A short and rapid-acting anticholinesterase

o

Positively charged quaternary alcohol that binds reversibly to the anionic site oncholinesterase

Indications:
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1. For the differential diagnosis of myasthenia gravis (the Tensilon Test)andas an adjunct in the evaluation of treatment requirements in this disease. It mayalso be used for evaluating emergency treatment in myasthenic crises. Because ofits rapid onset of action (30 sec) and brief duration of action (~5 minutes), it is notrecommended for maintenance therapy in myasthenia gravis (Drachman, 2012).

YouTube videoof the Tensilon Test performed in a dog with Myasthenia

Gravis

2.

Useful whenever an antagonist is needed to reverse the neuromuscularblock produced by curare, or curare-like NMJ blocker(e.g. tubocurarine,gallamine triethiodide or dimethyl-tubocurarine)

It is not effective against depolarizing skeletal muscle relaxants

(succinylcholine)3. It may be used adjunctively in the treatment of respiratory depression caused by

curare overdosage Contraindications:

o Known hypersensitivity to anticholinesterase agentso Intestinal and urinary obstructions of mechanical type

Side Effects:

o The myasthenic patient in crisis who is being tested with edrophonium should beobserved for bradycardia or cardiac standstill and cholinergic reactions if anoverdose is given.

o Muscarine-like symptoms (nausea, vomiting, diarrhea, sweating, increased bronchialand salivary secretions and bradycardia) often appear with overdosage (cholinergiccrisis)

o An important complication that can arise is obstruction of the airway by bronchialsecretions

Pharmacokinetics:o IV and IM administrationo

Rapid renal excretion, resulting in a short duration of action Major drug Interactions:

o Care should be given when administering this drug to patients with symptoms ofmyasthenic weakness who are also on anticholinesterase drugs

o Since symptoms of anticholinesterase overdose (cholinergic crisis) may mimicunderdosage (myasthenic weakness), their condition may be worsened by the use ofthis drug

References:o Drachman DB (2012):Myasthenia Gravis and Other Diseases of the Neuromuscular

Junction (Chapter 386). In: Harrison's Internal Medicine. 18e.McGraw-Hill.

o

Pappano AJ (2012)Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs(Chapter 7). In: Basic & Clinical Pharmacology.12e. Katzung BG, Masters SB, Trevor

AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)o rxlist.com (Enlon )

Keywords

Organophosphate CholinesteraseInhibitors

Echothiophate
http://youtu.be/k7YX9kuWrxAhttp://youtu.be/k7YX9kuWrxAhttp://www.accessmedicine.com/content.aspx?aID=9148909http://www.accessmedicine.com/content.aspx?aID=9148909http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55820947http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55820947http://www.rxlist.com/enlon-drug.htmhttp://www.rxlist.com/enlon-drug.htmhttp://www.rxlist.com/enlon-drug.htmhttp://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55820947http://www.accessmedicine.com/content.aspx?aID=9148909http://youtu.be/k7YX9kuWrxA


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Trade Name:Phospholine Iodide Drug Class:Anticholinesterase (Organophosphate) Mechanism of Action:

o Irreversible long-acting cholinesterase inhibitorfor topical use to enhance theeffect of endogenously liberated acetylcholine in the iris, ciliary muscle, and otherparasympathetically innervated structures of the eye

o It causes miosis, increases the outflow of aqueous humor, causes a fall in intraocular

pressure, and potentiation of accommodation Indications:

o Treatment of glaucoma(if beta-blockers fail)o Because of it's long duration of action, it is useful for round the clock control of

intraocular pressureo Also indicated for accommodative esotropia (a pediatric use)

Contraindications:o Active uveal inflammationo Most cases of angle-closure glaucoma, due to the possibility of increasing angle

blocko Hypersensitivity to the active or inactive ingredients

Side Effects:

o Retinal detachment has been reported in a few caseso Stinging, burning, lacrimationo Iris cysts may formo Lens opacitieso Cardiac irregularities

Pharmacokinetics:o Administered in eye drops to patients with glaucomao Forms an irreversible covalent bond with the ACh binding site on

cholinesterase (duration of action is ~100 hrs)

Drug Interactions:o Potentiates other cholinesterase inhibitors such as succinylcholine or

organophosphate and carbamate insecticideso Patients undergoing systemic anticholinesterase treatment should be warned of the

possible additive effects References:


AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)o rxlist.com (Phospholine )

Keywords

Sarin (GB)

Drug Class:o Organophosphate anticholinesterase& a human-made chemical warfare

agent (nerve agent)o Originally synthesized as a pesticide

Mechanism of Action:

o

Sarin is the most volatile of the nerve agents, which means that it can easily andquickly evaporate from a liquid into a vapor and spread into the environment

o People can be exposed to the vapor even if they do not come in contact with theliquid form of sarin
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o Once sarin binds to cholinesterase the chemical stability of it's interaction withthe enzyme can become irreversible with time due to the loss of an alkylgroup. When this happens it's binding becomes irreversible (aging) and thecomplex becomes resistant to the effects of oxime regenerators such as pralidoxime

o Aging develops within 3-5 hours with sarin. Indications:

o Terrorism / Chemical Warfare, Weapon of Mass Destruction

Effects:o Remember SLUDE muscarinic & nicotinic symptomso Symptoms will appear within a few seconds after exposure to the vapor form of

sarin and within a few minutes to up to 18 hours after exposure to the liquid form(see below)

o A long term study of soldiers exposed to sarin & cyclosarin during the first Gulf War(1991) indicated that exposure was significantly associated with less proficientneurobehavioral functioning on tasks involving fine psychomotor dexterity andvisuospatial abilities 45 years after exposure (Proctor et al, 2007).

