Case History #1: Pilocarpine

Local 1% pilocarpine was ordered by instillation

every six hours for a 64 year old man with chronic,
open-angle glaucoma. His vision had been declining
for a number of years, although he was not really
aware of it. The intraocular pressure (IOP) dropped
from 35 mm Hg to 18 mm Hg (normal pressure limits
are 10 to 22 mm Hg) following instillation. He
complained of brow ache for the first few days and
some dimness of vision, although visual acuity was
not altered. He also wonders why he should use the
drug now as he has already lost a lot of sight.



Questions:
Why (and how) does pilocarpine lower the IOP?
Why are there side effects of brow ache and dimness of
vision?
What other side effects may be associated with
pilocarpine?
How [and why] would you encourage compliance?



What is glaucoma?
BLOCKED
OR FAULTY



Open-angle Glaucoma



Mechanism of action pilocarpine in OAG
Pilocarpine lowers IOP
by increasing the fluid
outflow






Pilocarpine 1% solution
Well absorbed by the cornea and released slowly in to
the aqueous humor
Applied topically in the eye
Produces a reduction in IOP that starts after one hour
and lasts for 4 - 8 hours.
Administered every 6 hours to ensure good reduction
in IOP
Increases outflow by stimulating the ciliary muscles,
pulling traction on the scleral spur and the trabecular
mesh work



Side effects:
Temporary irritation/burning/stinging of the eye
temporary blurred vision
poor vision in dim light
headache, or brow ache



Diarrhea
Diaphoresis
Miosis
Nausea
Urinary urgency
Other side effects



Case History #2:Organophosphates
A forty-eight year old man required the use of
echothiophate by instillation twice daily for the
control of his glaucoma. After about two weeks on the
drops he developed a definite change in bowel habits
consisting of a mild diarrhea. He consulted his
internist about this, who, after a presumably thorough
history, ordered a complete GI series which was
negative. He then did a proctoscopy, a sigmoidoscopy,
a test for occult blood in the stools, stool cultures, and
stool smears. All were negative.



Case History #2:Organophosphates
About one month later the patient went out to
spray his orchard with parathion. He was found dead
two hours later by his wife under a peach tree in full
bloom. The death was said to be due to the careless
handling of a dangerous insecticide.



Questions:
What is echothiophate?
What about the diarrhea? What other problems
may he have experienced?
What factors may have been responsible for the
patient's death?
Explain how parathion poisoning should be
treated.



Echothiophate iodide
A long-acting cholinesterase inhibitor for
topical use
Approx.100 hours duration of action
Depresses both plasma and erythrocyte
cholinesterase levels in most patients
after a few weeks of eyedrop therapy



Echothiophate iodide
for ophthalmic solution
enhances the effect of endogenously liberated Ach in
iris, ciliary muscle, and other parasympathetically
innervated structures of the eye causing;
Miosis
increase in facility of outflow of aqueous humor
fall in intraocular pressure, and
potentiation of accommodation



Adverse effects of ophthalmic
solution of echothiophate
Stinging, burning
Lacrimation
Lid muscle twitching
Conjunctival and ciliary redness
Browache
Induced myopia with visual blurring
Iritis or uveitis



GI effects of Echothiophate
Attributed to muscarinic effects in the GIT
Increases secretory and motor activity in the gut
Increased peristaltic activity
diarrhea



To avoid systemic effects;
Digital compression of the
nasolacrimal ducts for a
minute or two following
instillation to minimize
drainage into the nasal
chamber
Hands should be washed
following instillation



Other problems related to
muscarinic toxicity
Miosis
Salivation
Sweating
Bronchial constriction
Cognitive disturbances
Convulsions
Coma



Echothiophate and Parathion
Both are cholinesterase inhibitors
Additive systemic effects of both drugs could have
been the cause of patients death
Possibly from absorption of the pesticide through the
respiratory tract or skin



Precaution
During periods of exposure to such pesticides, advise
patient to;
wear respiratory masks
wash hand frequently
change clothing



Treatment of organophosphate
poisoning
Airway control and adequate oxygenation
Remove all clothing and gently cleanse patients
suspected of organophosphate exposure with soap and
water
organophosphates are hydrolyzed readily in aqueous
solutions with a high pH
Irrigate the eyes of patients
isotonic sodium chloride solution or lactated Ringer's
solution



For health care worker
In decontaminating the patient;
Use personal protective equipment such as neoprene
gloves and gowns because hydrocarbons can penetrate
nonpolar substances such as latex and vinyl
Use charcoal cartridge masks for respiratory protection



Drugs for organophosphate poisoning
Atropine IV/IM
Competitive inhibitor at autonomic postganglionic
cholinergic receptors, including receptors found in GI
and pulmonary smooth muscle, exocrine glands, heart,
and eye
Purpose: reduce respiratory secretion, thus improve
oxygenation
Pralidoxime (2-PAM)
Benzodiazepines



Pralidoxime (2-PAM)
2-PAM (2-pyridine aldoxime methyl chloride)
Antidote for OP poisoning by reactivating the
phosphorylated AChE
2-PAM attaches to the site where the cholinesterase
inhibitor has attached to and blocked cholinesterase
2-PAM then attaches to the cholinesterase inhibitor and
removes it from cholinesterase, allowing the enzyme to
work normally again
sometimes referred to as regeneration of cholinesterase



AchE action



AchE inhibitors action
Organophosphate



Possibilities after cholinesterase inhibition
1.Hydrolyze to
original state (slow)
reversibility of
enzyme inhibition
2. Regenerate with an oxime (fast)
3. Age (cannot regenerate)



How 2-PAM works?



