PG2 Autonomics ANSWERS F16 1 (PDF)

PHARMACOLOGY SMALL GROUP 2:
AUTONOMIC DRUGS
ANSWERS
1. Cardiovascular Effects Of Autonomic Drugs
Two new drugs (drug X and drug Y) are being studied for their cardiovascular
effects. Each drug is given to 5 rats and their heart rate is recorded. The first
animal has received no pretreatment (= control), the second has been
pretreated with prazosin, the third has been pretreated with hexamethonium,
the fourth has been pretreated with propranolol and the fifth has been
pretreated with atropine. The following tables show the effects of drug X and
drug Y on the heart rate of the 5 experimental animals:
A. DRUG X
PRE-TREATMENT
No pre-treatment (Control)
Prazosin
Hexamethonium
Propranolol
Atropine

EFFECT OF DRUG X
ON HEART RATE
↑
↑
↓
↓
No effect

Drug X is probably a drug similar, in mechanism of action, to:
A.
B.
C.
D.
E.

Nitric oxide
Acetylcholine *
Edrophonium
Norepinephrine
Phenylephrine

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B. DRUG Y
PRE-TREATMENT
No pre-treatment (Control)
Prazosin
Hexamethonium
Propranolol
Atropine

EFFECT OF DRUG Y
ON HEART RATE
↓
No effect
No effect
↓
No effect

Drug Y is probably a drug similar, in mechanism of action, to:
A.
B.
C.
D.
E.

Nitric oxide
Acetylcholine
Edrophonium
Norepinephrine
Phenylephrine *

BASIC STRATEGY FOR SOLVING QUESTIONS WITH
GANGLION BLOCKERS
1. Compare the effect of the unknown drug on the control animal with the effect
of the unknown drug on the animal pre-treated with the ganglion blocker.
2. If the two effects are the same there is no baroreceptor reflex involved and
both show the direct effect of the drug.
3. If they are different then the effect on the animal pre-treated with the ganglion
blocker shows the direct effect of the drug and the effect on the control
animal shows the effect of the baroreceptor reflex.
A. DRUG X
The control rat shows an increase in HR, whereas the HM-treated rat shows a
decrease in HR. This means that the direct cardiac effect of the drug is to
decrease HR. The increase in HR seen in the control rat is therefore the
consequence of the baroreflex. The drug must then evoke vasodilation.
Let’s consider the drugs one by one:
Nitric oxide: Nitric oxide would cause vasodilation and a reflex increase in HR
(mediated by activation of cardiac β1 receptors). But its effects would not be
abolished by atropine. Therefore NO cannot be drug X.

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Acetylcholine: Acetylcholine would cause vasodilation (via M3-mediated NO
release) and thus cause a reflex increase in HR (mediated by activation of
cardiac β1 receptors). Additionally: Atropine would abolish the effect of
acetylcholine (by blocking vascular M3 receptors). Prazosin, an α1 blocker, would
not have any effect on the effect of acetylcholine. Propranolol would block the
reflex tachycardia (by blocking cardiac β1 receptors). Therefore, acetylcholine fits
all the available data. Drug X is similar to acetylcholine.
Edrophonium: Edrophonium would not have any significant effect on the
vasculature (vascular M3 receptors are not innervated), therefore it would not
evoke reflex tachycardia in the control rat. Edrophonium would (indirectly) activate
cardiac M2 receptors, by inhibiting acetylcholinesterase, thus inducing
bradycardia in the control rat. This is not observed, therefore edrophonium cannot
be drug X. Additionally, edrophonium would have no effect in the HM-treated
animal, since HM would block release of acetylcholine.
Norepinephrine: Norepinephrine causes vasoconstriction (by activating vascular
α1 receptors). The baroreflex would cause a decrease in HR in the control rat (by
activation of cardiac M2 receptors). This is the opposite of what we see.
Therefore norepinephrine cannot be drug X.
Phenylephrine: Phenylephrine would cause vasoconstriction (α1 effect) and a
reflex drop in HR (mediated by activation of cardiac M2 receptors). Therefore
phenylephrine cannot be drug X.
B. DRUG Y
The control rat shows a decrease in HR, whereas the HM-treated rat shows no
effect. This means that drug Y has no direct effect on the heart. The decrease in
HR is therefore the consequence of the baroreflex. The drug must then evoke
vasoconstriction.
Let’s consider the drugs one by one:
Nitric oxide: Nitric oxide would cause vasodilation and a reflex increase in HR
(mediated by activation of cardiac β1 receptors). Therefore NO cannot be drug Y.
Acetylcholine: Acetylcholine would cause vasodilation (via M3-mediated NO
release) and a reflex increase in HR (mediated by activation of cardiac β1
receptors). Therefore acetylcholine cannot be drug Y.
Edrophonium: Edrophonium would activate cardiac M2 receptors, thus inducing
bradycardia in the control rat. Additionally, edrophonium would have no effect in
the HM-treated animal, since HM would block release of acetylcholine. However,
the effect of edrophonium would not be blocked by prazosin. Therefore
edrophonium cannot be drug Y.

