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ANS Neurotransmitters
Acetylcholine
Muscarine and nicotine are naturally occurring alkaloids that were used to
pharmacologically identify and characterize receptor subtypes before the
endogenous neurotransmitter (acetylcholine or Vagusstoff) was identified.
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 (Miochol )
o
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Norepinephrine
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. When
given as an i.v. bolus, redistribution (and associated fall in concentration) also
contributes 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 intravenously
administered epinephrine or norepinephrine, resulting in an increased incidence of
cardiac arrhythmias
o Norepinephrine should be used with extreme caution in patients receiving
monoamine 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 )
o
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Epinephrine
Keywords
Dopamine
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Cholinomimetic Agents
Pilocarpine
Keywords
Bethanechol
Peptic ulcer
Latent or active bronchial asthma,
Pronounced bradycardia or hypotension
Vasomotor instability
Coronary artery disease
Epilepsy
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 blocking
compounds because a critical fall in blood pressure may occur. Usually, severe
abdominal 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)
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Nicotine
Vomiting, diarrhea,
Diaphoresis (profuse sweating)
Flushing
Dizziness
Disturbed hearing and vision,
Confusion
Weakness
Palpitations
Altered respiration
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 medications
may need to be adjusted in patients who successfully quit smoking.
Notes:
o Acute tolerance (a reduction in response for a given dose) develops rapidly (less
than 1 hour), but not at the same rate for different physiologic effects (skin
temperature, heart rate, subjective effects)
o Withdrawal symptoms such as cigarette craving can be reduced in most individuals
by 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, sleep
disturbances, 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. (AccessMedicine)
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 (Nicotrol )
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Neostigmine
Keywords
Pyridostigmine
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1. For the differential diagnosis of myasthenia gravis (the Tensilon Test) and
as an adjunct in the evaluation of treatment requirements in this disease. It may
also be used for evaluating emergency treatment in myasthenic crises. Because of
its rapid onset of action (30 sec) and brief duration of action (~5 minutes), it is not
recommended for maintenance therapy in myasthenia gravis (Drachman, 2012).
YouTube video of the Tensilon Test performed in a dog with Myasthenia
Gravis
2. Useful whenever an antagonist is needed to reverse the neuromuscular
block 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 agents
o Intestinal and urinary obstructions of mechanical type
Side Effects:
o The myasthenic patient in crisis who is being tested with edrophonium should be
observed for bradycardia or cardiac standstill and cholinergic reactions if an
overdose is given.
o Muscarine-like symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial
and salivary secretions and bradycardia) often appear with overdosage (cholinergic
crisis)
o An important complication that can arise is obstruction of the airway by bronchial
secretions
Pharmacokinetics:
o IV and IM administration
o 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 of
myasthenic weakness who are also on anticholinesterase drugs
o Since symptoms of anticholinesterase overdose (cholinergic crisis) may mimic
underdosage (myasthenic weakness), their condition may be worsened by the use of
this 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 Cholinesterase
Inhibitors
Echothiophate
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 and
quickly 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 the
liquid form of sarin
Once sarin binds to cholinesterase the chemical stability of it's interaction with
the enzyme can become irreversible with time due to the loss of an alkyl
group. When this happens it's binding becomes irreversible (aging) and the
complex 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 symptoms
o 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 proficient
neurobehavioral functioning on tasks involving fine psychomotor dexterity and
visuospatial abilities 45 years after exposure (Proctor et al, 2007).
o
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 that
contains sarin.
o Following contamination of food with sarin, people can be exposed by eating the
contaminated food
o A persons clothing can release sarin for about 30 minutes after it has come in
contact 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 skin with large amounts of soap and water
Rinse the eyes with 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
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 Medicine Vol 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 Mass
Destruction. (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 during
the 1991 Gulf War on neurobehavioral functioning in US army veterans. Neurotoxicology
27(6): 931-939.