Symptoms within seconds to hours of exposure:Runny nose Chest tightness Low or high blood pressure

Watery eyes Rapid breathing Slow or fast heart rate

Drooling Cough Muscle fasiculations / twitching

Excessive sweating Increased urination Weakness

Eye pain Diarrhea Drowsiness

Blurred vision Nausea, vomiting Headache

Small or pinpoint pupils Abdominal pain Confusion

High Concentrations Can Cause:

Loss of consciousness

Seizures

Respiratory failure - leading to death(increased bronchial secretions, bronchoconstriction,paralyzed diaphragm & central effects can all contribute to respiratory failure)

Routes of exposure:o Following release of sarin into the air, people can be exposed through skin contact

or eye contact. They can also be exposed by breathing air that contains sarin.o Sarin mixes easily with water, so it could be used to poison water. Following release

of sarin into water, people can be exposed by touching or drinking water thatcontains sarin.

o Following contamination of food with sarin, people can be exposed by eating thecontaminated food

o A persons clothing can release sarin for about 30 minutes after it hascome incontact with sarin vapor, which can lead to exposure of other people

Treatment after exposure:o Decontamination:

Remove & dispense of contaminated clothing As quickly as possible

Wash skinwith large amounts of soap and water

Rinse the eyeswith plain water for 10 to 15 minutes if they are burning or if

vision is blurred If sarin has been swallowed, do not induce vomiting or give fluids to drink

o Give atropine and pralidoxime STAT as antidotes


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o Supportive measures such as assisted ventilation, diazepam for convulsions,phentolamine for 2-PAM induced hypertension

Notes:o Sarin is a clear, colorless, and tasteless liquid that has no odor in its pure formo Sarin can evaporate into a vapor (gas) and spread into the environmento Sarin is also known as GBo Sarin and other nerve agents may have been used in chemical warfare during the

Iran-Iraq War in the 1980so Sarin was used in two terrorist attacks in Japan in 1994 and 1995. These

attacks & their outcomes have been described in an article by Yanagisawa et al(2006).

References:

1. Center for Disease Control & Prevention (Sarin - GB)2. Hurst CG, Newmark J, Romano JA Jr (2012):Chemical Bioterrorism (Chapter 222). In:

Harrison's Principles of Internal MedicineVol 2 18e. Fauci, Brauwald, Kasper, Hauser,Longo, Jameson & Loscalzo. Vol 2 18e. McGraw Hill. (ISBN 978-0-07174889-6)

3.

Morgan DL, Ortiz C (2011):Nuclear, Biologic & Chemical Agents; Weapons of MassDestruction. (Chapter 3). In: Current Diagnosis & Treatment: Emergency Medicine 7e.McGraw-Hill. (Access Medicine)

4. Proctor SP, Heaton KJ, Heeren T, White RF: Effects of sarin and cyclosarin exposure duringthe 1991 Gulf War on neurobehavioral functioning in US army veterans. Neurotoxicology27(6): 931-939.

5.Yanagisawa N, Morita H, Nakajima T: Sarin experiences in Japan: Acute toxicity and long-term effects. Journal of the Neurological Sciences 249(1):76-85, 2006

Keywords

Soman (GD)

Drug Class:Organophosphate Chemical Warfare Agent classified as a Nerve Agent Mechanism of Action:

o Inhibits the destruction of acetylcholine by cholinesteraseo Aging occurs within a half-life of only 2 minutes with somano Rapid aging can make it almost impossible to give pralidoxime rapidly enough to be

beneficial after the first noticeable detection of symptoms of poisoning are felt Effects:

o

Same assarin Routes of exposure:

o Same assarin Treatment after exposure:

o Same as sarin except pralidoxime may be ineffective due to rapid aging caused bysoman.

Notes:o Soman is a clear, colorless, tasteless liquid with a slight camphor odor (for example,

Vicks Vapo-Rub) or rotting fruit odoro More difficult to vaporize compared to Sarin

o

It can become a vapor if heatedo Also known as GD

References:o Center for Disease Control & Prevention (Soman - GD)
http://www.bt.cdc.gov/agent/sarin/index.asphttp://www.bt.cdc.gov/agent/sarin/index.asphttp://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=9126337http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=9126337http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55745388http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55745388http://tmedweb.tulane.edu/pharmwiki/doku.php/sarinhttp://tmedweb.tulane.edu/pharmwiki/doku.php/sarinhttp://tmedweb.tulane.edu/pharmwiki/doku.php/sarinhttp://tmedweb.tulane.edu/pharmwiki/doku.php/sarinhttp://tmedweb.tulane.edu/pharmwiki/doku.php/sarinhttp://tmedweb.tulane.edu/pharmwiki/doku.php/sarinhttp://www.bt.cdc.gov/agent/soman/basics/facts.asphttp://www.bt.cdc.gov/agent/soman/basics/facts.asphttp://www.bt.cdc.gov/agent/soman/basics/facts.asphttp://tmedweb.tulane.edu/pharmwiki/doku.php/sarinhttp://tmedweb.tulane.edu/pharmwiki/doku.php/sarinhttp://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55745388http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=9126337http://www.bt.cdc.gov/agent/sarin/index.asp