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Norepinephrine: Norepinephrine causes vasoconstriction (by activating vascular
α1 receptors). The baroreflex would cause a decrease in HR in the control rat (by
activation of cardiac M2 receptors), as observed. Prazosin would block the α1mediated vasoconstriction, unmasking the direct β1 effects of norepinephrine on
the heart: in the presence of prazosin norepinephrine would then cause an
increase in HR (mediated by activation of cardiac β1 receptors). Also,
norepinephrine would cause an increase in HR in the presence of atropine. This
is not observed. Therefore norepinephrine cannot be drug Y.
Phenylephrine: Phenylephrine would cause vasoconstriction (α1 effect) and a
reflex drop in HR (mediated by activation of cardiac M2 receptors), as observed.
Also, prazosin would abolish the phenylephrine-evoked vasoconstriction and
therefore abolish the effect on HR, as seen. Propranolol, a β blocker, would have
no effect on phenylephrine actions. Finally, atropine would block the reflex
bradycardia evoked by phenylephrine (by blocking cardiac M2 receptors).
Therefore phenylephrine fits all the available data. Drug Y is similar to
phenylephrine.

2. Clinical case: Palpitations, anxiety and hypertension.
F.H., a 37 year-old man in good physical shape, presents with complaints of
sudden attacks of palpitations, diaphoresis, severe headaches, intense
anxiety and tremulousness. During such an attack, his BP was found to be
230/150 mm Hg. Current physicals are largely unremarkable (BP 130/70 mm
Hg, HR 72/min). A pheochromocytoma is suspected.
What is a pheochromocytoma? Describe the pathophysiology of the
disease and the typical clinical manifestations.
A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells
typically located in the adrenals. It causes persistent or paroxysmal hypertension.
Catecholamines typically secreted include norepinephrine and epinephrine;
rarely, dopamine is secreted. The clinical manifestations of a pheochromocytoma
result from excessive catecholamine secretion by the tumor. Stimulation of α1
receptors results in elevated blood pressure, glycogenolysis, gluconeogenesis,
and intestinal relaxation. Stimulation of β1-receptors results in an increase in
heart rate and contractility.
Catecholamine secretion in pheochromocytomas is not regulated in the same
manner as in healthy adrenal tissue. Unlike the healthy adrenal medulla,
pheochromocytomas are not innervated, and catecholamine release is not
precipitated by neural stimulation. The trigger for catecholamine release is
unclear, but multiple mechanisms have been postulated, including direct
pressure, medications, and changes in tumor blood flow.

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Hypertension is the most common clinical manifestation. In approximately 60% of
cases the hypertension is sustained, although significant blood pressure lability is
usually present, and half of patients with sustained hypertension have distinct
crises or paroxysms. The other 40% have blood pressure elevations only during
an attack. The hypertension is often severe, occasionally malignant, and may be
resistant to treatment with standard antihypertensive drugs.
Pheochromocytoma is the cause of hypertension in 0.1% of patients with
hypertension.
Patients may be completely asymptomatic. The majority of pheochromocytomas
are first discovered at autopsy. Approximately 10% of pheochromocytomas are
discovered incidentally.
About 90% of pheochromocytomas are located in the adrenal medulla, but they
may also be located in other tissues derived from neural crest cells.
Pheochromocytomas in the adrenal medulla occur equally in both sexes, are
bilateral in 10% of cases (20% in children), and are malignant in < 10%. Of extraadrenal tumors, 30% are malignant.
What is the differential diagnosis?
The differential diagnosis of pheochromocytoma includes a long list of conditions
that may suggest the presence of the tumor. Some of them are:











