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JackieJackieJackieJackieJackieJackieJackieJackie Wirkus, DNP, APNP, CORLNWirkus, DNP, APNP, CORLNWirkus, DNP, APNP, CORLNWirkus, DNP, APNP, CORLNWirkus, DNP, APNP, CORLNWirkus, DNP, APNP, CORLNWirkus, DNP, APNP, CORLNWirkus, DNP, APNP, CORLN3939thth Annual SOHN Congress Annual SOHN Congress

& Nursing Symposium& Nursing Symposium

Pharmacology Day Pharmacology Day

September 25, 2015September 25, 2015

Objectives� Define undesirable effects from

medications.

� Consider methods for assessment and treatment of drug reactions.

� Explore resources that provide drug information.

� Investigate medication side effects in ENT.

� Examine treatment options for medication side effects in ENT.

� Participate in interactive discussion on identification and management of medication side effects.

Adverse Drug Reactions

� Major cause of morbidity and mortality worldwide

� MOST COMMON iatrogenic illness� Complicates 5-15% of drug

courses

� 100,000 deaths annually

� 3-6% of hospital admissions

� Affects 6-15% of hospitalized patients

Adverse Drug ReactionsTwo ClassificationsTwo ClassificationsTwo ClassificationsTwo ClassificationsImmunologic (Hypersensitive)� 5-10% of all drug reactions

� True drug hypersensitivity

� IgE-mediated

� Gell and Coombs described

� Type I: anaphylaxis from β-lactam antibiotic

� Type II: hemolytic anemia from PCN

� Type III: serum sickness from anti-thymocyte globulin

� Type IV: contact dermatitis from topical antihistamine

Adverse Drug ReactionsTwo ClassificationsTwo ClassificationsTwo ClassificationsTwo ClassificationsNon-Immunologic (General)

� 75-80% are predictable

� Remainder are unpredictable—may or may not be immune mediated� Pseudoallergic: result of direct mast cell activation and degranulation by

drugs

� anaphylactoid reaction after radiocontrast media

� Idiosyncratic: cannot be explained by known pharmacologic action

� hemolytic anemia in patient with G6PD deficiency after primaquine therapy ***

� Intolerance: lower threshold to normal pharmacologic action of drug

� tinnitus after single, small dose of aspirin

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Adverse Drug ReactionsTwo ClassificationsTwo ClassificationsTwo ClassificationsTwo ClassificationsNon-Immunologic—Predictable� Pharmacologic side effect

� Dry mouth from antihistamine

� Secondary pharmacologic side effect

� Thrush while taking antibiotic

� Drug toxicity

� Hepatotoxicity from methotrexate

� Drug-drug interactions

� Seizure from theophylline while taking erythromycin

� Drug overdose

� Seizure from excessive lidocaine

Drug Information Resources� U.S. Food & Drug Administration www.fda.gov

� Index to Drug-specific information:

/Drugs/DrugSafety/PostmarketDrugSafetyInformationforpatientsandProviders/ucm111085.htm

� Medication Guides:

/Drugs/DrugSafety/ucm085729.htm

� Drug Safety Communications

/Drugs/DrugSafety/ucm199082.htm

� MedlinePlus

� www.nlm.nih.gov/medlineplus/druginformation.html

� Merck Manual

� www.merckmanuals.com/professional

Ototoxic Medications

� Drugs that affect hearing and/or balance through one or more mechanisms

� Incidence is unknown

� Over 200 medications can produce toxicity

� 3 Major locations to exert ototoxicity

� Cochlea

� Vestibulum

� Stria Vascularis

Sites of Ototoxicity� Cochlea

� Hearing loss� High frequencies then low frequencies with speech

� Unilateral, bilateral, and fluctuant in severity

� May manifest as tinnitus, constant or fluctuant

� Vestibulum� Balance-related problems

� Spinning sensation

� Aggravated by motion

� Associated with nausea

� Stria Vascularis� Type of epithelium uniquely able to produce endolymph

in cochlea� Excessive endolymph=Meniere’s syndrome

Factors Affecting Ototoxicity

� Dose

� Duration of therapy

� Concurrent renal failure

� Infusion rate

� Lifetime dose

� Co-administration with other drugs having ototoxic potential

� General susceptibility

� Method of delivery

� Avoid ototoxic medications through non-intact tympanic membrane

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Common Ototoxic Medications� Aminoglycoside antibiotics