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o Hurst CG, Newmark J, Romano JA Jr (2012):Chemical Bioterrorism (Chapter 222).In: Harrison's Principles of Internal MedicineVol 2 18e. Fauci, Brauwald, Kasper,Hauser, Longo, Jameson & Loscalzo. Vol 2 18e. McGraw Hill. (ISBN 978-0-07174889-6)

o Morgan DL, Ortiz C (2011):Nuclear, Biologic & Chemical Agents; Weapons of MassDestruction. (Chapter 3). In: Current Diagnosis & Treatment: Emergency Medicine7e.McGraw-Hill. (Access Medicine)

Keywords

VX

Drug Class:Chemical Warfare Agent classified as a Nerve Agent Mechanism of Action & Effects:

o Same assoman&sarin Routes of exposure:

o VX can be absorbed through the eyes or the skin of the victim

o

As little as one drop of VX on the skin can be fatal (as compared to 1 to 10 mls ofsarin or soman)o The LD50 for humans is estimated to be ~10 mg

Notes:

o Amber (honey brown)colored, tasteless & odorless, oily liquid with low volatility

unless temperatures are higho The V of VX signifies it very long persistence compared to sarin and

somano VX decomposes at a rate of ~ 5% a month at 71 Co VX-inhibited cholinesterase can be reactivated by 2-PAM for as long as 48 hours

(Sidell & Groff : The reactivatibility of cholinesterase inhibited by VX and sarin inman. Toxicol Applied Pharmacol 27(2):241-52, 1974) References:

o Center for Disease Control & Prevention (VX)o Hurst CG, Newmark J, Romano JA Jr (2012):Chemical Bioterrorism (Chapter 222).

In: Harrison's Principles of Internal MedicineVol 2 18e. Fauci, Brauwald, Kasper,Hauser, Longo, Jameson & Loscalzo. Vol 2 18e. McGraw Hill. (ISBN 978-0-07174889-6)

o Morgan DL, Ortiz C (2011):Nuclear, Biologic & Chemical Agents; Weapons of MassDestruction. (Chapter 3). In: Current Diagnosis & Treatment: Emergency Medicine7e.McGraw-Hill. (Access Medicine)

VX is not fluorescent green as depicted in the movie The Rock (1996 - with Nicholas Cage &

Sean Connery). It is amber colored (CDC Facts About VX). Also (as depicted in the movie)stabbing yourself in the heart with the antidote (atropine/2-PAM) contained in the military Mark 1kit auto-injectors is probably not wise, although it certainly is dramatic. The auto-injectors aredesigned to be applied to a victim's thigh.

Keywords

Cholinesterase Regenerator
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Pralidoxime (2-PAM)

Trade Names:generic, Protopam Drug Class:cholinesterase regenerator, oximes Mechanism of Action:

o regenerates cholinesterase activity that has become inhibited by anorganophosphate compound (but is most effective when given before chemical

aging between the organophosphate & cholinesterase enzyme has occurred).o The oxime group (=NOH) in pralidoxime has a very high affinity for the

phosphorous atom of oragnophosphates and can cause the bond betweenthe organophosphate agent and the cholinesterase to hydrolyze if thecomplex has not agedor stabilized due to the spontaneous loss of an alkylgroup from the organophosphate compound.

o Pralidoxime's effect on non-aged organophosphate-enzyme complexes causes areactivation of cholinesterase activity.

o Because of it's positive charge, pralidoxime does not cross the blood-brain barrier.

Organophosphate aging and the effect of pralidoxime to regenerateacetylcholinesterase (AChE).

Indications:o Used together with atropine to treat poisoning caused by

organophosphate cholinesterase inhibitorsthat are used as pesticides (e.g.,
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diazinon, malathion, mevinphos, parathion) or in chemical warfare (e.g. the nervegas sarin).

o 2-PAM is not as effective against the chemically different carbamate typecholinesterase inhibitors (such as neostigmine and pyridostigmine) becausecarbamates do not have phosphate groups and do not undergo aging.

o Because pralidoxime is less effective in relieving depression of the respiratory center,atropine is always required concomitantly to block the effect of accumulated

acetylcholine at this site.o Pralidoxime relieves muscarinic signs and symptoms, salivation, bronchospasm, etc.,

but this action is relatively unimportant since atropine is adequate for this purpose. Relative Contraindications:

o Much less effective against against nerve gases that have alreadyinhibited cholinesterase and aged to a resistant form .

o Pralidoxime may make the symptoms of myasthenia gravis worse.o Pralidoxime's effects may be intensified in patients with kidney disease.

Side Effects:o Excessive doses can induce neuromuscular weakness & other adverse effects

Pharmacokinetics:

o typically given by i.v. infusion over 15-30 min, although multiple doses given overseveral days may produce beneficial effects in severe poisoning.

References:

o Hurst CG, Newmark J, Romano JA Jr (2012):Chemical Bioterrorism (Chapter 222).In: Harrison's Principles of Internal MedicineVol 2 18e. Fauci, Brauwald, Kasper,Hauser, Longo, Jameson & Loscalzo. Vol 2 18e. McGraw Hill. (ISBN 978-0-07174889-6)


AJ (Editors). McGraw-Hill / Lange. (Access-Medicine)o

rxlist.com (Protopam )

Keywords

Muscarinic Cholinolytics

Atropine

Trade Name:generic, Atropen

Drug Class:Muscarinic blocker (nonselective) Mechanism of Action:

o Competitive muscarinic receptor antagonist (of all muscarinic receptorsubtypes).

