NR PHARMACOLOGY INTRODUCTION TO PHARMACOTHERAPEUTICS

Exam (elaborations) NR PHARMACOLOGY INTRODUCTION TO PHARMACOTHERAPEUTICS NR PHARMACOLOGY INTRODUCTION TO PHARMACOTHERAPEUTI CS INTRO TO PHARMACOTHERAPEUTICS Prescription Writing Need at least 2 patient identifiers: Name, DOB, Address, Date of Rx, Prescriber name, address, license number, DEA number if applicable, Info for supervising MD, Drug: name/strength/dose/route/QTY/refills, Signature JC ¡§Do Not Use¡¨ List ¡E U: write out ¡§unit¡¨ ¡E IU: write out ¡§international units¡¨ ¡E Q.D., Q.O.D.: write out daily or every other day ¡E Trailing/leading zeros ¡E MS, MSO4, MgSO4: write morphine sulfate or magnesium sulfate ¡E £gg: write mcg ¡E H.S.: write half-strength or at bedtime ¡E T.I.W.: write three times weekly or 3 times weekly ¡E S.C. or S.Q.: write Sub-Q or subQ or subcutaneously ¡E D/C: write discharge ¡E c.c.: write mL ¡E AS, AD, AU, OS, OD, OU: write out, e.g., both eyes or left ear ANTIBIOTICS Class Drug MOA Uses/Coverage ADR/DDI Education/Other PCN: 1st Gen Pen G (IV) Inhibit cell wall synthesis, Bactericidal Pneumococcal pneumonia Benzathine penicillin (IM) Syphilis, strep throat Pen VK (PO) Gram + coverage and Treponema pallidum PCN: 2nd Gen Nafcillin (IM/IV) Antistaphylococcal, Cloxacillin (PO) MSSA Dicloxacillin (PO) PCN: 3rd Gen Ampicillin (PO) Extended-spectrum: G(+) PLUS some G(-); Amoxicillin (PO) OM, URI Augmentin (amox + clavulanate) Diarrhea, Good for beta-lactamase: H.Flu, M.Cat PCN: 4th Gen Zosyn (piperacillin + tazobactam) (IV) Broad spectrum, covers Pseudomonas, many G(-) Cephalosporin: 1st Gen Cefazolin (IM, IV) Inhibit cell wall synthesis good Gram + coverage, NO MRSA coverage Cross-sensitivity with PCNs Cephalexin (PO) Cephalosporins: 2nd Gen Cefaclor Not as good G+ but some G(-); OM, Strep Cefuroxime (IM, IV, PO) pharyngitis Cephalosporins: 3rd Gen Ceftriaxone (IM, IV) better G- but lower G+ coverage, High risk w/ some for ESBL resistance Ceftriaxone good for gonorrhea d/t single dose Cefotaxime (IM, IV) Cefixime (PO) Cephalosporins: 4th Gen Cefepime (IM/IV) Good G+ and G- coverage, Covers Pseudomonas Cephalosporins: 5th Gen Ceftaroline (IV) G- as 3rd-gen plus MRSA coverage Carbapenems Doripenem Inhibit cell wall synthesis Broader than other BL-abx All IV, IM, saved for very broad coverage May have cross-sensitivity to PCNs Ertapenem Ertapenem: not good Pseudomonas coverage Imipenem & cilastatin Meropenem Monobactam Aztreonam: IM, IV, inhale Inhibit cell wall G- ONLY, Covers Pseudomonas Never use for empiric tx, 1 synthesis Good for PCN-allergic Vancomycin IV Inhibit cell wall synthesis Mainly for G+ and MRSA IV ADR: dose-related ototoxicity & nephrotoxicity; Red man (infusion NOT allergy) Dose for renal fxn, monitor serum levels Vancomycin PO For C. diff. colitis Telavancin Inhibit cell wall synthesis Alternative to vancomycin Covers G+ and MRSA ADR: Teratogenic and QT prolongation No drug monitoring Macrolides Erythromycin Inhibit protein synthesis, bind to 50s ribosomal subunit G+, G-, and atypicals, Often used to treat G+ in pen-allergic patients; Enzyme inhibitor: E > C >> A Must watch with: CBZ, warfarin, statins, etc. Allergic reactions are rare! Clarithromycin ADR: n/v, metallic taste Improved H.Flu vs. E-mycin Azithromycin Long 1/2 life, good for Chlamydia, other atypicals Tetracyclines Doxycycline Inhibit protein synthesis, bind to 30s ribosomal subunit Coverage very broad: G+, G-,aerobic and anaerobic, spirochetes, mycoplasmas, rickettsiae, chlamydiae, some protozoa, MRSA PO High levels of resistance CI: Avoid with chelating agents (MVI, antacid, milk, iron), Avoid in pregnancy and small children (<8) ¡V Binds Ca and will stain teeth ADR: n/v, liver Minocycline disease, phototoxicity Tigecycline IV Derivative of minocycline MRSA, MDRSp, VRE, ESBL-producing G-, many anaerobes, NOT for Pseudomonas; for Complicated SSTIs, intraabdominal ifxn, CAP Aminoglycoside Amikacin Inhibit protein