Adrenal medullary hyperplasia
Hyperthyroidism
Arrhythmias
Angina pectoris
Anxiety
Panic disorder
Cocaine
Sympathomimetic drugs
Alcohol withdrawal
Abrupt clonidine withdrawal

Many of these conditions can be excluded readily on the basis of a thorough
history and physical examination.
How is pheochromocytoma diagnosed?
The diagnosis of pheochromocytoma is established by the demonstration of
abnormally high concentrations of catecholamines or catecholamine metabolites
in plasma or urine.
The diagnosis can usually be made by the analysis of a single 24-h
urine sample, provided the patient is hypertensive or symptomatic at
the time of collection.
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The assays employed include those for vanillylmandelic acid (VMA), the
metanephrines, and catecholamines. The VMA assay is both less sensitive and
less specific than assays of metanephrines or catecholamines.
After biochemical confirmation of a tumor, imaging is necessary to locate it. CT or
MRI can be used for tumor localization. PET has also been used successfully.
How should F.H. be managed?
Surgical removal is the treatment of choice. The operation is usually delayed until
hypertension is controlled by a combination of α- and β-blockers (usually
phenoxybenzamine and propranolol). Note: β-Blockers should not be used until
adequate α-blockade has been achieved.
Preoperative Management
Once the diagnosis of pheochromocytoma is established, the patient should be
placed on phenoxybenzamine to induce a long-lasting, α-receptor blockade in
order to control blood pressure and eliminate the paroxysms. Phenoxybenzamine
should be administered for at least 10 to 14 days prior to surgery. Before
adequate α-adrenergic blockade with phenoxybenzamine is achieved, paroxysms
may be treated with oral prazosin or intravenous phentolamine.
Nitroprusside, calcium channel blocking agents, and possibly angiotensinconverting enzyme inhibitors reduce blood pressure in patients with
pheochromocytoma. Nitroprusside may also be useful in the treatment of pressor
crises.
Why would it be deleterious to treat an attack with a β-blocker (e.g.
propranolol) alone?
Activation of vascular β2 receptors leads to vasodilation. Therefore,
administration of a β-blocker would evoke an increase in blood pressure by
blocking β2 receptor-mediated vasodilation in skeletal muscle.
β-blockers must be administered only after adequate α blockade has been
induced, because unopposed α-adrenergic receptor stimulation by circulating
catecholamines can precipitate a hypertensive crisis.
β -blockers are usually administered if significant tachycardia occurs after the
induction of α blockade.
Surgical removal of the tumor
An experienced anesthesiologist and an experienced surgeon are crucial to the
success of the operation. Surgical mortality rates are less than 2-3% with an
experienced anesthesiologist and surgeon.

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Hypertension and cardiac arrhythmias are most likely during induction of
anesthesia, intubation, and manipulation of the tumor. Intravenous phentolamine
is usually sufficient to control the blood pressure, but nitroprusside may be
required. Propranolol may be given in the treatment of tachycardia or ventricular
ectopy.
Complete removal cures the hypertension in approximately ¾ of patients. In the
remainder, hypertension recurs but is usually well controlled by standard
antihypertensive agents.
Unresectable And Malignant Tumors
In cases of metastatic or locally invasive tumor in patients with intercurrent illness
that precludes surgery, long-term medical management is required. When the
manifestations cannot be adequately controlled by adrenergic blocking agents,
the concomitant administration of metyrosine may be required. Metyrosine inhibits
tyrosine hydroxylase, diminishes catecholamine production by the tumor, and
often simplifies chronic management.

3. Clinical case: Sudden Onset of Ocular Pain
D.H., a 72-year-old man, presents to the emergency department with an
intensely red right eye, a “steamy” appearing cornea, complaints of haloes
around lights, and extreme pain. A diagnosis of acute angle-closure
glaucoma is made.
What is glaucoma? What is angle-closure glaucoma?
Glaucoma is a group of eye disorders characterized by progressive optic nerve
damage at least partly due to increased intraocular pressure (IOP).
Glaucoma can be categorized as open-angle or closed-angle (angle-closure) The
“angle” refers to the angle formed by the junction of the iris and cornea at the
periphery of the anterior chamber. The angle is where > 98% of the aqueous
humor exits the eye via either the trabecular meshwork and Schlemm's canal (the
major pathway, particularly in the elderly) or the ciliary body face and choroidal
vasculature.
Closed angle glaucoma is glaucoma associated with a physically obstructed
anterior chamber angle. Symptoms of acute closed angle glaucoma are severe
ocular pain and redness, decreased vision, colored halos around lights,
headache, nausea, and vomiting. Intraocular pressure (IOP) is elevated.

