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Local 1% pilocarpine was ordered by instillation every six hours for a 64 year old man
Local 1% pilocarpine was ordered by instillation every six hours for a 64 year old man

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

Local 1% pilocarpine was ordered by instillation every six hours for a 64 year old man

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

Case History #1: Pilocarpine

from 35 mm Hg to 18 mm Hg (normal pressure limits

not altered. He also wonders why he should use the

drug now as he has already lost a lot of sight.

  • How [and why] would you encourage compliance?

  • Why (and how) does pilocarpine lower the IOP?

Questions:

  • 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?  Why (and how) does pilocarpine lower the
What is glaucoma? OR FAULTY BLOCKED
What is glaucoma? OR FAULTY BLOCKED
What is glaucoma?
OR FAULTY
BLOCKED
Open-angle Glaucoma
Open-angle Glaucoma
Open-angle Glaucoma

Open-angle Glaucoma

Mechanism of action pilocarpine in OAG Pilocarpine lowers IOP by increasing the fluid outflow
Mechanism of action pilocarpine in OAG Pilocarpine lowers IOP by increasing the fluid outflow
Mechanism of action pilocarpine in OAG
Pilocarpine lowers IOP
by increasing the fluid
outflow
 Applied topically in the eye  Produces a reduction in IOP that starts after one
 Applied topically in the eye  Produces a reduction in IOP that starts after one
 Applied topically in the eye  Produces a reduction in IOP that starts after one
  • Applied topically in the eye

  • Produces a reduction in IOP that starts after one hour and lasts for 4 - 8 hours.

  • Well absorbed by the cornea and released slowly in to

  • Administered every 6 hours to ensure good reduction

Pilocarpine 1% solution

the aqueous humor

in IOP

 Applied topically in the eye  Produces a reduction in IOP that starts after one
  • Increases outflow by stimulating the ciliary muscles, pulling traction on the scleral spur and the trabecular mesh work

  • headache, or brow ache

  • poor vision in dim light

  • temporary blurred vision

Side effects:

  • Temporary irritation/burning/stinging of the eye

 headache, or brow ache  poor vision in dim light  temporary blurred vision Side
 headache, or brow ache  poor vision in dim light  temporary blurred vision Side
 Urinary urgency  Diaphoresis  Diarrhea  Nausea  Miosis
 Urinary urgency
 Diaphoresis
 Diarrhea
 Nausea
 Miosis
 Urinary urgency  Diaphoresis  Diarrhea  Nausea  Miosis Other side effects
Other side effects
Other side effects
A forty-eight year old man required the use of drops he developed a definite change in

A forty-eight year old man required the use of

drops he developed a definite change in bowel habits

negative. He then did a proctoscopy, a sigmoidoscopy,

Case History #2:Organophosphates

consisting of a mild diarrhea. He consulted his internist about this, who, after a presumably thorough history, ordered a complete GI series which was

echothiophate by instillation twice daily for the control of his glaucoma. After about two weeks on the

a test for occult blood in the stools, stool cultures, and stool smears. All were negative.

handling of a dangerous insecticide.

bloom. The death was said to be due to the careless

two hours later by his wife under a peach tree in full

spray his orchard with parathion. He was found dead

Case History #2:Organophosphates

About one month later the patient went out to

handling of a dangerous insecticide. bloom. The death was said to be due to the careless

patient's death?

  • What is echothiophate?

Questions:

  • What factors may have been responsible for the

patient's death?  What is echothiophate? Questions:  What factors may have been responsible for the
  • What about the diarrhea? What other problems may he have experienced?

  • Explain how parathion poisoning should be treated.

topical use  Approx.100 hours duration of action after a few weeks of eyedrop therapy 

topical use

  • Approx.100 hours duration of action

after a few weeks of eyedrop therapy

  • A long-acting cholinesterase inhibitor for

Echothiophate iodide

topical use  Approx.100 hours duration of action after a few weeks of eyedrop therapy 
  • Depresses both plasma and erythrocyte cholinesterase levels in most patients

iris, ciliary muscle, and other parasympathetically innervated structures of the eye causing;

iris, ciliary muscle, and other parasympathetically innervated structures of the eye causing;  Miosis  fall
  • Miosis

  • fall in intraocular pressure, and

Echothiophate iodide

  • increase in facility of outflow of aqueous humor

for ophthalmic solution

  • enhances the effect of endogenously liberated Ach in

    • potentiation of accommodation

  • Browache

  • Lacrimation

  • Iritis or uveitis

  • Stinging, burning

  • Lid muscle twitching

  • Conjunctival and ciliary redness

  • Induced myopia with visual blurring

Adverse effects of ophthalmic solution of echothiophate

 Browache  Lacrimation  Iritis or uveitis  Stinging, burning  Lid muscle twitching 
  • diarrhea

