All of the following conditions are contraindicated or likely to worsen in a case of Primary open Angle Glaucoma when treated with Timolol Maleate Eye drop 0.5 % except:
The US Pharmacopeia’s provided with the Harrison’s 15th Edition CD states the following important in formations:
Side effects of Timolol due to systemic absorption may include:
Alopecia ; Anxiety ( reported with Levobetoxalol only)
Chest pain ; confusion , MENTAL DEPRESSION – for Betoxalol and Timolol
CHF , Cystitis , Hallucinations –with Timolol only , Asthma , Epistaxis , Diarrhea , Drowsiness
HYPERTENSION – reported for Levobetoxalol , and Timolol Reference --- American Medical Association Drug Study , Chicago , 1986 ---- Given in the Product information of ALCON laboratories --- Van Buskirk EM –May 1980)
HYPOTENSION --- for Levobetaxalol only
Impotence for Timolol
Parasthesia for Timolol
HYPERCHOLESTEROLEMIA AND HYPERLIPIDEMIA reported ONLY for Levobetaxolol.
Sorry, the answer is still "Hypertension". Read the following lines from the article: Levobunolol vs Timolol for Open‑Angle Glaucoma and Ocular Hypertension (http://www.med.wayne.edu/kresgeeye/online/research/articles_html/LevobunololvsTimolol85-1.htm)
Systemic safety
Figure 4 indicates that levobunolol and timolol had similar effects on heart rate with maximum mean decreases of approximately 5 to 10 beats/min. The overall mean decreases for 15 months were 4.3 beats/min for 0.5% levobunolol, 6.5 beats/min for 1% levobunolol, and 2.9 beats/min for timolol with no significant differences among the groups. Among‑group differences were observed at three follow‑up examinations, and on each occasion mean heart rate decreases in the 1% levobunolol group were somewhat greater than those in the timolol group. While statistically significant, these differences between the treatments were not considered clinically significant.
Slight changes in mean systolic and diastolic blood pressure were also seen in all three treatment groups. The analysis of overall mean changes from baseline showed no significant among‑group differences with average mean decreases of 1.2 to 5 mm Hg in systolic pressure and 1.2 to 1.8 min Hg in diastolic blood pressure. Figure 5 shows that again levobunolol and timolol were similar in their effects on blood pressure.
Besides, Timolol is available in Oral form for treatmet of hypertension as Timolol Mal/bendroflumethiaz (Prestim) 10mg/2.5mg Tabs marked by Masters Marketing.
it is a good point raised by Dr_ mithun......
but here i think the moot point is that we all know non selective beta blockers can adversely affect lipid profile....timolol being one,,,,,is expected to have the same effect...that is why i think hypertension is the answer......but hey u never know.....if the question setters have gone through the very same pages of harrison........javascript:emoticon('')javascript:emoticon('')
Medical therapy of glaucoma is often compromised by adverse
reactions. Unwanted side effects from orally or parentally administered
agents, such as the carbonic anhydrase inhibitors, are expected and well
known to all prescribing ophthalmologists. Sometimes overlooked, however,
is the fact that ocular therapy, in addition to its inconvenient visual and
irritative side effects, may occasionally induce adverse reactions that
account for significant ocular or systemic morbidity. While many other
factors are contributory, it is possible that patient rejection of
therapeutic regimens because of their side effects may lead to
noncompliance, a principal reason for failure to achieve medical control of
glaucoma. (1) Advance consideration of possible adverse effects is helpful
in planning glaucoma regimens that are compatible with both the life-style
of the patient and with successful management of the disease.
The establishment of the National Registry for Drug Induced Ocular
Side Effects, now at the University of Oregon Health Sciences Center in
Portland, has increased our awareness of the many adverse effects from
medications we use in Ophthalmology
. (2) The Registry collects preliminary
data on those effects and warns of potentially serious reactions to new and
established medications. In most cases, the incidence of side effects is
unknown, and proof of direct causal relationships requires long-term,
controlled prospective studies.
Compendiums of the spectrum of glaucoma drug side effects are
available elsewhere and are not the subject of this discussion. (2-6)
Examples of potentially occult and serious effects, however, may encourage
ophthalmologists to be wary about the development of unwanted, and
sometimes avoidable, adverse reactions to glaucoma medications.