� Damage through the ability to generate free radicals in the inner ear

� Cochleotoxic and affects stria vascularis to cause vestibulotoxicity

� Streptomycin tends to affect vestibular > auditory, temporary or permanent� About 4-15% of patients who receive 1g/day > 1 week = measurable hearing loss,

occurring after short latent period of 7-10 days and slowly worsens if treatment is continued, possibly leading to permanent deafness

� Neomycin has greatest cochleotoxic effect of all antibiotics� Can impact with oral or colonic irrigation

� Do not use for wound, intrapleural, or intraperitoneal irrigation

� Tobramycin

� Glycopeptide antibiotics=Vancomycin� Loss of hearing and vestibular disorders on higher doses with impaired

renal function; often reversible.

� Increased risk of ototoxicity if used with aminoglycosides and ethacrynic acid

Topical Otic Medications� May be beneficial over oral medications

� Higher concentration into ear

� Increased efficacy with combination therapy

� Rapid delivery

� Good compliance

� Less cost

� Avoid systemic effect

� With perforation, greater ototoxic potential

� Allows for vestibular ablation for Meniere’s

� Quinolones recommended

Common Ototoxic Medications� Loop diuretics

� Affect potassium gradient in stria vascularis and electrical potential of endocochlear structure

� Toxicity is dose related

� Greater toxicity with rapid infusion and renal failure

� Furosemide-related ototoxicity is usually reversible

Common Ototoxic Medications� Quinine

� Can cause tinnitus, vertigo, or hearing loss (may be permanent)

� 200-300 mg over sustained period experience 20% risk of hearing loss

� FDA against OTC use, outdated as antimalarial

� Synthetic substitutes can also cause (temporary) hearing loss� Hydroxychloroquine is derived from quinine and cinchonine

� Antimalarial that modulates work of immune system

� Tea Tree Oil� May produce high frequency hearing loss

Common Ototoxic Medications� Antineoplastics

� Platinum-containing drugs

� Cisplatin affects cochlea and stria vascularis through generation of free radicals in inner ear

� Hearing loss can be profound and permanent after first dose or delayed after several months or completion of therapy

� Salicylates

� Impact cochlea at higher doses—reversible

� Linear relationship between salicylate concentration and level of hearing loss

� 20-50 mg/dL produce little risk

� Higher concentrations = hearing loss > 30 dB

� > 12 – 325 mg tabs per day

� Avoid topical use of counterirritants containing methyl salicylate

Other Medications affecting ears� Phosphodiesterase type 5 inhibitors (PDE-5i)

� Erectile dysfunction medication, sildenafil also used for pulmonary hypertension

� Most cases occur within 24 hours of use, most of those in 12 hours

� Lack of information on potentially confounding characteristics has precluded definitive conclusions regarding causality� PDE-5i cause congestion of nasal erectile tissue to elevate middle ear

pressure

� PDE-5i may intensify effects of nitric oxide . . . or simulate effects by facilitating increase proteins that are known to damage cochlear hair cells

� vardenafil (Levitra), tadalafil (Cialis), and sildenafil (Viagra)

� may be permanent

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Other Medications affecting ears� Acetaminophen/Hydrocodone potentially ototoxic

(Yorgason, J., Kalinec, G., Luxford, W., et al. 2010)

� Cochlear organ cultures exposed to combinations of acetaminophen and hydromorphone for 24 hours� Death of cochlear cells noted after about 24 hours

� No survivor cells by 96 hours

� Cytotoxic effect more evident in cells exposed to combination than acetaminophen alone� Hydromorphone-alone exposed cells thrived after about 72 hours

� Doses of acetaminophen > 4.5 mg/ml showed hair cell death near 100%

� More hair cells killed with combination of 4 mg/ml acetaminophen and 20 μg/ml hydromorphone than 4 mg/ml acetaminophen alone