synthesis, bind to 30s ribosomal subunit G- including Pseudomonas Monitor renal function and serum drug levels! Gentamicin ADR: ototoxicity, nephrotoxicity Tobramycin Clindamycin Inhibit protein synthesis, bind to 50s ribosomal subunit Mainly for anaerobic coverage PO or IV and in some topicals, MRSA PO ADR: rashes and high rate of C.diff. Linezolid (Zyvox) Inhibit protein synthesis, bind to 50s ribosomal subunit PO & IV Use for resistant organisms: MRSA, VRSA, VRE, penicillin-resistant Strep. pneumo Caution for Serotonin Syndrome Might offer benefit when transitioning to outpatient Fluoroquinolones Ciprofloxacin Inhibit nucleic acid synthesis ¡V inhibit topoisomerase UTI, GI, Pseudomonas broad G-, respiratory FQs with improved G+ coverage ADR: C.diff colitis!! CNS: seizure, dizziness; Cardiac: QT prolong; MS: tendon, cartilage; Endo: glycemic control; Skin: photosensitivity, rash DDI: antacids, Fe, Ca, Zn Levofloxacin UTI, GI, LRI, URI, skin Moxifloxacin LRI, URI, GI, skin (no UTI!!) Others PO, otic, ophthalmic Folate Antagonist TMP-SMX (Bactrim, Septra) Broad with G+ and G-, NO Pseudomonas Common for UTI, MRSA PO ADRs: rash (simple to SJS), photosensitivity, crystalluria (need to counsel) Dose based on TMP (more important in PO liquid) Miscellaneous Metronidazole Covers protozoa, anaerobes **DOC: C.diff. colitis Trichomoniasis; Various infections of: skin, bone, CNS, GYN, GI, LRI, endocarditis ADR: Avoid with EtOH. Metallic taste Nitrofurantoin unclear, thought to inhibit several enzyme pathways and possibly Use in simple UTI treatment and prophylaxis NOT pyelonephritis or complicated cystitis CI: ClCr <60 mL/min; Do not use in renal impairment Warnings/Caution: Hepatic disease, Elderly 2 cell wall synthesis 3 PHARM FALL 2013 BLOCK I: DERM & EENT INTRODUCTION TO DERMATOLOGIC PRODUCTS Determinant of Pharmacologic Response 1. Permeability and penetration ¡V hydrated > dehydrated, thin > thick, trauma > no trauma 2. Concentration gradient ¡V greater concentration „³ greater amount per unit time (threshold may exist) 3. Dosing ¡V time left on skin, frequency, quantity; dermis acts as barrier and can effect duration 4. Vehicle ¡V cream, ointment, liquid, solution 5. Occlusion ¡V maximizes efficacy, increases absorption, protection Drug Delivery Systems „h Emulsions ¡V drug particle contained w/in vehicle/base; Indication for different types of products (dry/wet, sensitivity/pain, size, location, acute/chronic) „h Creams ¡V most common vehicle, no occlusion „h Ointments ¡V common, good for dry lesions due to occlusive properties; NOT for intertriginous areas; can be cosmetically unpleasing „h Gels ¡V clear, non-greasy, non-staining, non-occlusive, quick drying; can sting on application and be drying (due to EtOH) „h Solutions ¡V evaporate quickly (drying), used in acute/weeping/oozing wounds o Tinctures ¡V alcohol-based solution, used for extreme drying properties „h Aerosols ¡V advantage for painful skin, but expensive and not efficient dosage form „h Lotions ¡V good for tender areas, spreads easily, evaporates quickly, good for large areas „h Powders ¡V used to absorb moisture/friction; caution w/ very wet lesions due to crusting Choosing Which Drug Delivery System to Use DRY wet lesions and WET dry lesions **more liquid agents dry better „h Acute inflammation (oozing/weeping/vesication/edema/pruritis) „³ aqueous vehicles, powders, lotions, sprays, aerosols „h Subacute inflammation (crusting/oozing/pruritis) „³ creams, gels „h Chronic inflammation (lichenification/dryness/erythema/pruritis/scaling) „³ ointments ANDROGENIC ALOPECIA Tx goal: reduce loss and maintain existing hair **If you stop therapy, hair loss WILL return! Drug MOA Indication ADRs/DDI/CI Specific Education/Other Minoxidil Changes follicle size & growth cycle of hair to „^ f hair & thicker/longer shaft Topical formulation only to limit and contain ADR („`BP); OTC, 1st line M & F ADR: local irritation, undesirable