Its antagonism which can be overcome by increasing the concentration ofacetylcholine at receptor sites of the effector organ (e.g., by usinganticholinesterase agents which inhibit the enzymatic destruction ofacetylcholine)

o Recent evidence indicates that muscarinic receptors are constitutivelyactive, and most drugs that block the actions of acetylcholine are inverse

agonists (including atropine) that shift the equilibrium to the inactivestate of the receptor(Pappano, 2012)
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o The receptors antagonized by atropine are the peripheral structures that arestimulated or inhibited by muscarine (i.e., exocrine glands, smooth and cardiacmuscle).

o Responses to postganglionic cholinergic nerve stimulation also may be inhibited byatropine but this occurs less readily than with responses to injected (exogenous)choline esters.

Indications:

1.

preanesthetic medication: to prevent or reduce secretions of the respiratory tractthat occur during surgery where general anesthetics are used

2. to restore cardiac rate and arterial blood pressure during anesthesiawhenvagal stimulation produced by intra-abdominal surgical traction causes a suddendecrease in pulse rate and cardiac output.

3. to reduce the degree of atrioventricular (A-V) heart blockwhen increasedvagal tone is a major cause (e.g. as in cases of digoxin toxicity, or following aninferior MI).

4. to prevent severe bradycardia and syncope due to a hyperactive carotid sinus reflex.5. as an antidote (with external cardiac massage) for cardiovascular collapse from the

injudicious use of a choline ester (cholinergic) drug.6.

treatment of anticholinesterase poisoning from organophosphorusinsecticides.

7. antidote for the rapid type of mushroom poisoningdue to the presence ofthe muscarine that is found in certain fungi such asAmanita muscaria

8. may improve the tremor & rigidity of Parkinsonism9. as an eye-drop medication to cause prolonged relaxation of over-contracted eye

muscles due to chronic eye inflammation. Atropine's effects last for more than aweek (7-10 days of mydriasis, & ~2 weeks of cycloplegia) - this is why it is not usedfor routine retinal exams requiring mydriasis.

Note: shorter acting antimuscarinics such as homatropine, cyclopentolate or

tropicamide are typically used to produce mydriasis during routine eye exams,as illustrated below (Wikipedia commons).

Contraindications:o Atropine generally is contraindicated in patients with glaucoma, pyloric

stenosis or prostatic hypertrophy, except in doses ordinarily used for preanesthetic

medication.o Atropine Sulfate Injection, USP should be used with caution in all individuals over 40

years of age Side Effects:

o Most of the side effects of atropine are directly related to its antimuscarinic action.o Dryness of the mouth, blurred vision, photophobia and tachycardia

commonly occur with chronic administration of therapeutic doses.o Anhidrosis may occur and produce heat intolerance or impair temperature regulation

in persons living in a hot environment.o Constipation and difficulty in micturation may occur in elderly patients.o

Occasional hypersensitivity reactions have been observed, especially skin rasheswhich in some instances progressed to exfoliation.

o Occasionally, therapeutic doses dilate cutaneous blood vessels, particularly in theblush area (atropine flush).
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o Marked excitement and convulsions may occur with toxic doses (in comparison,scopolamine has greater CNS effects). The fatal adult dose of atropine is not known;200 mg doses have been used and cumulative doses as high as 1000 mg have beengiven.

o Remember the phrase: Blind as a bat, Mad as a hatter, Dry as a bone, Red asa beet, Hot as hell, Full as a Flask(see theAntimuscarnics wiki module for themechanisms responsible for these side effects).

Pharmacokinetics:o Administered i.v., s.c. or i.m..o Atropine disappears rapidly from the blood following injection (half life is 2 hrs) and

is distributed throughout the body.o Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver; from

13 to 50% is excreted unchanged in the urine. Traces are found in varioussecretions, including milk.

o Atropine readily crosses the placental barrier and enters the fetal circulation.o Atropine's effect on parasympathetic function declines rapidly in all organs except

the eye. Effects on the iris and ciliary muscle persist for several days. Drug Interactions:

o Concomitant administration of other drugs having anticholinergic effects (TCA's,antihistamines) may precipitate the complications listed above.

References:

o Pappano A (2012):Cholinoceptor-Blocking Drugs. (Chapter 8). In: Basic and ClinicalPharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors)

o rxlist.com (Atropine)

Keywords

Scopolamine

Trade Names:generic, Transderm Scop Drug Class:Antimuscarinic (competitive antagonist) Mechanism of Action:

o Antimuscarinic drug having more marked central effects, producing drowsinessand amnesia in sensitive individuals.

Indications:

1. Prevention of nausea and vomiting associated with motion sicknessand the use ofopioid analgesics (e.g. following surgery). The patch should be applied only to skinin the postauricular area.

2.

To produce mydriasis & cycloplegiain diagnostic procedures. For some pre- andpostoperative states when a mydriatic and cycloplegic state is needed in treatmentof iridocyclitis. It blocks the responses of the sphincter muscle of the iris and theaccommodative muscle of the ciliary body to cholinergic stimulation, producingpupillary dilation (mydriasis) and paralysis of accommodation (cycloplegia).