� Hydrocodone seems to be working synergistically to increase negative effects of acetaminophen on auditory cells

Other Medications affecting ears� 2002: House Ear Clinic presented increasingly growing

database of patients with hearing loss in setting of acetaminophen/hydrocodone abuse with no other explainable cause� progressive, irreversible toxicity

� Problem of acetaminophen/hydrocodone ototoxicity more prevalent than suggested by few case reports in literature

� Common comorbidity of hepatitis C� More sensitivity to acetaminophen/hydrocodone exposure

possibly from imbalance of liver enzymes that lead to buildup of metabolites toxic to inner ear

� Need future studies to better characterize mechanism of toxicity

The nose knows� The nose . . .

� Processes the air you breathe before it enters your lungs� Turbinates filter , warm and humidfy 18,000 to 20,000 L of air /day

� Nose congestion . . .� Reduces sense of smell

� Causes mouth breathing, dry mouth, and thick lung secretions due to dry, cold air

� Can contribute to asthma

� A dry nose . . .� Impairs its functions

� May lead to infection

Medications and your nose� Antihistamines

� Relieve sneezing, itching, and runny nose

� Can cause drowsiness, slow ciliary movement, thicken mucous

� Diuretics� Dry nose to increase susceptibility to germs and pollens

� Anti-anxiety/Antidepressants� Dry nose . . .

� Nasal congestions due to:� Birth control pills

� Beta-blockers

� Viagra

� Eye drops can aggravate nose

Medications and your nose� Epistaxis is the most common bleeding symptom

� Multifactorial cause

� Drying factors

� Anticoagulants

� Part of 2012 ACCF/AHA Guidelines for MI/Angina

� Aspirin, clopidigrel, warfarin, ???

� Dizdar, O., et al (2008) found 53% of patients with nosebleeds had consumed aspirin in past week

� Aspirin and NSAIDs affect arachidonic acid metabolism and alter platelet function to enhance bleeding

� Herbal supplements

� Garlic, ginger, gingko, fish oil . . .

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Open your mouthDrug-induced Cutaneous Reactions

� Reactions common with skin but limited in oral cavity

� Categories� Hyposalivation/Xerostomia

� Lichenoid reaction/Lichen planus

� Aphthous-like and Non-Aphthous-like ulcers

� Bullous disorders

� Fibrovascular Hyperplasia

� Pigmentation

� Keratosis/epithelial Hyperplasia

� Dysesthesia

� Jaw osteonecrosis

� Angioedema

� Malignancy

Drug-induced oral reactions

� Medication use is one of most common causes of dry mouth

� Listed as adverse effect for > 500 medications

� Associated with > 80% of the 100 most prescribed medications

� Older individuals 3 X more likely to report

� Those take 1+ drugs > 2 X more likely to report

� 1 medication=16.7%

� 2-3 medications=33.3%

� 3+ medications=36.9%

Drying Medications� Too many to list all

� Most common� Antidepressants

� Antipsychotics

� Antihistamines

� Muscarinic receptor and α-receptor antagonists

� Antihypertensives� Diuretics

� β-blockers

� ACE inhibitors

� Bronchodilators

� Skeletal muscle relaxants

Saliva is important� Neutralizes acids

� Limits bacterial growth

� Wash away food particles

� Enhances taste

� Lubricates to ease swallow

� Contains enzymes that aid digestion

Dry mouth signs & symptoms� Dryness in mouth and throat� Saliva seems thick and stringy� Bad breath� Difficulty with

� Chewing� Speaking� Swallowing

� Altered taste� Problems wearing dentures� Tooth decay� Gum irritation and gum disease� Candidiasis/infection� Erythema� Burning discomfort

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Treating dry mouth� Change medication if possible

� Recommend products to moisturize mouth

� WATER

� Chew sugar-free gum or suck on sugar-free candies

� Breathe through nose

� Avoid drying products

Drug-induced oral reactions� Lichen planus is one of the most common inflammatory

conditions affecting skin and oral mucosa

� Difficult to distinguish from idiopathic cutaneous lichen planus—clinically and histopathologically

� Medications associated with lichenoid hypersentivityreactions� NSAIDs

� Antihypertensives

� Sulfonylurea antidiabetic medications

� Antifungals

� Immunomodulatorydrugs

� Anticonvulsants

� Others also suspect: levothyroxine, statins, antituberculosis, biolotic agents

Lichen Planus� Why?