5. Yanagisawa N, Morita H, Nakajima T: Sarin experiences in Japan: Acute toxicity and longterm effects. Journal of the Neurological Sciences 249(1):76-85, 2006
Keywords
Soman (GD)
Keywords
VX
o Amber (honey brown) colored, tasteless & odorless, oily liquid with low volatility
unless temperatures are high
o The V of VX signifies it very long persistence compared to sarin and
soman
o VX decomposes at a rate of ~ 5% a month at 71 C
o 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 in
man. 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 Medicine Vol 2 18e. Fauci, Brauwald, Kasper,
Hauser, Longo, Jameson & Loscalzo. Vol 2 18e. McGraw Hill. (ISBN 978-0-071748896)
o Morgan DL, Ortiz C (2011): Nuclear, Biologic & Chemical Agents; Weapons of Mass
Destruction. (Chapter 3). In: Current Diagnosis & Treatment: Emergency Medicine
7e. 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 1
kit auto-injectors is probably not wise, although it certainly is dramatic. The auto-injectors are
designed to be applied to a victim's thigh.
Keywords
Cholinesterase Regenerator
Pralidoxime (2-PAM)
Indications:
o Used together with atropine to treat poisoning caused by
organophosphate cholinesterase inhibitors that are used as pesticides (e.g.,
Keywords
Muscarinic Cholinolytics
Atropine
The receptors antagonized by atropine are the peripheral structures that are
stimulated or inhibited by muscarine (i.e., exocrine glands, smooth and cardiac
muscle).
o Responses to postganglionic cholinergic nerve stimulation also may be inhibited by
atropine 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 tract
that occur during surgery where general anesthetics are used
2. to restore cardiac rate and arterial blood pressure during anesthesia when
vagal stimulation produced by intra-abdominal surgical traction causes a sudden
decrease in pulse rate and cardiac output.
3. to reduce the degree of atrioventricular (A-V) heart block when increased
vagal tone is a major cause (e.g. as in cases of digoxin toxicity, or following an
inferior 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 organophosphorus
insecticides.
7. antidote for the rapid type of mushroom poisoning due to the presence of
the muscarine that is found in certain fungi such as Amanita muscaria
8. may improve the tremor & rigidity of Parkinsonism
9. 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 a
week (7-10 days of mydriasis, & ~2 weeks of cycloplegia) - this is why it is not used
for 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).
o
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 rashes
which in some instances progressed to exfoliation.
o Occasionally, therapeutic doses dilate cutaneous blood vessels, particularly in the
blush area (atropine flush).
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 been
given.
o Remember the phrase: Blind as a bat, Mad as a hatter, Dry as a bone, Red as
a beet, Hot as hell, Full as a Flask (see the Antimuscarnics wiki module for the
mechanisms 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 various
secretions, 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 Clinical
Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors)
o rxlist.com (Atropine)
o
Keywords
Scopolamine
Toxic doses can cause excitement, agitation, hallucinations & coma (more likely than
with 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 metabolites
over 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 (including
meclizine), 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 )
o
Keywords
Ipratropium bromide
Keywords
Glycopyrrolate
Keywords
Nicotinic Cholinolytics
Trimethaphan
References:
Pappano A (2012): Cholinoceptor-Blocking Drugs. (Chapter 8). In: Basic and Clinical
Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors)
Drugs.com (Trimehtaphan)
rxlist.com (Mecamylamine)
Keywords
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 pharmacologic
properties of neuromuscular blocking agents on human neuronal nicotinic acetylcholine
receptors. Anesth 105:521-33, 2006.
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Examples of Newer Agents that have different durations of actions & fewer side
effects:
References:
o Hibbs RE, Zambon AC (2011): Agents Acting at the Neuromuscular Junction and
Autonomic Ganglia (Chapter 11). In: Goodman & Gilman's Pharmacological Basis for
Therapeutics. 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)
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Reserpine
Note:
Reserpine readily crosses the blood brain barrier & depletes cerebral catecholamine
stores. This can cause side effects such as those listed above.
Keywords
Octopamine
Keywords
Bretylium
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Guanethidine
It can produce an initial pressor effect (due to tyramine & cocaine like actions), but
later results in sympathoplegia (due to reserpine & bretylium like effects). This
pressor 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 due to lack of availability, but is
available in the UK (wikipedia)
o Was used for severe cases of hypertension, either alone or as an adjunct drug
Contraindications:
o Guanethidine can cause a hypertensive crisis in patients with pheochromocytoma
due to the release of catecholamines (tyramine like action).