3. Reduction of the tremor of Parkinson's disease. Contraindications:

o Patients with angle-closure (narrow angle) glaucoma, or history of hypersensitivity toscopolamine.

Side Effects:

o

Therapeutic doses can cause drowsiness & amnesia, dry mouth, transientimpairment of eye accommodation, including blurred vision and dilation of thepupils.
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o Toxic doses can cause excitement, agitation, hallucinations & coma (more likely thanwith atropine).

Pharmacokinetics:o Scopolamine is rapidly and fully distributed into the CNS where it has greater effects

than most other antimuscarinics.o Following patch removal, plasma levels decline in a log linear fashion with an

observed half-life of 9.5 hours.

o

Less than 10% of the total dose is excreted in the urine as parent and metabolitesover 108 hours.

Major drug Interactions:o Scopolamine should be used with care in patients taking other drugs that are

capable of causing CNS effects such as sedatives, tranquilizers, or alcohol.o Special attention should be paid to potential interactions with drugs having

anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (includingmeclizine), tricyclic antidepressants, and muscle relaxants.

References:o Pappano A (2012):Cholinoceptor-Blocking Drugs. (Chapter 8). In: Basic and Clinical

Pharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors)o rxlist.com (Transderm-Scop )

Keywords

Ipratropium bromide

Trade Name:Atrovent Drug Class:Antimuscarinic Mechanism of Action:

o A syntheticquaternary analog of atropine Indications:

o A bronchodilator for maintenance treatment of bronchospasm associated withasthma, chronic obstructive pulmonary disease, including chronic bronchitisand emphysema.

o It does not have the same efficacy in every patient, because patients differ in theextent of muscarinic involvement in their asthmatic symptoms.

o Administered either alone or with other bronchodilators, especially beta adrenergics, Contraindications:

o Ipratropium bromide inhalation aerosol is contraindicated in patients with a historyof hypersensitivity to soya lecithin or related food products such as soybean and

peanut. Side Effects:

o Tachycardia, palpitations, eye pain, urinary retention, urinary tract infection andurticaria.

o A single case of anaphylaxis thought to be possibly related to ipratropium bromidehas been reported.

o Cases of precipitation or worsening of narrow-angle glaucoma and acute eye painhave been reported.

Pharmacokinetics:o Given as an inhaled medication.

o

The bronchodilation following inhalation of ipratropium bromide is primarily a local,site-specific effect, not a systemic one.

o Much of an administered dose is swallowed but not absorbed, as shown by fecalexcretion studies.
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o The half-life of elimination is about 1.6 hours after intravenous administration.o Ipratropium bromide is minimally (0 to 9% in vitro) bound to plasma albumin and

1-acid glycoproteins. It is partially metabolized. References:

o Pappano A (2012):Cholinoceptor-Blocking Drugs. (Chapter 8). In: Basic and ClinicalPharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors)

o rxlist.com (Atrovent HFA )

Keywords

Glycopyrrolate

Trade Name:Robinul Drug Type:A quaternary analog of atropine Mechanism of Action:

o The same asatropinebut without significant CNS effectso It has a quaternary structure & does not cross the Blood-Brain-Barrier.

Indications:1. as a pre-op medication to reduce salivary & respiratory secretions, as wellas the volume and acidity of gastric secretions, and to block cardiac vagal reflexesduring intubation & induction of general anesthesia.

2. used along in combination with neostigmine to reverse the effects of non-depolarizing skeletal muscle relaxants at the conclusion of surgery.

3. as an adjunctive drug for treatment of peptic ulcerwhen rapid anticholinergiceffect is desired, or when oral medication is not tolerated.

Pharmacokinetics:o Given parenterally.o When given i.v., its onset of action is ~1 minuteo When given i.m. it's onset of action occurs in 15-30 mins, with peak effects in 30-45

minso The vagal blocking effects last for 2-3 hrs, and decrease in salivation for up to 7 hrs

(longer than for atropine) Side Effects:

o Similar to atropine (w/o CNS component) - e.g. dry mouth, blurred vision,photophobia due to mydriasis, cycloplegia, tachycardia, decreased sweating. Casesof (rare) malignant hyperthermia have been reported.

References:o Pappano A (2012):Cholinoceptor-Blocking Drugs. (Chapter 8). In: Basic and Clinical

Pharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors)o Morgan GE Jr, Mikhail MS, Murray MJ (2006):Anticholinergic Drugs (Chapter 11). In:

Clinical Anesthesiology 4e. Morgan GE Jr, Mikhail MS, Murray MJ (Editors). McGraw-Hill (Access Medicine)

o rxlist.com (Robinul )

Keywords

Nicotinic Cholinolytics

Trimethaphan

Trade Name:Arfonad
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Drug Class:Short acting, nondepolarizing ganglionic blocker Mechanism of Action:

o Selectively blocks the ganglionic subtype of nicotinic receptor Indications:

o Treatment of hypertensive emergencieso Treatment of & dissecting aortic aneurysmo To produce controlled hypotension in neurosurgery to reduce bleeding in the

operative field, and in patients undergoing electroconvulsive therapy Side Effects:

o The opposite of predominant tone (reflecting its loss): cycloplegia

hypotension

postural (orthostatic) hypotension tachycardia decreased GI motility hesitancy in urination & urinary retention

Pharmacokinetics:

o Inactive orally, given by i.v. infusiono Trimethaphan is a quaternary drug that does not cross the blood brain barrier (in

contrast to mecamylamine, another ganglionic blocker that produces CNS effectssuch as tremor, choreiform movements, and mental aberrations)

Notes:

o Another similar ganglionic blocker that is orally effective is mecamylamine(Inversine ). Their effects on autonomic parameters (e.g. loss of predominant tone& block of reflexes ) are similar, although their side effect profiles are slightlydifferent due to different effects on the CNS.