Patients on miotics should be observed, not only for the
development of possible cataract and retinal detachment, but also for
changes in the iridocorneal angle. The combination of advancing nuclear
sclerosis and miotic-induced changes in lens shape and position may induce
intermittent relative pupillary block which may lead to subacute or chronic
angle closure. Failure to perform gonioscopy on such patients may lead the
ophthalmologist to mistakenly attribute a rise in intraocular pressure to
loss of medical control of open angle glaucoma rather than to the
introduction of pupillary block. To raise the concentration of the miotic
in this situation will only increase the pupillary block, converting
medically controllable open angle glaucoma into intractable chronic angle
closure. Probably, this is a more common cause of the development of angle
closure in patients with open angle glaucoma than that brought about by the
administration of mydriatic glaucoma agents, such as epinephrine.
Timolol has been available for the treatment of glaucoma for nearly
2 years and has proved to be efficacious and safe in many cases. Some
patients, however, have developed side effects. Although a few have
complained of the external ocular irritation common with many collyria,
most patients have had system adverse reactions, especially of the
cardiovascular, respiratory, and central nervous systems. (4,5)
Epinephrine also has the potential for producing cardiotoxicity, although
few cases have been reported. It should be remembered that many ocularly
administered agents, including epinephrine and timolol, may be rapidly
absorbed via the lacrimal tract and nasopharyngeal mucose. The usual
hepatic detoxification that occurs with gastrointestinal absorption is thus
bypassed, making the ocular route of systemic administration more similar
to intravenous than to gastrointestinal absorption. This consideration may
help to explain the high incidence of systemic effects from ocularly
applied timolol. Moreover, recent studies have demonstrated that more than
50% of ocularly applied epinephrine is absorbed systemically, making the
usual ocular dosage comparable to regularly used therapeutic systemic
dosages. (8) Hence, neither of these agents is an ideal first choice for
patients with cardiovascular disease. Moreover, the importance of lacrimal
canalicular compression should be emphasized to all glaucoma patients on
topical therapy, but particularly to those for whom epinephrine and timolol
are necessary.
Those with lacrimal shunts, such as Jones Pyrex tubes, especially
need to be reminded of the potential systemic effects of using eye drops.
These patients experience the rapid nasopharyngeal absorption of collyria
and could find themselves hospitalized with unrecognized cholinergic,
adrenergic, or other drug toxicity. (9-10)
Because many of our patients seem to be treated successfully with
the same agent for many years, we may occasionally be lured into
unjustified complacency about the efficacy and safety of their therapy.
The example of miotic-induced angle closure is most clear-cut, but we have
also seen patients develop cholinergic, adrenergic, or allergic symptoms
after previously tolerating certain agents for many years. Hence, even
with what seems to be adequate control, it is worthwhile occasionally to
stop and reconsider the appropriateness of any therapeutic regimen.
Prospective studies are needed to determine the incidence of
adverse effects and their causal relationship to ocular drugs.
Tentatively, however, we can state that, in our glaucoma patients, the side
effects seem to be somewhat more common with miotics, and possibly with
epinephrine, than with timolol. However, it is more important to consider
that the side effects from Timolol and possibly from epinephrine are more
likely to be systemic and thus to be associated with significant morbidity.
Active research into new methods of drug delivery may permit the
achievement of adequate therapeutic intraocular dosage while minimizing
that available for systemic absorption. Meanwhile, many glaucoma patients
will require a combination of agents; it is important to keep in mind the
possible adverse reactions of each. Rather than seek an ideal first-line
drug for glaucoma, it is preferable to design specific regimens for
individual patients based upon their ocular needs and their general medical
condition.
The National Registry is grateful for the many reports it receives
from ophthalmologists and urges the continued reporting of adverse effects
observed after the administration of glaucoma and other ophthalmic
medications.
E. Michael Van Buskirk, MD
The National Registry for Drug-Induced
Ocular Side Effects
Department of Ophthalmology
University of Oregon Health Sciences Center
Portland, OR 97201
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Glaucoma Medications and Their Side Effects
The only symptom in most cases of glaucoma is gradual loss of vision which can lead to blindness. The loss of vision usually begins with the peripheral vision, and good central vision is maintained until the end stages. By the time the patient notices the visual loss, extensive damage has already occurred.
I. WHAT IS THE PURPOSE OF TREATMENT?
The whole purpose of treatment for glaucoma is to prevent further loss of vision. Once the nerve cells have been damaged and the vision carried by those nerve cells lost, they cannot be replaced. LOSS OF VISION IN GLAUCOMA IS IRREVERSIBLE. Bringing the pressure under control will not restore lost vision, but only prevent further vision from being lost. In order to minimize or prevent further visual loss from glaucoma, IOP must be constantly controlled.