growth if inappropriately use **welltolerated Wash hands after application, treatment must be continuous Finasteride Type II 5-alpha-reductase inhibitor, PO (tablet) formation that only grows *CI: pregnancy Caution in women of child-bearing 4 Vehicles for Topically Applied Drugs Cream Ointment Gel/Foam Lotion/Solution/Foam Pharmacological Advantage Leaves concentrated drug at skin surface Protective oil film on skin Concentrates drug at surface after evaporation Advantages for Patient Spreads and removes easily, no greasy feel Spreads easily, slows water evaporation, gives cooling effect Non-staining, grease-less, clear appearance Low residue on scalp Locations on Body Most locations Avoid intertriginous areas* Foams well for scalp and other hairy locations Solutions and foams are well accepted on scalp Disadvantages Needs preservatives Greasy to very greasy, stains clothes Needs preservatives, high alcohol can be drying Occlusion Low Moderate to high, increases skin moisture inhibits conversion of testosterone to dihydrotestosterone (reverse loss) hair at vertex/frontal scalp; first line for men, second line for women ADR: „`libido, erectile dysfunction, ejaculation disorder, „`ejaculation vol age, wash hands/gloves, treatment must be continuous SYSTEMIC ANTIFUNGALS Class Drug MOA Indication ADRs/DDI/CI Specific Education/Other Amphotericin B (¡§Amphoterrible¡¨) binds to ergosterol and alters permeability; large spectrum of activity IV; only used in infectious disease with high resistance *lipid formations are less toxic, but still not good ADRs: EXTREMELY TOXIC (nephrotoxicity, infusionrelated toxicity) Azoles Fluconazole (Diflucan) inhibit synthesis of ergosterol by blocking demethylation of lanosterol IV and PO; Important treatment for infections due to Candida; drug of choice for vaginal yeast infections Itraconazole IV and PO *bioavailability varies, PO solution achieves higher serum concentrations; Used for fungal nail infections Can cause liver problems ¡V must get liver enzymes checked every 4- 6 weeks Voriconazole IV and PO; Broad spectrum triazole used for serious infections, first line for aspergillosis ADR: visual abnormality Posaconazol e PO suspension Broad-spectrum triazole, but can cause many DDIs *Enhanced w/ high-fat meal, splitting dose in fasting Echinocandins disrupts cell wall structure formation by inhibiting £]- glucan synthase IV only; used to treat significant fungal infection ¡V integral component of Aspergillus and Candida cell wall Generally well tolerated (but expensive) *more common/better tolerated/less DDIs than azole Flucytosine disrupts cell wall formation via pyrimidine analog PO only, rarely used as monotherapy due to rapid resistance development Spectrum: Cryptococcus spp, Candida spp; used to treat cryptococcal meningitis in combination w/ AmB Key Points of Systemic Antifungals „h Always consider hepatic function (liver disease, heavy EtOH use, etc.) „h Review patient¡¦s medical history to avoid DDIs „h Systemic ¡Vazole agents in primary care are mainly used for skin/nail disorders, vaginal yeast infections (fluconazole) TOPICAL ANTIFUNGALS Class Drug MOA Indication Specific Education/Other Topical Azoles Block biosynthesis of ergosterol Tinea pedis/cruris/corporis, tinea versicolor, cutaneous candidiasis, vaginal candidiasis *Most effective topical antifungal for treatment of dermatophytes Topical Allylamines, Butylamine Naftifine inhibit squalene epoxidase (key enzyme in ergosterol biosynthesis pathway) Tinea pedis/cruris/corporis, tinea versicolor Terbinafine (Lamisil) **Terbinafine = tx for nail fungus Butenafine Topical Polyene Nystatin Bind to ergosterol in fungal cell membrane, changes membrane permeability cutaneous infections caused by Candida albicans, other Candida spp *not useful against dermatophytes *highly toxic systemically Other Selenium exerts a cytostatic effect of cell of epidermis tinea versicolor