therapy in NIDDM. Diabetes Care. 1994;17:1300.
Amaryl [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; July 2009.
glimepiride and glibenclamide. Eur Heart J. 1999;20:439.
Donath MY et al. Mechanisms of beta-cell death in type 2 diabetes. Diabetes. 2005;54(Suppl 2):S108.
Yki-Järvinen H. Thiazolidinediones. N EnglJ Med. 2004;351:1106.
Actos [package insert]. Deerfield, IL: Takeda Pharmaceuticals America; September 2009.
Avandia [package insert]. Brentford, UK: Glaxo Smith Kline; October 2008.
appears in Ann Intern Med. 2000;133:237]. Ann Intern Med. 2000;132:121.
Su DH et al. Liver failure in a patient receiving rosiglitazone therapy. Diabet Med. 2006;23:105.
Farley-Hills E et al. Fatal liver failure associated with pioglitazone. BMJ. 2004;329:429.
causes [published correction appears in N EnglJ Med. 2007;357:100]. N EnglJ Med. 2007;356:2457.
cardiovascular mortality. Arch Intern Med. 2010:170(14);1191–1201.
meta-analysis of randomized trials. JAMA. 2007;298:1180.
infarction in type 2 diabetes. Pharmacoepidemiol Drug Saf 2007;16:1065.
patients treated with rosiglitazone or pioglitazone. JAMA. 2010;304:411.
Ryan EH Jr et al. Diabetic macular edema associated with glitazone use. Retina. 2006;26:562.
http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm. Accessed December 9, 2010.
insulin resistance? Diabetes Care. 2007;30:1670.
Dormuth CR et al. Thiazolidinediones and fractures in men and women. Arch Intern Med. 2009;169:1395.
Diabetes Obes Metab. 2010;12:716.
formation. Endocrinology. 2005;146:1226.
Scheen AJ. Pharmacokinetic interactions with thiazolidinediones. Clin Pharmacokinet. 2007;46:1.
Precose [package insert]. Pittsburgh, PA: Bayer Corporation; 2011.
Glyset [package insert]. NY, NY: Pfizer/Pharmacia and Upjohn Company; 2012.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl
peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696.
Victoza [package insert]. Bagsvsrd. Denmark: Novo Nordisk A/S; 2016.
Tanzeum [package insert]. Wilminton, DE: GlaxoSmithKline LLC; 2015.
Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Co; 2015.
Byetta [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals P; 2015
Bydureon [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals P; 2015.
Drab SR. Incretin-based therapies for type 2 diabetes mellitus: current status and future prospects.
appears in Diabetes Care. 2010;33:692]. Diabetes Care. 2009;32:1224.
in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26:268.
Januvia [package insert]. Whitehouse Station, NJ: Merck and Co; 2010.
Onglyza [package insert]. New York, NY: Bristol-Myers Squibb Company; 2009.
Tradjenta [package insert]. Ridgefield, CT: Boehringer ingelheim Pharmaceuticals; 2015.
Nesina [package insert]. Deerfield, IL: Takeda Pharmaceuticals America; 2013.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl
peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696.
Pharmacotherapy. 2007;27:1163.
Golightly LK et al. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin
Pharmacokinet. 2012;51(8):501–514.
diabetes mellitus. Expert Opin Pharmacother. 2014;15(17):2565–2585.
systematic review and meta-analysis of randomised and non-randomised studies. BMJ. 2014;348:2366.
Symlin [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015.
Invokana [package insert]. Titusville, NJ:Jannsen Pharmaceuticals; September 2015.
Farxiga [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; March 2015.
Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; June 2015.
diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(5):457–466.
FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious
condition of too much acid in the blood. Available at
http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm2015.
on overallsafety and cardiovascular outcomes. Diabetes Care. 2010; 33:1503.
1998;352:1558]. Lancet. 1998;352:854.