Side Effects:
o Postural hypotension, diarrhea (from increased GI motility), impaired ejaculation
Pharmacokinetics:
o Guanethidine is too polar to enter into the CNS, and hence has little or no CNS side
effects.
Major drug Interactions:
o Tricyclic antidepressants will decrease guanethidine's antihypertensive effects by
blocking its uptake into nerve terminals. Concurrent use with other
sympathomimetics (OTC cold medications) may produce hypertension.
Notes:
o Yes this is a dinosaur drug (hence the cartoon)
o Q1: Will you ever prescribe this drug? (Not in the USA)
o Q2: Is guanethedine a nice tool for understanding the pharmacology of the nerve
terminal? (Yes)
o Q3: Do I need to know it for the boards? (Extremely unlikely).
Reference:
o rxlist.com (Ismelin ) (no longer sold in the US under this trade name)
o
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Alpha Sympathomimetics
Clonidine
Clonidine acts relatively rapidly. The patients blood pressure declines within 30
to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4
hours.
Major drug Interactions:
o May potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating
drugs.
o May produce bradycardia & depress sinus node function in patients on digitalis,
calcium channel blockers and beta-blockers.
References:
o Benowitz NL (2012): Antihypertensive Agents (Chapter 11). In: Basic and Clinical
Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors). McGraw-Hill (Access
Medicine).
o rxlist.com (Catapres )
o
Keywords
Phenylephrine
References:
o Biaggioni I, Robertson D (2012): Adrenoceptor Agonists & Sympathomimetic Drugs
(Chapter 9). In: Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ
Trevor (Editors); McGraw-Hill (Access Medicine).
o rxlist.com (Neo-Synephrine )
Keywords
Beta Sympathomimetics
Isoproterenol
Adams-Stokes attacks
Pulmonary edema
Pharmacokinetics:
o Isoproterenol is readily absorbed when given parenterally or as an aerosol. It is
metabolized primarily in the liver and other tissues by COMT.
o Isoproterenol is a relatively poor substrate for MAO and is not taken up by
sympathetic neurons to the same extent as are epinephrine and norepinephrine. The
duration of action of isoproterenol may therefore be longer than that of epinephrine,
but is still brief.
Major drug Interactions:
o Isoproterenol should be used with caution, if at all, when potent inhalational
anesthetics such as halothane are employed because of potential to sensitize the
myocardium to effects of sympathomimetic amines.
References:
o Biaggioni I, Robertson D (2012): Adrenoceptor Agonists & Sympathomimetic Drugs
(Chapter 9). In: Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ
Trevor (Editors); McGraw-Hill (Access Medicine).
o rxlist.com (Isuprel )
o
o
Keywords
Dobutamine
Keywords
Albuterol
Keywords
Terbutaline
Keywords
Note:
Tyramine is found in relatively high concentrations in fermented foods such as
cheese, sausage, pepperoni, salami, pickled or smoked fish & yeast
supplements. Small amounts are found in red wine & chicken liver as well; See
Table 9-5 in ( Biaggioni & Robertson (2012)).
Reference:
o Biaggioni I, Robertson D (2012): Adrenoceptor Agonists & Sympathomimetic Drugs
(Chapter 9). In: Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ
Trevor (Editors); McGraw-Hill (Access Medicine).
o
Keywords
Indications:
o attention-deficit disorders
o narcolepsy
Contraindications:
o Lactation
o Contraindicated for long-term use for treating obesity (due to development of
tolerance &/or drug dependence)
Side Effects:
o nervousness
o insomnia
o palpitations
o hypertension
o hyperpyrexia
o headaches
o dizziness
o anorexia
o weight loss
o dryness of the mouth
Pharmacokinetics:
o Dexedrine - PO, completely absorbed in 3 hr. Duration: PO, 4-24 hr; t1/2, adults:
10-12 hr; children: 6-8 hr.