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What are other possible causes of acute, severe ocular pain?
Other causes of acute, severe ocular pain associated with visual loss include
corneal disorder, anterior uveitis, scleritis, endophthalmitis, optic neuritis.
What are other possible causes of red eye?
Other causes of red eye include conjunctival causes (e.g. keratoconjunctivitis),
corneal causes (e.g. keratitis), other causes (e.g. trauma)
How is glaucoma diagnosed?
The diagnosis of acute closed angle glaucoma is based upon the clinical
presentation of painful vision loss and a physical examination revealing a fixed
mid-dilated pupil. Tonometry must be performed and must demonstrate
increased IOP.
What is the pathophysiology of the disease?
In people with narrow angles, the distance between the pupillary iris and the lens
is also very narrow. Dilation of the iris can block aqueous humor outflow
resulting in rapid (within hours) and severe (> 40 mm Hg) elevation of IOP.
Because of the rapid onset, this condition is called primary acute angle-closure
glaucoma.
Axons of retinal ganglion cells travel through the optic nerve carrying images from
the eye to the brain. Damage to these axons causes ganglion cell death with
resultant optic nerve atrophy and patchy vision loss. Elevated IOP plays a role in
axonal damage, either by direct nerve compression or diminution of blood flow.
The relationship between pressure and nerve damage is variable. Of people with
IOP > 21 mm Hg (ie, ocular hypertension), only about 1 to 2%/yr (roughly 10%
over 5 yr) develop glaucoma. Additionally, about 1/3 of patients with glaucoma do
not manifest IOPs > 21 mm Hg (known as low-tension glaucoma or normaltension glaucoma).
IOP is determined by the balance of aqueous secretion and drainage. Elevated
IOP is caused by inhibited or obstructed outflow, not oversecretion.
In open-angle glaucoma, IOP is elevated because outflow is inadequate despite
an angle that appears unobstructed. In angle-closure glaucoma, IOP is elevated
when a physical distortion of the peripheral iris mechanically blocks outflow.

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What can trigger an attack of acute angle-closure glaucoma?
In people with narrow angles an attack may be precipitated by dilation of pupils
due to darkness, dim light, stress or excitement.
Is acute angle-closure glaucoma an emergency? Why?
Yes. Acute angle closure glaucoma is an ophthalmic emergency requiring
immediate treatment with multiple topical and systemic drugs to prevent
permanent vision loss.
How should D.H. be managed?
Treatment must be initiated immediately, because vision can be lost quickly and
permanently.
The treatment of acute angle-closure glaucoma consists of IOP reduction,
suppression of inflammation, and reversal of angle closure.
The initial intervention includes systemic acetazolamide, a topical βblocker, apraclonidine, and a topical glucocorticoid.
Acetazolamide is given IV followed by oral administration. A dose of a topical βblocker (eg timolol) also aids in lowering IOP. Both β-blockers and acetazolamide
decrease aqueous humor production and enhance opening of the angle. An αagonist, such as apraclonidine, can be added for a further decrease in IOP.
Inflammation is an important part of the pathophysiology of acute angle-closure
glaucoma. Topical glucocorticoids decrease the inflammatory reaction and reduce
optic nerve damage.
Approximately 1 hour after beginning treatment, pilocarpine, a miotic that leads
to opening of the angle, should be administered. In the initial attack, the elevated
pressure in the anterior chamber causes a pressure-induced ischemic paralysis
of the iris. At this time, pilocarpine is ineffective. After one hour the initial agents
have decreased the elevated IOP and reduced the ischemic paralysis so
pilocarpine becomes beneficial in relieving pupillary block.
If the IOP is not reduced 30 minutes after pilocarpine, an osmotic agent must be
considered. An oral agent like glycerol can be administered in nondiabetics. In
diabetics, oral isosorbide is used to avoid the risk of hyperglycemia associated
with glycerol. Patients who are unable to tolerate oral intake or do not experience
a decrease in IOP despite oral therapy should be given IV mannitol.

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