� Susceptible patients have polymorphisms of cytochromeP450 enzymes that results in poor metabolism of some of the medications

� Active thiol groups found in chemical structure of some medications trigger reaction

� Idiopathic

� Difficult to diagnose and treat

Oral ulcers� Aphthous-like and non-aphthous like ulcers

� Offending medications

� NSAIDs

� Trimethoprim-sulfamethoxazole

� COX 2 inhibitors

� ARB Losartan

� Chemotherapy agents

Bullous Disorders� Common autoimmune reaction on skin—Rare in mouth

� Pemphigus vulgaris, erythema multiforme, Steven Johnson Syndrome

� Offending medications

� NSAIDs

� Procainamide

� Hydralazine

� Biologic agents

� Augmentin

� Anticonvulsants phenytoin, Lamictal

Pigmentation� Metabolites of medications deposit in oral mucosa and

chelate with iron and melanin to cause pigmentation

� Offending medications

� Antimalarials

� Tetracyclines and Minocyclines

� Also deposit in teeth, bones, nails, thyroid and sclera

� Zidovudine (AZT)—on tongue

� Oral contraceptives—on maxillary and mandibular gingiva

� Some chemotherapy agents—on tongue dorsum, buccalmucosa, nails

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Fibrovascular hyperplasia

� Diffuse, generalized, often nodular overgrowth of densely fibrous gingival tissue

� Due to increased production of collagen by reduced activity of various enzymes

� Calcium channel blockers nifedipine and amlodipineknow to cause; also cyclosporine and tacrolimus (Prograf)

Dysthesias� Includes sensitivity, burning, dysgeusia, and other

altered sensation (+dysosmia)

� Damage to salivary glands reduce production of saliva, which affects function of taste bud chemoreceptors

� Offending medications � Macrolides

� Antimyotics

� Fluoroquinolones

� Protein kinase inhibitors

� ACE inhibitors

� Statins

� PPIs

� Chemotherapy—neuropathies common

Jaw Osteonecrois

� Antiresorptive medications markedly slow bone turnover and remodeling to increase bone density

� Presents either as exposed bone or nonhealingextraction socket

� Offending medications

� Bisphosphonates

� Denosumab

Angioedema� Abrupt swelling of orofacial region and lips

� Mediated by inflammatory cytokines, complement activation, and vascular permeability

� Many offending medications

� ACE inhibitors commonly

� ARBs

� CCB

� Diuretics

� Antiplatelet agents

� Statins infrequently

Candidiasis� Overgrowth of normal organism in the lining of

mouth, sometimes extending downward

� Predisposing factors

� Endocrine imbalance

� Immunodeficiency state

� Reduced salivary flow

� Poor oral hygiene

� Malnutrition

� Intake of broad-spectrum antibiotics

� Use of topical steroids

� Chemotherapy/radiation therapy of head/neck

� Often comorbid diagnoses

Candidiasis� Signs & Symptoms

� Creamy white lesions on tongue, inner cheeks, and sometimes roof of mouth, gums, tonsils, throat

� Redness or soreness that can be severe enough to cause dysphagia

� Slight bleeding if lesions are rubbed or scraped

� Cracking and redness at corners of mouth

� Cottony feeling in mouth

� Loss of taste

� Treatments� Antifungal liquid, lozenges, or tablets

� Practice good oral hygiene; clean dentures

� Rinse mouth after steroid inhalers

� Limit sugar- and yeast-containing foods

� Promote healthy oral environment

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Medication Use

� Weigh benefit of use against risk (side effects)

� Consider necessity of medication

� Explore availability of substitutes

� Determine side effect severity and frequency

� Investigate lowering dose to eliminate side effect

� Contemplate treating side effect