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Cocaine
Indications:
o Topical anesthesia of the upper respiratory tract (due to its combined
vasoconstrictor & local anesthetic properties)
o Use in Emergency Department as one ingredient in a topical anesthetic
solution called TAC (containing: Tetracaine, Adrenaline & Cocaine) that
is applied to a wound prior to cleaning & suturing
Contraindications:
o Hypersensitivity to ester anesthetics
Side Effects:
o Signs of systemic toxicity include signs of CNS stimulation:
tachycardia
hypertension
hyperthermia
mydriasis
seizures
o cardiac arrhythmias (multiple contributing variables: Na & K channel block,
possible coronary vasoconstriction)
very high potentially lethal plasma concentrations of cocaine (e.g. >30 uM) typically cause a fall
in blood pressure due to: a) a reduction in cardiac contractility due to cocaine block of L-type Ca
channels, and b) local anesthetic effects on vascular smooth muscle resulting in vasodilation.
Cocaine also does not typically produce an increase in heart rate under general anesthesia. These
cardiovascular effects are opposite of those typically seen in conscious animals (e.g.
simultaneous tachycardia & hypertension). This is because the simultaneous increase in blood
pressure and heart rate requires a functional CNS & result, in large part, from an increase in
sympathetic outflow from the CNS.
Black Box Warnings for Topical Cocaine: NOT FOR INJECTION OR OPTHALMIC USE
Not for injection or ophthalmic use.
Pharmacokinetics:
o A topical local anesthetic (its only FDA approved use)
o As a drug of abuse the HCl can be sniffed, taken orally or injected IV. The base form
(crack or freebase) is typically smoked
o Half life is ~50 min
Major drug Interactions:
o MAOI inhibitors would be expected to increase cocaine's effects & toxicity.
o Ethanol consumption will convert cocaine to cocaethylene, a derivative that
has a half life of 3-4 hours and shares a similar pharmacology as cocaine. Most
cocaine abusers consume ethanol to prolong their high. This may also increase
cocaine's cardiotoxicity.
Notes:
o One of the most addictive drugs known (Schedule II).
References:
o Biaggioni I, Robertson D (2012): Adrenoceptor Agonists & Sympathomimetic Drugs
(Chapter 9). In: Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ
Trevor (Editors); McGraw-Hill (Access Medicine).
o Clarkson CW, Xu YQ,Chang C,Follmer CH (1996): Analysis of the ionic basis for
cocaine's biphasic effect on action potential duration in guinea-pig ventricular
myocytes. J Mol Cell Cardiol 28:667678.
o Crumb WJ Jr, Clarkson CW (1992): Characterization of the sodium channel blocking
properties of the major metabolites of cocaine in single cardiac myocytes. J
Pharmacol Exp Ther 261:910917.
o Ferreira S, Crumb WJ Jr, Carlton CG, Clarkson CW (2001): Effects of Cocaine and Its
Major Metabolites on the HERG-Encoded Potassium Channel. J Pharmacol Exp Ther
299: 220-226.
o Luscher C (2012) Drugs of Abuse (Chapter 32). In: Basic & Clinical Pharmacology.
12e. Katzung BG, Masters SB, Trevor AJ (Editors). McGraw-Hill / Lange. (AccessMedicine)
o Prosser JM, Perrone J (2012): Cocaine, Methamphetamine, and Other Amphetamines
(Chapter 181). In: Harrison's Internal Medicine. 18th Edition. McGraw-Hill.
o rxlist.com (cocaine / topical)
Keywords
Imipramine
Mechanism of Action:
o Blocks reuptake of norepinephrine & serotonin at nerve endings (therapeutic
effects)
o Na channel blocker (contributes to cardiotoxicity)
o Antimuscarinic (contributes to side effects)
o Antihistamine (contributes to side effects)
o Alpha receptor blocking properties (contributes to side effects)
o Several weeks to months are required for antidepressant effects to appear (or be
significantly greater than a placebo), although its direct effects (e.g. on reuptake)
develop within a matter of hours.