Pralidoxime (2-PAM)
Prevent aging of AChE and reverse muscle paralysis
with OP poisoning
Not effective once the OP compound has bound AChE
irreversibly (aged)
Should be administered within 48 h of OP poisoning



Pralidoxime (2-PAM)
Does not significantly relieve depression of respiratory
center or decrease muscarinic effects of AChE
poisoning
administer atropine concomitantly to block these effects
Signs of atropinization might occur earlier with
addition of 2-PAM to treatment regimen
2-PAM administration is not indicated for carbamate
exposure since no aging occurs



Case History #3:
Timolol and EchothiophateIodide
Two severe episodes of acute asthma prompted
evaluation of a 63-year old man in the pulmonary clinic.
The patient had had symptoms of atopic asthma up to the
age of 20 but had remained asymptomatic since. Three
weeks before he experienced the first asthmatic attack, he
had begun using Timoptic (timolol) eye drops, O.5%
solution, gtts i o.u., bid, for treatment of open-angle
glaucoma. Phospholine iodide (Echothiophate iodide),
0.05% solution, gtts i o.u., bid, was substituted for timolol
resulting in adequate control of the glaucoma but the
patient suffered another asthmatic attack 6 weeks later.



Case History #3:
Timolol and Echothiophate Iodide
On the day following this last asthmatic attack he was
involved in an auto accident and went into shock from
blood loss. He was hospitalized and taken to surgery for
wound repair. After anesthesia was instituted,
succinylcholine was administered intravenously to secure
relaxation of the laryngeal and pharyngeal muscles for
intubation. The patient become apneic and remained so
for the next eight hours. The anesthetist noted this
promptly and instituted artificial respiration which he
continued for the rest of the day. In the meantime, the
wounds were repaired and the surgical shock was
effectively treated by appropriate measures. Recovery was
uneventful.



Questions
1. What is timolol and what is it's mechanism of action?
2. Could the asthmatic attacks be associated with the use
of either of the ophthalmic solutions used by the
patient?
3. Why the prolonged apnea in this case?
4.Could the apnea have been treated more
expeditiously?



Timolol
A non-selective beta-receptor blocker
No partial agonist activity
No local anesthetic action
Elimination half-life is 4-5 hours
Applied topically in the eye for the treatment of
glaucoma
Lowers IOP by decreasing aqueous secretion from the
ciliary epithelium



Secretion of the aqueous humor



Mode of Action of Timolol in Medical
Treatment of Glaucoma
This invention demonstrates that in contrast to
previously believed c-AMP-mediated mechanism,
timolol, the widely-used therapeutic agent for
glaucoma, acts by specifically blocking either the
sodium-proton or the bicarbonate-chloride
exchanger. Both of these mechanisms are considered
critical in supporting the formation of aqueous humor
of the eye.
http://upenn.technologypublisher.com/technology/3995



Strategies for the treatment of
Glaucoma
Reduction of aqueous humor production
Beta blockers such as timolol, betaxolol, carteolol,
levobunolol, metipranol
Alpha-2 selective agonist apraclonidine, brimonidine
Diuretics CAIs (oral/topical)
Acetazolamide. Dichlorphenamide, methazolamide (oral)
Dorzolamide, brinzolamide (topical)
Enhancement of aqueous humor outflow



Strategies for the treatment of
Glaucoma
Reduction of aqueous humor production
Enhancement of aqueous humor outflow
Cholinergics pilocarpine, carbachol, physostigmine,
echothiophate, demecarium
Non-selective alpha agonist epinephrine, dipiverin
Prostaglandins latanaprost, bimatoprost, travaprost,
unoprostone



Immunohistochemical data have shown that the
IOP reduction with topical PGF2-alpha is associated
with a reduction of collagens within the
uveoscleral outflow pathway. The ciliary body
contains several prostaglandin receptors (mainly FP
and EP2 receptors), whose activation seems to
stimulate a second messenger cascade for
metalloproteinases synthesis (metalloproteinases are
enzymes involved in extracellular matrix remodeling).
Latanoprost ophthalmic solution in the treatment of open angle
glaucoma or raised intraocular pressure: a review