Welchol [package insert]. Parsippany, NJ: Daiichi Sankyo Inc; October 2014.
metformin: glucose and lipid effects. Arch Intern Med. 2008;168:1975.
glycemic control receiving insulin-based therapy. Arch Intern Med. 2008;168:1531.
inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care. 2008;31:1479.
Cycloset [package insert]. Tiverton, RI: VeroScience LLC; September 2010.
microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713.
UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and
microvascular complications in type 2 diabetes: UKPDS 38 [published correction appears in BMJ.
1999;318:29]. BMJ. 1998;317:703.
2 diabetes. Diabetes Care. 2009;32:1620.
metformin—results from four UK centres. Br J Diabetes Vasc Dis. 2007;7:225.
Pelletier AL et al. Metformin stinks, literally. Ann Intern Med. 2010;152:267.
deficiency: randomised placebo controlled trial. BMJ. 2010;340:c2181.
systematic review. Diabetes Care. 2005;28:1510.
appears in N EnglJ Med. 2007;356:1387]. N EnglJ Med. 2006; 355:2427.
DeFronzo RA et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in
metformintreated patients with type 2 diabetes. Diabetes Care. 2005;28:1092.
glucose: the Western New York Health Study. Ann Epidemiol. 2009;19:365.
Stang M et al. Incidence of lactic acidosis in metformin users. Diabetes Care. 1999;22:925.
Intern Med. 1996;124(1, pt 2):136.
The Multicenter Metformin Study Group. N EnglJ Med. 1995;333:541.
gain, and hypoglycemia in type 2 diabetes. JAMA. 2010;303:1410.
patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275.
ACCORD Study Group et al. Effects of medical therapies on retinopathy progression in type 2 diabetes
[published correction appears in N EnglJ Med. 2011;364:190]. N EnglJ Med. 2010;363:233.
applications. JAMA. 2003;289:2265.
of type 2 diabetic patients. Diabetes Care. 2003;26:3080.
Anderson JH Jr et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia and
Arch Intern Med. 1997;157:1249.
OADS with/without basal insulin therapy [abstract]. Diabetes. 2005;54:A69.
statement. Int J Clin Pract. 2009;63:1571.
Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26(6):1902–1912.
Phenformin: removal from the general market. FDA Drug Bull. 1977;7:19.
Gambert SR. Atypical presentation of diabetes mellitus in the elderly. Clin Geriatr Med. 1990;6:721.
2003;51(5, Suppl Guidelines):S265.
Shorr RI et al. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr Soc.
Molitch ME et al. Nephropathy in diabetes. Diabetes Care. 2004;27(Suppl 1):S79.
New York, NY: McGraw-Hill; 2003:723.
Diabetes Mellitus. 6th ed. New York, NY: McGraw-Hill; 2003:823.
Fong DS et al. Diabetic retinopathy. Diabetes Care. 2004;27:2540.
in Diabetes Care. 2011;34:247; Diabetes Care. 2010;33:2129]. Diabetes Care. 2010;33:1395.
Vinik A et al. Diabetic autonomic neuropathy. Diabetes Care. 2003;26:1553.
injection. 2010. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm170934.htm. Accessed
treatments. Diabetes Care. 2010;33:2285.
J Neurol. 2010;17(9):1113–e88. doi:10.1111/j.1468-1331.2010.02999.x. Epub 2010 Apr 9.
Database Syst Rev. 2009;(3):CD007076. doi:10.1002/14651858.CD007076.pub2.
peripheral neuropathy. Pan Pract. 2014;14:167–184.
part II. Circulation. 2003;108:1655.
Mayfield JA et al. Preventive foot care in diabetes. Diabetes Care. 2004;27(Suppl 1):S63.
Vue M et al. Drug-induced glucose alterations. Part 1: drug-induced hypoglycemia. Diabetes Spectr.
Pietraszek A et al. Alcohol and type 2 diabetes. A review. Nutr Metab Cardiovasc Dis. 2010;20:366.