This requires chronic use of medications. If a drop is given four times a day, it is because the effect of the drop only lasts about 6 hours. Drops given twice a day have a duration of action of about 12 hours. Proper spacing of drop instillation and use of punctal occlusion (pressing with the finger over the tear duct for 1 minute to prevent the drop from running into the nose) will result in about 50% more medication getting into the eye, a longer duration of action, less fluctuation in IOP, less absorption into the blood stream, and fewer systemic side effects. If you have not already been given an instruction sheet about these, ask for one. If you have any questions about your drops or how to take them or store them, do not hesitate to ask. If enough people ask the same question for which we do not already have a printout or instruction sheet, we can add it.
II. SIDE EFFECTS
One of the most difficult problems faced by glaucoma patients is that of having to take medications which may have both ocular and systemic side effects to control a disease which is usually painless and has no symptoms. Understanding the necessity for the medication often helps to reduce the severity of a side effect, since it is often magnified by anxiety. A side effect is any action produced by a drug beyond the intended one of lowering IOP. Some patients have no side effects whatsoever, while others find them too severe to tolerate. Why a drug causes side effects in some persons and not others or why the same side effect of the same drug is severe in one person and mild in another are poorly understood.
Quality of life is important. We sometimes have to make the decision to perform laser or surgery, even if IOP can be controlled, if the side effects of the medications necessary for control are intolerable. It is up to you, the patient, to participate in and ultimately make the decision in such a situation. What you should not do is skip taking the medications and lose vision because of side effects. You should also not be afraid to mention any side effects you might have or attribute to the drugs, since it is not your fault that the drugs cause them.
All drops may cause some burning or stinging when instilled. Often, this effect is due not to the drug but to the antibacterial preservatives in the solution. It is rarely intolerable and can be used to advantage, since it lets you know that the drop got into the eye. Many patients don't think a drop is really medicine if it doesn't cause a little irritation.
III. TYPES OF ANTIGLAUCOMA DRUGS
(1) PARASYMPATHOMIMETICS:
Cholinergic agents, or miotics, are drops which help to open the drain and increase the rate of fluid flow out of the eye. The most common is pilocarpine. Carbachol is similar but somewhat stronger.
Echothiophate (PHOSPHOLINE IODIDE*) is even stronger but has a tendency to cause cataracts and is only used in patients who have already had cataracts removed.
(2) SYMPATHOMIMETICS:
1. Epinephrine (adrenaline) lowers IOP by increasing the rate of fluid flow out of the eye and decreasing the rate of aqueous humor production. Dipivefrin (PROPINE*) is converted to epinephrine once inside the eye.
2. ALPHA AGONISTS reduce aqueous humor production and increase aqueous outflow. Uveoscleral outflow normally accounts for about 10% of the outflow from the eye. The rest is handled by the trabecular meshwork. However, when the meshwork is damaged by glaucoma, uveoscleral outflow becomes more important. Apraclonidine (IOPIDINE*) and brimonidine (ALPHAGAN*) are presently marketed. Brimonidine has a significantly higher relative selectivity for the alpha-2 receptors, while apraclonidine has mixed alpha-1 and alpha-2 stimulatory activity.
(3) ADRENERGIC ANTAGONISTS:
BETA-BLOCKERS decrease the rate at which fluid flows into the eye. The nonspecific beta- blockers, timolol (TIMOPTIC*), levobunolol (BETAGAN*), carteolol (OCUPRESS*), and metipranolol (OPTIPRANOLOL*) appear to have a slightly greater pressure-lowering effect than betaxolol (BETOPTIC*), but the latter is safer in patients with pulmonary disease, such as asthma or emphysema, and may have less of an effect on blood pressure. Oral beta-blockers are commonly used for hypertension and angina and in these situations, also lower IOP. The latter group includes propranolol, timolol,atenolol, and nadolol.
(4) CARBONIC ANHYDRASE INHIBITORS:
CARBONIC ANHYDRASE INHIBITORS reduce fluid flow into the eye. For 40 years, these were used in the form of pills, which commonly cause side effects. The most frequently used have been acetazolamide (DIAMOX*) and methazolamide (NEPTAZANE*). Dorzolamide (TRUSOPT*) has been introduced as the first topical carbonic anhydrase inhibitor.
(5) ALPHA-AGONISTS decrease the rate of fluid flow into the eye. The only currently available drug in this class in IOPIDINE.
(6) PROSTAGLANDIN ANALOGUES:
Latanoprost (XALATAN), the agent most recently brought to market in the U.S., represents a new class of compounds which should prove additive with all other agents, as it acts predominantly by increasing uveoscleral outflow.