EFFECTS OF BETA BLOCKERS
In the eye
Reduce intraocular pressure
Used therapeutically in glaucoma
In the respiratory tract
Increase airway resistance (beta-2)
Selective beta-1 blockers do not exhibit this effect
Atenolol is the prototype drug of selective beta-1 blockers
Should be avoided by patients with COPD/asthma



Endocrine effects Beta blockers
Non-selective beta blockers are contraindicated in
diabetic patients
This is because catecholamines utilize the beta
2
receptor to
promote glycogenolysis and mobilize glucose
Selective beta
1
blockers should be used with caution
in patients with diabetes
In addition all beta blockers mask the tachycardia
associated with hypoglycemia
As a result, the diabetic patient is deprived of one of the
earliest physiologic responses to hypoglycemia



EFFECTS OF BETA BLOCKERS
Not related to beta blockade
Intrinsic sympathomimetic activity
Observed in partial beta agonist (e.g. Pindolol)
Sometimes desired to prevent the untoward effects like
exacerbation of asthma or excessive bradycardia
Local anesthetic action (membrane-stabilizing action)
Due to blockade of sodium channel
Not used topically in the eye
Sotalol (non-selective beta blocker) lacks local anesthetic
action



Prolonged Apnea.
Echothiophate potentiated the effects of
succinylcholine
Relaxation of the respiratory muscle
Respiratory failure
Deficiency in plasma cholinesterase due to blood loss



Case Study # 4
A 46-year-old woman sees her physician because
of palpitations and headaches. She enjoyed good
health until 1 year ago when spells of cardiac
palpitations began. These became more severe and
were eventually accompanied by throbbing headaches
and drenching sweats. Physical examination reveals a
blood pressure of 150/90 mm Hg and heart rate of 88
bpm.



During the physical examination, palpation of the
abdomen elicits a sudden and typical episode, with a
rise in blood pressure to 210/120 mm Hg, heart rate to
122 bpm, and facial pallor. This is accompanied by
severe headache and profuse sweating.
What is the likely cause of her episodes?
What caused the blood pressure and heart rate to rise
so high during the examination?
What treatments might help this patient?



Pheochromocytoma
A tumor of the adrenal medulla or sympathetic
ganglion cells
Tumor secretes catecholamines especially NE and EPI
Diagnosis:
Elevated plasma and urinary level of catecholamines
Imaging CT scan and MRI using radiomarkers such as
MIBG (
131
I-meta-iodobenzylguanidine)
Release of stored catecholamines may be spontaneous,
but it can be triggered by physical pressure, chemical
stimulation



Common symptoms in
pheochromocytoma
Hypertension
Headache
Sweating
Other symptoms include;
heart palpitations
Pallor
shortness of breath
Weakness
symptoms that resemble panic attacks



Treatment
Nitroprusside and alpha blockers
For hypertension during operative manipulation of
pheochromocytoma
Phenoxybenzamine
Clinically useful in the management of
pheochromocytoma
Useful in the chronic treatment of inoperable or
metastatic pheochromocytoma
Metyrosine
Inhibits tyrosine hydroxylase









SELECTIVE ALPHA
1
-ANTAGONISTS
Prazosin and Prazosin analogs
Terazosin, Doxazosin, Trimazosin
Reversible antagonists
CARDIOVASCULAR EFFECTS
Relaxes arterial and venous smooth muscle as
well as nonvascular smooth muscle.
Decreases peripheral vascular resistance and
venous return.
Decreases systemic arterial blood pressure
without a significant increase in heart rate.



SELECTIVE ALPHA
1
-ANTAGONISTS
OTHER EFFECTS
Miosis and nasal stuffiness
Decrease resistance to the flow of urine



SELECTIVE ALPHA
1
-ANTAGONISTS
CLINICAL USES
Treatment of Hypertension
Treatment of urinary retention due to
prostatic hyperplasia (Benign prostatic
hypertrophy)
SIDE EFFECTS
Orthostatic hypotension
Nasal stuffiness
Inhibition of ejaculation
Syncope - Prazosin



SELECTIVE ALPHA
1
-ANTAGONISTS
Prazosin and Prazosin analogs (terazosin, doxazosin,
trimazosin)



NON-SELECTIVE ALPHA BLOCKERS
Phentolamine
Competitive antagonist
Used in erectile dysfunction in combination
with papaverine (a non-specific smooth muscle
relaxant)
Phenoxybenzamine
Irreversibly blocks alpha receptors
Blocks H1, Ach, and SE receptors as well as alpha
receptors
Used clinically in pheochromocytoma



Other uses of alpha blockers
In peripheral vascular disease
Ocassionally , in Raynauds phenomenon
Chronic hypertension*
Hypertensive emergencies
Prazosin family
* With limited application



SOME ADVERSE EFFECTS COMMONLY
OBSERVED WITH ALPHA BLOCKERS
Orthostatic hypotension
Tachycardia
Vertigo
Sexual dysfunction