References:

Pappano A (2012):Cholinoceptor-Blocking Drugs. (Chapter 8). In: Basic and ClinicalPharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors)

Drugs.com (Trimehtaphan) rxlist.com (Mecamylamine)

Keywords

d-Tubocurarine (Prototype Nondepolarizing

Neuromuscular Blocker) Trade Name:generic Drug Class:Nondepolarizing neuromuscular blocking agent (prototype) Mechanism of Action:

o There are 3 mechanismsby which nondepolarizing neuromuscular blockers cancontribute to skeletal muscle relaxation:

1.At low concentrations they compete with acetylcholine (ACh) forbinding to postsynaptic nicotinic receptor sitesin the skeletal muscleneuro-muscular junction.

2. Nondepolarizing relaxants alsointerfere with presynaptic release of AChfrom motor nerve endings by still poorly understood mechanism(s). Bothblock of Na channels and block of pre-synaptic nicotinic autoreceptors havebeen implicated. The presynaptic nicotinic receptors have a different subunitcomposition compared to the muscle-type nicotinic receptors.
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3.At higher concentrations they can also produce a more intense motorblockade by blocking the poreof the nicotinic receptor-channel complex.

Contraindications:o Clients in whom release of histamine is hazardous. Use with caution during

pregnancy and lactation and in children. Side Effects:

o Allergic reactions.

o

Of the nondepolarizing neuromuscular blockers, d-tubocurarine causes themost histamine release by a direct effect on mast cells.Histamine release cancause bronchospasm, hypotension, salivary secretions.

o High doses of d-tubocurarine (& to a lesser extent other non-depolarizing blockers)can produce ganglionic blockade, which can contribute to producing hypotension.

Pharmacokinetics:o Given by injection (i.m., i.v.).o Narrow margin between therapeutic dose and toxic dose.o Onset, IV: 1 min; IM: 15-25 min. Time to peak effect 2-5 min.o Duration, IV: 80-120 min. t1/2: 1-3 hr.o About 43% excreted unchanged in urine.

Notes:

o d-tubocurarine is the prototype non-depolarizing skeletal muscle relaxant. It is nowrarely used, but is sometimes mentioned on board/shelf exams.

o Its muscle relaxant properties are qualitatively similar to the othernewer non-depolarizing relaxantssuch as pancuronium, vecronium, rocuronium (to name just afew).

o The newer drugs have fewer side effects and superior pharmacokinetic profiles.o Tubocurarine is the main active ingredient in the South American arrow poison -

curare.

-

References:

www.healthdigest.org Kruidering-Hall M, Campbell L (2012):Skeletal Muscle Relaxants. (Chapter 27). In: Basic

and Clinical Pharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors) Access Medicine - Neuromuscular Blocking Agents (Chapter 9).In: Clinical Anesthesiology.

4e.Morgan GE Jr, Mikhail MS, Murray MJ (Editors). 2006. Encyclopedia Britannica

Jonsson M, Gurley D, Dabrowski M, Larsson O, Johnson EC: Distinct pharmacologicproperties of neuromuscular blocking agents on human neuronal nicotinic acetylcholinereceptors. Anesth 105:521-33, 2006.

Keywords

Other Nondepolarizing Neuromuscular Blockers

The ideal skeletal muscle relaxant should have:

a rapid onset of action (to allow rapid intubation) a duration of action similar to the duration of the interventional procedure (endoscopy,

surgery) no side effects
http://tmedweb.tulane.edu/pharmwiki/doku.php/other_nondepolarizing_nm_blockershttp://tmedweb.tulane.edu/pharmwiki/doku.php/other_nondepolarizing_nm_blockershttp://tmedweb.tulane.edu/pharmwiki/doku.php/other_nondepolarizing_nm_blockershttp://tmedweb.tulane.edu/pharmwiki/doku.php/other_nondepolarizing_nm_blockershttp://www.healthdigest.org/drug-prescribing-database/tubocurarine-chloride-2194.htmhttp://libproxy.tulane.edu:2048/login?url=http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55825139http://libproxy.tulane.edu:2048/login?url=http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55825139http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=889540http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=889540http://www.britannica.com/EBchecked/topic/146779/curare/146779rellinks/Related-Linkshttp://www.britannica.com/EBchecked/topic/146779/curare/146779rellinks/Related-Linkshttp://www.britannica.com/EBchecked/topic/146779/curare/146779rellinks/Related-Linkshttp://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=889540http://libproxy.tulane.edu:2048/login?url=http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx?aID=55825139http://www.healthdigest.org/drug-prescribing-database/tubocurarine-chloride-2194.htmhttp://tmedweb.tulane.edu/pharmwiki/doku.php/other_nondepolarizing_nm_blockershttp://tmedweb.tulane.edu/pharmwiki/doku.php/other_nondepolarizing_nm_blockers


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Tubocurarine- the original nondepolarizing relaxant has:

relatively slow onset of action (4-6 mins) long duration of action (80-120 mins) significant side effects - histamine release from mast cells - causing bronchospasm,

hypotension, salivary secretions.