  • Increased peristaltic activity

  • Attributed to muscarinic effects in the GIT

    • Increases secretory and motor activity in the gut

 diarrhea  Increased peristaltic activity  Attributed to muscarinic effects in the GIT  Increases

GI effects of Echothiophate

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

To avoid systemic effects;  Digital compression of the nasolacrimal ducts for a minute or two
To avoid systemic effects;  Digital compression of the nasolacrimal ducts for a minute or two
  • Coma

  • Miosis

  • Salivation

  • Sweating

  • Convulsions

  • Bronchial constriction

  • Cognitive disturbances

 Coma  Miosis  Salivation  Sweating  Convulsions  Bronchial constriction  Cognitive disturbances

Other problems related to muscarinic toxicity

  • Possibly from absorption of the pesticide through the respiratory tract or skin

 Possibly from absorption of the pesticide through the respiratory tract or skin Echothiophate and Parathion

Echothiophate and Parathion

  • Both are cholinesterase inhibitors been the cause of patient’s death

  • Additive systemic effects of both drugs could have

Precaution  During periods of exposure to such pesticides, advise patient to;  wear respiratory masks

Precaution

  • During periods of exposure to such pesticides, advise

patient to;  wear respiratory masks  wash hand frequently  change clothing
patient to;
 wear respiratory masks
 wash hand frequently
 change clothing

water

  • Irrigate the eyes of patients

  • Airway control and adequate oxygenation

water  Irrigate the eyes of patients  Airway control and adequate oxygenation Treatment of organophosphate

Treatment of organophosphate poisoning

  • Remove all clothing and gently cleanse patients suspected of organophosphate exposure with soap and

    • organophosphates are hydrolyzed readily in aqueous solutions with a high pH

    • isotonic sodium chloride solution or lactated Ringer's solution

  • In decontaminating the patient;

nonpolar substances such as latex and vinyl

  • Use charcoal cartridge masks for respiratory protection

For health care worker

 In decontaminating the patient; nonpolar substances such as latex and vinyl  Use charcoal cartridge
  • Use personal protective equipment such as neoprene gloves and gowns because hydrocarbons can penetrate

  • and pulmonary smooth muscle, exocrine glands, heart,
    Purpose: reduce respiratory secretion, thus improve

  • Pralidoxime (2-PAM)

Drugs for organophosphate poisoning

  • Benzodiazepines

  • Atropine IV/IM

oxygenation

and eye

and pulmonary smooth muscle, exocrine glands, heart,  Purpose: reduce respiratory secretion, thus improve  Pralidoxime
  • Competitive inhibitor at autonomic postganglionic cholinergic receptors, including receptors found in GI

work normally again inhibitor has attached to and blocked cholinesterase  2-PAM attaches to the site

work normally again

inhibitor has attached to and blocked cholinesterase

  • 2-PAM attaches to the site where the cholinesterase

    • sometimes referred to as “regeneration” of cholinesterase

Pralidoxime (2-PAM)

  • Antidote for OP poisoning by reactivating the phosphorylated AChE

    • 2-PAM then attaches to the cholinesterase inhibitor and removes it from cholinesterase, allowing the enzyme to

  • 2-PAM (2-pyridine aldoxime methyl chloride)

AchE action
AchE action

AchE action

AchE inhibitor’s action

Organophosphate
Organophosphate
Organophosphate
Organophosphate

Possibilities after cholinesterase inhibition

2. Regenerate with an oxime (fast) 3. “Age” (cannot regenerate) 1.Hydrolyze to original state (slow) –
  • 2. Regenerate with an oxime (fast)

  • 3. “Age” (cannot regenerate)

1.Hydrolyze to original state (slow) – reversibility of enzyme inhibition
1.Hydrolyze to
original state (slow)
– reversibility of
enzyme inhibition

How 2-PAM works?

How 2-PAM works?
How 2-PAM works?
How 2-PAM works?
with OP poisoning  Not effective once the OP compound has bound AChE irreversibly (aged) 
  • with OP poisoning
    Not effective once the OP compound has bound AChE irreversibly (aged)

  • Prevent aging of AChE and reverse muscle paralysis

  • Should be administered within 48 h of OP poisoning

Pralidoxime (2-PAM)

exposure since no aging occurs  2-PAM administration is not indicated for carbamate  administer atropine

exposure since no aging occurs

  • 2-PAM administration is not indicated for carbamate

    • administer atropine concomitantly to block these effects

  • Does not significantly relieve depression of respiratory

Pralidoxime (2-PAM)

  • center or decrease muscarinic effects of AChE poisoning
    Signs of atropinization might occur earlier with addition of 2-PAM to treatment regimen

Case History #3:

solution, gtts i o.u., bid, for treatment of open-angle

had begun using Timoptic (timolol) eye drops, O.5%

age of 20 but had remained asymptomatic since. Three

weeks before he experienced the first asthmatic attack, he

The patient had had symptoms of atopic asthma up to the

Case History #3: solution, gtts i o.u., bid, for treatment of open-angle had begun using Timoptic

glaucoma. Phospholine iodide (Echothiophate iodide), 0.05% solution, gtts i o.u., bid, was substituted for timolol

Two severe episodes of acute asthma prompted evaluation of a 63-year old man in the pulmonary clinic.

resulting in adequate control of the glaucoma but the patient suffered another asthmatic attack 6 weeks later.