IV. COMMON SIDE EFFECTS OF ANTIGLAUCOMA DRUGS
One should not become neurotic when reading a list of possible side effects of a drug, such as the package insert. You may not get any side effects at all. If you do, it may only be a minor bother. Serious side effects are rare. If they weren't, we wouldn't be using the drugs in the first place. Sometimes, the only way to prove a side effect, particularly subjective ones such as anxiety, depression, or vivid dreams, is due to the medication is to stop using it, wait for the reaction to go away, and try it again. This is known as retesting. If you think you have an unusual reaction to a drug, mention it to your physician or post it on the Internet. A good place for this is alt.support.glaucoma. If you retest yourself twice and prove the side effect related to the drug and it is an unusual one, contact the doctor. Remember that all drops may cause burning and stinging and that any drug may produce a rash. If you have a definite allergic reaction to a drug, you should stop using it.
MIOTICS may cause periorbital pain, browache, and pain inside the eye. This often disappears after a few days of taking the drop. Blurred vision and extreme nearsightedness are most common in younger patients, who often cannot tolerate these drops. Because miotics reduce the size of the pupil and prevent it from dilating normally in the dark, many patients complain of dim vision, particularly at night or when going into a dark room. Systemic side effects are rare with pilocarpine, more common with carbachol, and not unusual with echothiophate. These include stuffy nose, sweating, increased salivation, and occasional gastrointestinal problems. Rare side effects include retinal detachment, mostly on circumstantial evidence. Patients with high myopia and pigmentary dispersion are more prone to both retinal detahcment and glaucoma.
PILOCARPINE GEL is applied at bedtime and may be substituted for drops in many patients. In addition to the convenience of not having to use drops four times a day, the effect on the pupil is often less.
OCUSERTS are pilocarpine membranes worn under the lids and changed every 5 days. These cause less blurring of vision and are especially useful in younger patients.
EPINEPHRINE COMPOUNDS frequently cause burning on instillation. A red eye is common and is an effect not of the drop initially, which whitens the eye by constricting blood vessels, but of the rebound effect when it wears off. The most common problem is development of an allergic reaction, which may occur after years of use. Epinephrine may cause palpitations, elevated blood pressure, tremor, headache, and anxiety. Dipivefrin has a much lower rate of systemic side effects.
BETA-BLOCKERS cause few ocular side effects. A few patients have complained of blurring of vision. This is more common when beta-blockers and epinephrine are used together, because this combination dilates the pupil. The most common ystemic side effects include exacerbation of pulmonary disease, difficulty breathing, slowing of the pulse, and decreased blood pressure. Central nervous system side effects include dizziness, depression, fatigue, weakness, decreased exercise tolerance, hallucinations, insomnia, and impotence. Hair loss may occur in some patients.CARBONIC ANHYDRASE INHIBITORS commonly cause side effects. The most common are urinary frequency and tingling in the fingers and toes. These are often transient and disappear after a few days. Kidney stones may occur, but are also common without their use. Most glaucoma specialists use them unless a patient has had or develops a kidney stone or only has one kidney. A rare but serious side effect is aplastic anemia. Rashes are not uncommon. Potassium loss may occur when these drugs are taken simultaneously with digitalis, steroids, or chlorothiazide diuretics. Depression, fatigue, and lethargy are common side effects and are often not realized by the patient or by close family. These side effects may not appear immediately but develop gradually. Since many patients with glaucoma are elderly, these side effects are attributed to getting older. Patients and their families should be on the alert for these side effects and, when suspected, the drug can be stopped for a short time for verification. Other common side effects are gastrointestinal upset, metallic taste to carbonated beverages, impotence, and weight loss. Sequels cause less side effects than tablets.
The use of dorzolamide, which is as effective as acetazolamide in most patients, has markedly reduced the frequency and severity of these side effects. With chronic use, some 20% of patients develop a topical allergy, with conjunctival redness and itching, redness, and scaling of the lower eyelids.
ALPHA-AGONISTS are chemically related to systemic medications for the treatment of hypertension, systemic side effects of these medications are unusual. Ocular allergy develops in a high percentage of patients using apraclonidine on a prolonged basis; allergic reactions appear to be less with brimonidine. Patients who develop an allergy to apraclonidine can be switched to brimonidine. The most common side effects are slight elevation of the upper lid, dry mouth, dry nose, and mild sedation.