Van de Wiel A. Diabetes mellitus and alcohol. Diabetes Metab Res Rev. 2004;20:263.
requiring immediate intervention. Open-angle glaucoma is a chronic
condition, which can result in progressive loss of vision leading to
Treatment for open-angle glaucoma is targeted toward reducing
agonists are the mainstay of treatment. Treatment is not curative.
OCULAR AND SYSTEMIC SIDE EFFECTS OF DRUGS
Many widely used medications for various conditions cause ocular side
effects. The true incidence is frequently not known, making the
reporting of ocular side effects of drugs an important function for any
Conversely, many topically administered ocular medications may cause
Stye(hordeolum) is a common ocular disorder for which no viable overthe-counter treatment exists.
Conjunctivitis (pinkeye) is frequently related to bacterial or viral
infection, or allergy. Viral conjunctivitis is generally self-limiting.
Bacterial conjunctivitis should be treated with an appropriate
antimicrobial, recognizing that Gram-positive organisms are frequently
the cause. A number of agents are available for the treatment of
allergic conjunctivitis. Among those, decongestants (e.g.,
tetrahydrozoline) should be used for no more than 72 hours, because
they may mask a more serious condition or result in rebound redness.
Topicalcorticosteroids are used for a variety of ocular inflammatory
conditions. The most potent topical corticosteroid is prednisolone acetate
Topical and oral corticosteroids may be associated with serious side
effects such as increases in IOP and cataracts (with long-term use).
AGE-RELATED MACULAR DEGENERATION
There are two forms, dry (affecting 85% of patients) and the more
serious form, wet (affecting 15% of patients).
Wetmacular degeneration is associated with abnormal growth of blood
vessels behind the retina (choroidal neovascularization) and may be
treated by vascular endothelial growth factor (VEGF) inhibitors.
The eye is a highly complex organ composed of various parts, all of which must
function in integration to permit vision. A brief overview of the anatomy and
physiology of the eye prefaces the presentation of specific eye disorders. Readers
should consult an ophthalmology textbook for an understanding of ocular anatomy,
physiology, and general ophthalmology (e.g., Vaughan and Asbury’s General
The eyeball is approximately 1 inch wide and is housed in a cavity (i.e., eye socket)
formed by two bony orbits that are lined with fat, which serves to protect the eyeball.
Six ocular muscles facilitate movement of the eyeball (Fig. 54-1).
The outer coat of the eye is made up of the sclera, conjunctiva, and cornea. The
sclera is the white, dense, fibrous protective coating. The episclera, a thin layer of
loose connective tissue, contains blood vessels that cover and nourish the sclera. The
conjunctiva is a mucous membrane that covers the anterior portion of the eye and
lines the eyelids. The cornea is the transparent, avascular tissue that functions as a
refractive and protective window membrane through which light rays pass en route to
The corneal epithelium and endothelium are lipophilic, and the centrally located
stroma is hydrophilic. These three corneal layers are particularly important because
they affect drug penetration through the cornea. Ophthalmic medications, which are
both fat- and water-soluble, are best able to penetrate through the intact cornea.
The iris, choroid, and ciliary body are known collectively as the uveal tract. The
iris is a colored, circular membrane suspended between the cornea and the
crystalline lens. It controls the amount of light that enters the eye. The choroid,
located between the sclera and retina, is largely made up of blood vessels, which
nourish the retina. The ciliary body is adherent to the sclera and contains the ciliary
muscle and ciliary processes. The ciliary muscle contracts and relaxes the zonular
fibers, which hold the crystalline lens in place. The ciliary processes are responsible
for the secretion of aqueous humor, a clear liquid that occupies the anterior chamber.
The anterior chamber is bounded anteriorly by the cornea and posteriorly by the iris.
The posterior chamber lies between the iris and the crystalline lens.