Timolol and Echothiophate Iodide

Timolol and Echothiophate Iodide

for the next eight hours. The anesthetist noted this

promptly and instituted artificial respiration which he

relaxation of the laryngeal and pharyngeal muscles for

intubation. The patient become apneic and remained so

uneventful.

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

Case History #3:
Case History #3:

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

  • 2. Could the asthmatic attacks be associated with the use of either of the ophthalmic solutions used by the patient?

2. Could the asthmatic attacks be associated with the use of either of the ophthalmic solutions

expeditiously?

Questions

  • 3. Why the prolonged apnea in this case?

4.Could the apnea have been treated more

  • 1. What is timolol and what is it's mechanism of action?

Timolol

  • No local anesthetic action

  • No partial agonist activity

  • Elimination half-life is 4-5 hours

  • A non-selective beta-receptor blocker

Timolol  No local anesthetic action  No partial agonist activity  Elimination half-life is 4-5
  • 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
Secretion of the aqueous humor
Secretion of the aqueous humor

of the eye. “

http://upenn.technologypublisher.com/technology/3995

critical in supporting the formation of aqueous humor

  • “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

of the eye. “ http://upenn.technologypublisher.com/technology/3995 critical in supporting the formation of aqueous humor  “This invention

Mode of Action of Timolol in Medical Treatment of Glaucoma

  • Dorzolamide, brinzolamide (topical)

  • Diuretics – CAI’s (oral/topical)

    • Acetazolamide. Dichlorphenamide, methazolamide (oral)

  • Reduction of aqueous humor production

  • Enhancement of aqueous humor outflow

    • Alpha-2 selective agonist apraclonidine, brimonidine

    • Beta blockers such as timolol, betaxolol, carteolol, levobunolol, metipranol

 Dorzolamide, brinzolamide (topical)  Diuretics – CAI’s (oral/topical)  Acetazolamide. Dichlorphenamide, methazolamide (oral)  Reduction

Strategies for the treatment of Glaucoma

  • Reduction of aqueous humor production

  • Enhancement of aqueous humor outflow

    • Cholinergics pilocarpine, carbachol, physostigmine, echothiophate, demecarium

    • Prostaglandins latanaprost, bimatoprost, travaprost, unoprostone

    • Non-selective alpha agonist epinephrine, dipiverin

 Reduction of aqueous humor production  Enhancement of aqueous humor outflow  Cholinergics – pilocarpine,

Strategies for the treatment of Glaucoma

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”

and EP2 receptors), whose activation seems to stimulate a second messenger cascade for

“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

metalloproteinases synthesis (metalloproteinases are enzymes involved in extracellular matrix remodeling).” “ Latanoprost ophthalmic solution in the
  • Used therapeutically in glaucoma

    • Atenolol is the prototype drug of selective beta -1 blockers

  • Selective beta-1 blockers do not exhibit this effect

  • Increase airway resistance (beta -2)

  • Should be avoided by patients with COPD/asthma

  • Reduce intraocular pressure

  • In the respiratory tract

  • In the eye

 Used therapeutically in glaucoma  Atenolol is the prototype drug of selective beta -1 blockers

EFFECTS OF BETA BLOCKERS

diabetic patients

  • Non-selective beta blockers are contraindicated in

Endocrine effects Beta blockers

  • As a result, the diabetic patient is deprived of one of the earliest physiologic responses to hypoglycemia

  • This is because catecholamines utilize the beta 2 receptor to promote glycogenolysis and mobilize glucose

  • In addition all beta blockers mask the tachycardia associated with hypoglycemia

diabetic patients  Non-selective beta blockers are contraindicated in Endocrine effects Beta blockers  As a
  • Selective beta 1 blockers should be used with caution in patients with diabetes

 Due to blockade of sodium channel  Not used topically in the eye  Not
  • Due to blockade of sodium channel

  • Not used topically in the eye

  • Not related to beta blockade

exacerbation of asthma or excessive bradycardia

  • Intrinsic sympathomimetic activity

    • Observed in partial beta agonist (e.g. Pindolol)

    • Sometimes desired to prevent the untoward effects like

  • Local anesthetic action (“membrane -stabilizing” action)

  • EFFECTS OF BETA BLOCKERS

    • Sotalol (non-selective beta blocker) lacks local anesthetic action

    • Respiratory failure

    succinylcholine

    • Relaxation of the respiratory muscle

    • Echothiophate potentiated the effects of

     Respiratory failure succinylcholine  Relaxation of the respiratory muscle  Echothiophate potentiated the effects of
    • Deficiency in plasma cholinesterase due to blood loss

    Prolonged Apnea….

    bpm.