PROSTAGLANDIN ANALOGUES stimulate the uveoscleral pathway for aqueous outflow, and can be potent pressure-reduction medications. Although ocular injection and irritation may occur, these drugs are extremely well-tolerated and require only once daily dosing. A darkening of iris color occurs in approximately 5% of eyes with use of latanoprost for several months or more due to an increase in the production of melanin in the melanocytes of the iris. Pure brown eyes and pure blue eyes are not effected. Hazel, green, and golden-brown eyes are. Since the drug is new, other side effects are only beginning to be reported and have not been proven yet. Conjunctival redness is commo
Mild irritation, transient burning sensation, may cause bronchospam. Visual disturbances, cardiovascular and respiratory effects
Precaution should be taken during abrupt reduction in dosage, pregnancy, lactation, elderly, IHD,CCF, renal or hepatic dysfunction.
Pregnancy: Safety not established.
Breast Feeding: May be used.
Man: May be used.
The following adverse reactions have been reported either in clinical trials of up to 3 years duration prior to release in 1978 or since the drug has been marketed.
Dizziness, depression, increase in signs and symptoms of myasthenia gravis, paresthesia.
SKIN
Hypersensitivity, including localized and generalized rash; urticaria, alopecia.
RESPIRATORY
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough.
ENDOCRINE
Masked symptoms of hypoglycemia in diabetic patients (See WARNINGS).
SPECIAL SENSES
Signs and symptoms of ocular irritation, including conjunctivitis, blepharitis, keratitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis.
Causal Relationship Unknown: The following adverse effects have been reported, and a causal relationship to therapy with Timolol has not been established: Cardiovascular: Hypertension, pulmonary edema, worsening of angina pectoris; Digestive: Dyspepsia, anorexia, dry mouth; Nervous System/Psychiatric: Behavioral changes including confusion, hallucinations, anxiety, disorientation nervousness, somnolence, and other psychic disturbances; Special Senses: Aphakic cystoid macular edema; Urogenital: Retroperitoneal fibrosis, impotence.
The following additional adverse effects have been reported in clinical experience with oral timolol maleate, and may be considered potential effects of ophthalmic timolol maleate: Body As A Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular: Edema, worsening of arterial insufficiency, Raynaud's phenomenon, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting; Hematologic: Nonthrombocytopenic purpura; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating, cold hands and feet; Musculoskeletal: Arthralgia, claudication; Nervous System/Psychiatric: Vertigo local weakness, decreased libido, nightmares, insomnia, diminished concentration; Respiratory: Rales, bronchial obstruction; Special Senses: Tinnitus, dry eyes; Urogenital: Urination difficulties.
Potential Adverse Effects: In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and may be considered potential effects of ophthalmic timolol maleate: Digestive: Mesenteric arterial thrombosis, ischemic colitis; Hematologic: Agranulocytosis, thrombocytopenic purpura; Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Urogenital: Peyronie's disease.
There have been reports of a syndrome comprising psoriasiform skin rash, conjunctivitis sicca, otitis and sclerosing serositis attributed to the beta- adrenergic receptor blocking agent, practolol. This syndrome has not been reported with timolol maleate.
8)
CONTRAINDICATIONS
Timolol is contraindicated in patients with bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease (see WARNINGS); sinus bradycardia; second and third degree atrioventricular block; overt cardiac failure (see WARNINGS); cardiogenic shock; hypersensitivity to any component of this product.
WARNINGS
As with other topically applied ophthalmic drugs, this drug may be absorbed systemically.
The same adverse reactions found with systemic administration of beta Adrenergic blocking agents may occur with topical administration. For example, Severe respiratory reactions and cardiac reactions, including death due To bronchospasm in patients with asthma, and rarely death in association With cardiac failure, have been reported following administration of timolol (See contraindications).
Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.
In Patients Without A History Of Cardiac Failure continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure Timolol should be discontinued.
Obstructive Pulmonary Disease
PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (e.g., CHRONIC BRONCHITIS, EMPHYSEMA) OF MILD OR MODERATE SEVERITY, BRONCHOSPASTIC DISEASE OR A HISTORY OF BRONCHOSPASTIC DISEASE (OTHER THAN BRONCHIAL ASTHMA OR A HISTORY OF BRONCHIAL ASTHMA, IN WHICH "Timolol" IS CONTRAINDICATED, see CONTRAINDICATIONS), SHOULD IN GENERAL NOT RECEIVE BETA BLOCKERS, INCLUDING "Timolol". However, if Timolol is necessary in such patients, then the drug should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2 receptors.
Major Surgery
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol (see OVERDOSAGE).
Diabetes Mellitus
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.
Thyrotoxicosis
Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta adrenergic blocking agents which might precipitate a thyroid storm.
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