Figure 54-1 Anatomy of the human eye. (Adapted from
http://commons.wikimedia.org/wiki/File:Eyesection.svg)
The inner segment of the eye contains the retina with the optic nerve. The retina,
the light-sensitive tissue at the back of the eye, contains all of the sensory receptors
for light transmission. The optic nerve, a bundle of more than a million nerve fibers,
transmits visual impulses from the retina to the brain.
The crystalline lens, aqueous humor, and vitreous humor assist the cornea with the
refraction of light. The lens, located behind the iris, functions to focus light onto the
retina by changing its shape to accommodate near or distant vision. The innermost
part of the lens (i.e., the nucleus) is surrounded by the softer material of the cortex.
The aqueous humor, the thin watery fluid that fills the anterior chamber (i.e., the
space between the cornea and the iris) and posterior chamber of the eye, functions to
provide nourishment to the cornea and lens. Disorders involving the aqueous humor
are presented in the section on glaucoma. The primary function of the vitreous humor
(i.e., the jellylike substance between the lens and the retina) is to maintain the shape
of the eye and allow the transmission of light to the retina.
The eyelids and eyelashes are the outermost means of protection for the eye. The
eyelids contain various sebaceous and sweat glands, which may become infected or
inflamed, contributing to many ocular disorders.
The eye is innervated by both the sympathetic and parasympathetic nervous
systems. Parasympathetic fibers, originating from the oculomotor nerve in the brain,
innervate the ciliary muscle and sphincter pupillae muscle that constrict the pupil. As
a result, parasympathomimetic (cholinergic) medications generally are associated
with miosis (pupillary contraction), and parasympatholytic (anticholinergic) agents
with mydriasis (pupillary dilation) and cycloplegia. The term cycloplegia refers to a
paralysis of the ciliary muscle and zonules (fibrous strands connecting the ciliary
body to the lens) that results in decreased accommodation (adjustment of the lens
curvature for various distances) and blurred vision. Tear secretion by the lacrimal
glands also is a parasympathetic function.
Sympathetic fibers from the superior cervical ganglion in the spinal cord innervate
the dilator pupillae muscle, the blood vessels of the ciliary body, the episclera, and
the extraocular muscles. Sympathomimetics cause mydriasis without affecting
In this chapter, we will discuss glaucoma, ocular and systemic side effects of
drugs, common ocular disorders, ocular inflammatory conditions, and age-related
macular degeneration. These are all common conditions that the pharmacist may
encounter in all practices of pharmacy. It is important for the pharmacist to be
educated on these disorders and their associated treatment so that the pharmacist can
evaluate the appropriateness of pharmacotherapy, screen for adverse effects and drug
interactions, and counsel patients on their ocular medications.
Glaucoma is a leading cause of irreversible blindness worldwide. The estimated
number of suspected cases worldwide is 60 million, increasing to 76 million in 2020
and 111 million in 2040. In the United States, an estimated 3 million Americans are
living with glaucoma but only half know they have it. Glaucoma is a nonspecific term
used for a group of diseases that can irreversibly damage the optic nerve, resulting in
visual field loss. Increased intraocular pressure (IOP) is the most common risk factor
for the development of glaucoma; however, even people with “normal”
IOPs can experience vision loss from glaucoma. Generally, the higher the IOP is, the
greater the risk for developing glaucoma. Increasing age, African-American race,
family history, thinner central corneas, and larger vertical cup–disc ratios are other
The inner pressure of the eye (i.e., IOP) is influenced by the production of aqueous
humor by the ciliary processes and the outflow of aqueous humor through the
trabecular meshwork. The tonometry test to measure the IOP is based on the pressure
required to flatten a small area of the central cornea. Generally, an IOP of 10 to 20
mm Hg is considered normal. An IOP of 22 mm Hg or greater should arouse
suspicion of glaucoma, although a more rare form of glaucoma is associated with a
Ocular hypertension has been defined as an IOP exceeding 21 mm Hg, normal visual
fields, normal optic discs, open angles, and the absence of any ocular disease
contributing to the elevation of IOP. Only a small percentage of patients with ocular
hypertension have open-angle glaucoma. An ophthalmoscope can examine the inside
of the eye, especially the optic nerve, and a diagnosis of glaucoma can be applied
when pathologic cupping of the optic nerve is observed.