Indications:
o Depression
o Chronic pain
o Nocturnal enuresis (a pediatric indication - attributed to its antimuscarinic side
effects)
Contraindications:
o Drugs that inhibit monoamine oxidase (MAOI's) taken w/in 14 days, acute recovery
period after a myocardial infarction, or history of drug hypersensitivity
Side Effects:
o drowsiness
o dry mouth & eyes
o constipation
o orthotstatic hypotension
o mild tremor
o sweating
o agitation
o nausea
o tinnitus
o Overdose & Treatment: See Amitriptyline; potentially fatal disturbances of cardiac
conduction (widening of QRS), arrhythmias & seizures due to Na channel block
(cardiac & CNS)
Pharmacokinetics:
o PO, metabolized in the liver (P450 - 2D6); 16 hr half life
Major drug Interactions:
o Decongestants
o Local anesthetics w/ sympathomimetics
o Antihypertensives
o CNS depressants
o Drugs metabolized by P450-2D6
o Concomitant use of MAOI's can cause potentially fatal hyperpyretic crisis & seizures
Reference:
o Biaggioni I, Robertson D (2012): Adrenoceptor Agonists & Sympathomimetic Drugs
(Chapter 9). In: Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ
Trevor (Editors); McGraw-Hill (Access Medicine).
o DeBattista C (2012): Antidepressant Agents. Chapter 30. In: Basic & Clinical
Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors). McGraw Hill / Lange.
o rxlist.com (Tofranil )
Keywords
Keywords
Alpha Blockers
Phenoxybenzamine
Keywords
Phentolamine
Indications:
o prevention or control of hypertensive episodes that may occur in a patient with
pheochromocytoma as a result of stress or manipulation during preoperative
preparation and surgical excision.
o prevention or treatment of dermal necrosis and sloughing following intravenous
administration or extravasation of norepinephrine.
o diagnosis of pheochromocytoma by the phentolamine blocking test
Contraindications:
o Myocardial infarction or history of myocardial infarction
o Coronary insufficiency, angina, or other evidence suggestive of coronary artery
disease
o Hypersensitivity to phentolamine or related compounds
Side Effects:
o Acute and prolonged hypotensive episodes
o Tachycardia
o Cardiac arrhythmias
Pharmacokinetics:
o Not well absorbed if taken orally, and is given either i.m. or i.v.
o It produces an -adrenergic block of relatively short duration (half-life in the blood of
19 minutes following intravenous administration)
References:
o Biaggioni I, Robertson D (2012): Adrenoceptor Antagonist Drugs (Chapter 10). In:
Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors);
McGraw-Hill (Access Medicine).
o rxlist.com (Phentolamine mesylate)
Keywords
Prazosin
Benowitz NL (2012): Antihypertensive agents (Chapter 11). In: Basic and Clinical
Pharmacology. 12e. BG Katzung, SB Masters, AJ Trevor (Editors). Lange/McGrawHill.
Biaggioni I, Robertson D (2012): Adrenoceptor Antagonist Drugs (Chapter 10). In:
Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors);
McGraw-Hill (Access Medicine).
rxlist.com (Minipress )
Keywords
Doxazosin
Keywords
Yohimbine
Keywords
Beta Blockers
Propranolol
Keywords
Metoprolol
Hume JR, Grant AO (2012): Agents used in cardiac arrhythmias (Chapter 14). In:
Basic and Clinical Pharmacology. 12e. Katzung BG, Masters SB, Trevor AJ (Editors).
McGraw-Hill / Lange.
Robertson D, Biaggioni I (2012): Adrenoceptor Antagonists (Chapter 10). In: Basic
and Clinical Pharmacology. 12e. Katzung BG, Masters SB, Trevor AJ (Editors).
McGraw-Hill / Lange.
rxlist.com (Toprol )
Keywords
Pindolol
Keywords
Labetalol
Keywords
Nebivolol
References:
o Benowitz NL (2012): Antihypertensive agents (Chapter 11). In: Basic and Clinical
Pharmacology. 12e. BG Katzung, SB Masters, AJ Trevor (Editors). Lange/McGrawHill.
o Robertson D, Biaggioni I (2012): Adrenoceptor Antagonists (Chapter 10). In: Basic
and Clinical Pharmacology. 12e. Katzung BG, Masters SB, Trevor AJ (Editors).
McGraw-Hill / Lange.
o rxlist.com (Bystolic )
Keywords
Bisoprolol
Keywords
Timolol
Keywords
Butoxamine
Keywords
Other Pressors
Angiotensin II