    Case Study # 4

    health until 1 year ago when spells of cardiac

    blood pressure of 150/90 mm Hg and heart rate of 88

    bpm. Case Study # 4 health until 1 year ago when spells of cardiac blood pressure

    palpitations began. These became more severe and were eventually accompanied by throbbing headaches and drenching sweats. Physical examination reveals a

    A 46-year-old woman sees her physician because of palpitations and headaches. She enjoyed good

    • rise in blood pressure to 210/120 mm Hg, heart rate to
      What treatments might help this patient?

    • 122 bpm, and facial pallor. This is accompanied by severe headache and profuse sweating.
      What is the likely cause of her episodes?

    rise in blood pressure to 210/120 mm Hg, heart rate to  What treatments might help
    • During the physical examination, palpation of the abdomen elicits a sudden and typical episode, with a
      What caused the blood pressure and heart rate to rise so high during the examination?

    Pheochromocytoma  A tumor of the adrenal medulla or sympathetic ganglion cells  Tumor secretes catecholamines

    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

     
    Pheochromocytoma  A tumor of the adrenal medulla or sympathetic ganglion cells  Tumor secretes catecholamines

    Common symptoms in

    pheochromocytoma

    • Hypertension

    • Headache

    Common symptoms in pheochromocytoma  Hypertension  Headache
    • Sweating

    • Other symptoms include;

    heart palpitations

    Pallor

    shortness of breath

    Weakness

    symptoms that resemble panic attacks

    • Clinically useful in the management of pheochromocytoma

    • Inhibits tyrosine hydroxylase

    • Nitroprusside and alpha blockers

      • For hypertension during operative manipulation of pheochromocytoma

    Treatment

    • Phenoxybenzamine

    • Metyrosine

     Clinically useful in the management of pheochromocytoma  Inhibits tyrosine hydroxylase  Nitroprusside and alpha
    • Useful in the chronic treatment of inoperable or metastatic pheochromocytoma

     Clinically useful in the management of pheochromocytoma  Inhibits tyrosine hydroxylase  Nitroprusside and alpha
     Clinically useful in the management of pheochromocytoma  Inhibits tyrosine hydroxylase  Nitroprusside and alpha

    venous return.

    • Reversible antagonists

    • CARDIOVASCULAR EFFECTS

      • Terazosin, Doxazosin, Trimazosin

    • Prazosin and Prazosin analogs

    SELECTIVE ALPHA 1 -ANTAGONISTS

    • Decreases peripheral vascular resistance and

    venous return.  Reversible antagonists  CARDIOVASCULAR EFFECTS  Terazosin, Doxazosin, Trimazosin  Prazosin and Prazosin
    • Decreases systemic arterial blood pressure without a significant increase in heart rate.

    • Relaxes arterial and venous smooth muscle as well as nonvascular smooth muscle.

    • OTHER EFFECTS

      • Miosis and nasal stuffiness

      • Decrease resistance to the flow of urine

    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
    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 SOME ADVERSE EFFECTS COMMONLY  Prazosin and Prazosin analogs (terazosin, doxazosin, OBSERVED
    SELECTIVE ALPHA 1 -ANTAGONISTS
    SOME ADVERSE EFFECTS COMMONLY
    Prazosin and Prazosin analogs (terazosin, doxazosin,
    OBSERVED WITH ALPHA BLOCKERS
    trimazosin)
    Orthostatic hypotension
    Tachycardia
    Vertigo
    Sexual dysfunction
    • Phenoxybenzamine

      • Competitive antagonist

    • Phentolamine

    relaxant)

    NON-SELECTIVE ALPHA BLOCKERS

    • Irreversibly blocks alpha receptors

    • Used clinically in pheochromocytoma

    • Blocks H1, Ach, and SE receptors as well as alpha receptors

    • Used in erectile dysfunction in combination with papaverine (a non-specific smooth muscle

     Phenoxybenzamine  Competitive antagonist  Phentolamine relaxant) NON-SELECTIVE ALPHA BLOCKERS  Irreversibly blocks alpha receptors

    Other uses of alpha blockers

    • Ocassionally , in Raynaud’s phenomenon

    • In peripheral vascular disease

    • Hypertensive emergencies

    • Chronic hypertension*

      • Prazosin family

    * With limited application

    Other uses of alpha blockers  Ocassionally , in Raynaud’s phenomenon  In peripheral vascular disease
    Other uses of alpha blockers  Ocassionally , in Raynaud’s phenomenon  In peripheral vascular disease