Primary open-angle glaucoma (POAG) occurs in about 1.8% of people older than 40
years of age in the United States; however, glaucoma can affect other age groups,
In patients with POAG, aqueous humor outflow from the
anterior chamber is continuously subnormal primarily because of a degenerative
process in the trabecular meshwork. The IOP can vary in the course of a day from
normal to significantly high pressures.
1 The decreased outflow appears to be caused
by degenerative changes in outflow channels (i.e., the trabecular meshwork and
Schlemm canal) and tends to worsen with the passage of time.
outflow is normal even during a phase of elevated IOP, and the elevation appears to
be to the result of hypersecretion of aqueous humor.
The onset of POAG usually is gradual and asymptomatic. A defect in the visual
field examination may be present in early glaucoma, but loss of peripheral vision
usually is not seen until late in the course of the disease. Visual field defects
correlate well with changes in the optic disc and help differentiate glaucoma from
ocular hypertension in patients with increased IOP. Patients with normal visual fields
and an IOP of 24 mm Hg or greater have a 10% likelihood of developing glaucoma in
Examination of the anterior chamber angle by gonioscopy, using a corneal contact
lens, a magnifying device (e.g., a slit-lamp microscope), and a light source, assists in
cases. The sole cause of the elevated IOP in angle-closure glaucoma is closure of the
Angle-closure glaucoma, which is a medical emergency, usually presents as an
acute attack with a rapid increase in IOP, blurring or sudden loss of vision,
appearance of haloes around lights, and pain that is often severe. When patients are
predisposed to angle-closure glaucoma, their pupils should not be dilated (e.g.,
during an ophthalmic examination) and they should be taught the signs and symptoms
of angle closure. Acute attacks can terminate without treatment, but if the IOP remains
high, the optic nerve can be irreparably damaged.
and patients can be asymptomatic until the glaucoma is in an advanced stage.
Permanent medical management of acute or chronic angle-closure glaucoma is
difficult: Surgical procedures (e.g., peripheral iridectomies) often are needed.
Therapeutic Agents for Treatment of Primary OpenAngle Glaucoma
cost-effective treatment. Some of the PGAs are available as generic formulations
making their cost comparable to β-blockers.
Ophthalmic β-adrenergic antagonists block the β-adrenergic receptors in the ciliary
epithelium of the eye and lower IOP primarily by decreasing aqueous humor
production. On average, β-blockers decrease IOP by 20% to 35% depending on the
strength used and the frequency of administration.
-adrenergic antagonist, is one of the most
are compared with timolol for safety and effectiveness. Concentrations or dosages
exceeding one drop of timolol 0.5% twice daily (BID) do not produce further
15 Therapy usually is initiated with a 0.25% solution
administered as one drop BID. Monocular administration of timolol has resulted in
equal bilateral IOP reduction and can reduce the cost of therapy and side effects for
16 An escape phenomenon, or tachyphylaxis, can occur with timolol.
Timolol has been associated with a modest reduction of resting pulse rate (5–8
17,18 worsening of heart failure, and adverse pulmonary effects (e.g.,
dyspnea, airway obstruction, pulmonary failure).
19,20 After chronic administration in
susceptible individuals, timolol can cause corneal anesthesia.
has been reported in patients receiving ophthalmic timolol, a cause-and-effect
relationship has not been established.
Systemic absorption after topical administration does occur, but it may not be
significant in the majority of patients. Care should be taken when timolol is used in
patients with sinus bradycardia, heart failure (see Chapter 14, Heart Failure), or
pulmonary disease. Systemic side effects could be exaggerated in elderly patients
secondary to inadvertent overdosing associated with poor administration technique
Comments
Post a Comment
اكتب تعليق حول الموضوع