Examples of Newer Agents that have different durations of actions & fewer sideeffects:

Pancuronium:virtually no histamine release, but blocks muscarinic receptors. Similaronset of action & duration as tubocurarine.

Rocuronium:rapid onset (1-2 mins) & intermediate duration (30-60 mins). An alternativefor succinylcholine in emergency cases where rapid-induction of anesthesia is needed.

Vecuronium:intermediate onset of action (2-4 mins) & duration of action (25-40 mins).

Nomenclature Heads Up:

Steroid derivatives(pancuronium, pipercuronium, rocuronium, etc) end in curonium

Isoquinolone derivatives(atracurium, doxacurium, mivacurium, etc) end in curium

References:o Hibbs RE, Zambon AC (2011):Agents Acting at the Neuromuscular Junction and

Autonomic Ganglia (Chapter 11). In: Goodman & Gilman's Pharmacological Basis forTherapeutics. 11e. McGraw-Hill (Access Medicine)

o Kruidering-Hall M, Campbell L (2012):Skeletal Muscle Relaxants. (Chapter 27). In:

Basic and Clinical Pharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors)

Keywords

Depolarizing Neuromuscular Blocker /Relaxant

Succinylcholine

Trade Name:Anectine Drug Class:Depolarizing Neuromuscular Blocker Mechanism of Action:

o In the motor endplate it combines with nicotinic receptors to produce depolarizationwhich can be observed as uncontrolled focal muscle contractions (fasciculations).Subsequent transmission across the NMJ is inhibited as long as succinylcholineremains at the nicotinic receptor sites.

A depolarized post-junctional membrane (resulting in inactivation of Na

channels) causes the postjunctional membrane to become unresponsive to

ACh released by motor neurons. This is referred to as Phase I block &produces a characteristic reduction in contractile response (with no fade)during atrain of four stimuli.

o In less than a minute after IV administration a flaccid paralysisdevelops due tothe development of a desensitized state where the membrane becomes repolarized,
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but insensitive to ACh (due to receptor desensitization). This is referred to asPhase II block and responds to a train of four stimuli with a fade patternsimilar to that produced by non-depolarizing neuromuscular blockers.

o Succinylcholine's effects at muscarinic & nicotinic receptors outside of the NMJ areresponsible for numerous side effects.

o With a single IV dose, the period of flaccid paralysis lasts less than 10 minutes, andis terminated due to rapid hydrolysis of succinylcholine by cholinesterase in the

plasma & liver. Indications:

o Adjunct to general anesthesia to facilitate endotracheal intubation and relax skeletalmuscle during surgery or mechanical ventilation.

o It has a more rapid onset of actioncompared to most nondepolarizingneuromuscular blockers, making it a drug of choice for emergency cases whererapid endotracheal intubation is necessary.

Contraindications:o Genetic disorders of plasma pseudocholinesteraseo Family history of malignant hyperthermiao Recent burns or traumao Myopathies with elevated CPK levelso Acute narrow-angle glaucoma or penetrating eye injuries

Side Effects:

o Succinylcholine's stimulatory effect can cause hyperkalemia. It should not be givento patients 24 to 72 hrs after major burns or traumabecause it may cause acutehyperkalemia, hyperkalemic rhabdomyolysis & cardiac arrest.

o It has also produced acute hyperkalemia & cardiac arrest in otherwise healthy boyswith unrecognized muscular dystrophy, causing the FDA to issue a warning about itsuse in children (it should not be used in children except for emergency control of theairway).

o

Heavily muscled patientscan suffer from muscle pain due to muscle fasiculations, aswell as an increased risk for regurgitation & aspiration of gastric contents caused byincreases in intragastric pressure.

o Succinylcholine can cause a rapid increase in intraocular pressure due to effects onocular blood vessels & myofibrils.

o It can cause cardiac arrhythmias (increase or decrease in heart rate) because of itseffects on muscarinic receptors and nicotinic-ganglionic receptors.

o There is an increased risk for potentially fatal malignant hyperthermia. Pharmacokinetics:

o Given i.v. or i.m. Metabolized by plasma pseudocholinesterase, duration of action 4-

30 min depending on route of administration. Major drug Interactions:

o Aminoglycoside antibiotics (additive skeletal muscle blockade) Notes:

o Succinylcholine is the only depolarizing type NMJ blocker in clinical use in the USA References:

o Hibbs RE, Zambon AC (2011):Agents Acting at the Neuromuscular Junction andAutonomic Ganglia (Chapter 11). In: Goodman & Gilman's Pharmacological Basis forTherapeutics. 12e. McGraw-Hill (Access Medicine).

o Kruidering-Hall M, Campbell L (2012):Skeletal Muscle Relaxants. (Chapter 27). In:

Basic and Clinical Pharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors)o Morgan GE Jr, Mikhail MS, Murray MJ (2006):Neuromuscular Blocking Agents

(Chapter 9) In: Clinical Anesthesiology. 4th Edition.Morgan GE Jr, Mikhail MS,Murray MJ (Editors). McGraw-Hill (Access Medicine).

o rxlist.com (Anectine )
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Keywords

Drugs Effecting the Sympathetic NervousSystem

Methyldopa Trade Name:generic (Aldomet ) Drug Class:Antihypertensive Mechanism of Action:

o The antihypertensive effect of methyldopa is believed to be due to its metabolism toalpha-methylnorepinephrine , which then lowers arterial pressure by:

stimulation of central inhibitory 2 adrenergic receptors

false neurotransmissionand/or

reduction of plasma renin activity

Indications:o Treatment of hypertension during pregnancy as a replacement for ACE

inhibitors & ARBs(which are more efficacious, but are strongly contraindicated inpregnancy).

The patient can be switched back to an ACE inhibitor or ARB once pregnancy

is over Notes:

o Methyldopa is the L-isomer of alpha-methyldopa References:

o Benowitz NL (2012):Antihypertensive Agents (Chapter 11). In: Basic and ClinicalPharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors). McGraw-Hill (AccessMedicine).

o rxlist.com (Aldomet )

Keywords

Reserpine

Trade Name:generic Drug Class:Antihypertensive (catecholamine depletor) Mechanism of Action:

o A selective inhibitor of the catecholamine vesicular monoamine uptaketransporter (VMAT)that transports norepinephrine & epinephrine into presynapticvesicles found in sympathetic nerve terminals

o Produces a depletion of releasable neuronal catecholamine storeso Reserpine's effects produce a reduction in blood pressure due to a decreased cardiac

output & decreased peripheral vascular resistance Indications:

o Hypertension Side Effects:

o Sedationo

Depression (suicidal tendencies)o Parkinsonism symptoms

Pharmacokinetics:
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o Reserpine readily crosses the blood brain barrier & depletes cerebral catecholaminestores. This can cause side effects such as those listed above.

Note:o Reserpine is the active ingredient of a herbal tranquillizer from Rauwolfia serpentina

discovered by ancient Indian physicians.o Clinically, reserpine is primarily of historical importance, although it is used in

animal experiments to deplete catecholamine levels.

References:o Benowitz NL (2012):Antihypertensive Agents (Chapter 11). In: Basic and Clinical

Pharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors. McGraw-Hill (AccessMedicine).

o Medpedia.com(Clinical: Reserpine)

Keywords

Octopamine

Drug Class:False neurotransmitter. Mechanism of Action:

o Octopamine replaces norepinephrine in sympathetic neurons with chronicuse of monoamine oxidase inhibitors

Dopamine beta-hydroxylase converts tyramine to octopamine

Octopamine can be taken up into storage vesicles in nerve

terminals, and then be released by nerve stimulation Octopamine exerts only a small effect on postsynaptic receptors

compared to norepinephrine(hence the designation false transmitter) Notes:

o Octopamine typically exists in only trace amounts in the mammalian CNS, butaccumulates when MAO is inhibited (e.g. by MAO inhibitors).

o First identified in the octopuso Octopamine plays an important role in the innvertebrate nervous system where its

role is analogous to that of norepinephrine (NE) in vertebrates, and it is responsiblefor the fight or flight effect and fat mobilizing.

o Cocaine blocks its reuptake in insects, and thereby has insecticidal properties thatare protective to the coca plant.

References:o Katzung BG (2012):Introduction to Autonomic Pharmacology (Chapter 6). In: Basic

& Clinical Pharmacology.12e. B Katzung, SB Masters AJ Trevor (Editors. McGraw-Hill(Access Medicine).

o Roeder T (1999): Octopamine in Invertebrates. Progress in Neurobiology. 59(5):533-561.

o Wikipedia

Keywords

Bretylium
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Trade Name:generic Drug Class:Antiarrhythmic Mechanism of Action:

o Interferes with the neuronal release of catecholamines(after an initial phaseof causing the release of catecholamines)

o Bretylium also lengthens the duration and effective refractory period in heart tissue(a Class III effect), an effect that is most pronounced in ischemic cells (which have

shortened action potential durations) Indications:

o No longer available in the United Stateso Previously used for attempted resuscitation from ventricular fibrillation after lidocaine

and cardioversion have failed Side Effects:

o Precipitation of cardiac arrhythmias at the onset of drug therapy due to its ability tocause the initial release of catecholamines (when used as an antiarrhythmic).

o Postural hypotension (a sympathoplegic side effect)o Nausea & vomiting

Major drug Interactions:

o Digitalis toxicity may be aggravated by the initial release of norepinephrine causedby Bretylium.

o The pressor effects of catecholamines such as dopamine or norepinephrine areenhanced (mechanism unclear)

Note:o Considered a drug of last choice as an antiarrhythmico Primarily of historical significance

Reference:o rxlist.com (Bretylium)

Keywords

Guanethidine

Trade Name:generic

Drug Class:Antihypertensive, Adrenergic Neuron-blocking Agent Mechanism of Action:

o In high doses can cause profound sympathoplegia or pharmacologicsympathectomy

o Guanethidine has 4 mechanisms of action:1. Causes an initial release of norepinephrine (tyramine-like effect), followed

by replacement of norepinephrine by guanethidine in transmitter vesicles thateventually causes a

2. Gradual depletion of norepinephrine stores in the nerve ending (a reserpine-like effect).

3.

It's strong interaction with the nerve terminal transporter produces acocaine-like effect.4. Inhibits the release of norepinephrine from nerve terminals (bretylium-like

effect).
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o It can produce an initial pressor effect (due to tyramine & cocaine like actions), butlater results in sympathoplegia (due to reserpine & bretylium like effects). Thispressor effect is greatly reduced or not observed when the drug is taken orally &slowly absorbed.

Indications:o Guanethidine is no longer available in the USA du

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