Lotion, Shampoo formulations OTC (well- 5 Sulfide and follicular epithelium tolerated) Tolnaftate Distorts the hyphae and stunts mycelial growth of fungal species Tinea pedis/cruris/corporis, tinea versicolor (Tinactin) *tough-actin tinactin; Cream, solution, powder, spray, gel forumations OTC Ciclopirox alters integrity of fungal cell membrane skin, superficial nail infections; tinea pedis/cruris/corporis, tinea versicolor *activity against Candida Cream, lotion, nail laquer (Penlac) formulations Systemic Agents for Superficial Infections *Fluconazole Itraconazole Ketoconazole Terbinafine Griseofulvin Indicated for candidiasis *yeast/vaginal infections Single dose is used for treatment Indicated for candidiasis, dermatophytes (tineas), onychomycosis (nail fungus) Multiple DDIs ¡V Inhibited CYP3A4 Indicated for candidiasis, dermatophytes Multiple DDIs, potential hepatotoxicity *only last line in life-threatening infection PO and topical available Indicated for candidiasis, dermatophytes, onychomycosis Potential hepatotoxicity ¡V monitor liver enzymes Inhibits mitosis, rarely used Indicated for dermatophytes and onychomycosis *Pulse Therapy (Terbinafine and Itraconazole): Used in onychomycosis treatment, has some evidence for less toxicity (dosed daily 1 week, off 3 weeks) to decrease ADRs, DDIs DRUG ERUPTIONS Types of Drug Eruptions „h Mild rash, itching, dry skin „³ severe, potentially life-threatening conditions) „h SJS, TEN, Angioedema, Vasculitis, Coagulent-induced skin necrosis General Approach to Drug Reactions (1) Recognize that problem may be drug-related Identify agent (2) STOP OFFENDING AGENT (3) Determine severity (i.e. triage situation) (4) Treat sequelae **Don¡¦t forget to EDUCATE PATIENT Reaction Characteristics Common Offenders Acneiform Reactions Differ from true acne: no comedone, uniform appearance of lesions, location, age, recent drug exposure glucocorticoids, oral contraceptives, lithium, anabolic steroid Photosensitivity Reactions Phototoxic reactions ¡V exaggerated sunburn or increased sensitivity to light; UVA causes alteration of drug to toxic form (>common) Photoallergic reactions ¡V manifests in bullae, urticaria, sunburn; UVA alters drug to antigen and leads to allergic response (<common) antibiotics, antidepressants, hypoglycemics, oral contraceptives, antipsychotics, antihypertensives Allergic Contact Dermatitis Topical administration can cause localized allergic response, reaction widespread if given systemic drug after topical sensitization neomycin (Neosporin), benzocaine, diphenhydramine (Benadryl) Erythema Multiforme Lesions of various forms including Target lesions; affect mucous membranes allopurinol, barbiturates, phenothiazine, sulfonamides Stevens-Johnson Syndrome (SJS) Most common severe eruption; can be life-threatening (est. 5-20%) sulfonamides*, FQs, allopurinol, carbamazepine, pregnancy, infection, radiation, cancer, foods Topical Epidermal Necrosis (TEN) Prodrome of milder symptoms (fever, fatigue, arthralgias, sore throat); can be fatal (est. 30%) allopurinol, aminopenicillins, carbamazepine, sulfonamides*, infection, foods Erythema Nodosum Erythematous rash with tender nodules commonly on legs (usually no mucosal involvement) oral contraceptives*, analgesics, sulfonamides Drug Hypersensitivity Reaction Multiple names/varied constellation of symptoms and signs may lead to misdiagnosis; Typically start w/ fever, widespread maculopapular rash on trunk, arms, legs; organ damage may follow, fatal in 10% sulfonamides, PCNs, anticonvulsants, antimalarials Fixed Drug Eruption Erythematous lesions of various types (nodules, bullae) common on genitals, face *always in same spot Caused exclusively by drugs (antibiotics, anti-inflammatories, oral contraceptives) *generally resolve after offending drug d/c Maculopapular Typical rash, #1 drug reaction manifested in skin *classic PCN rash ampicillin, amoxicillin, allopurinol 6 Eruptions Scarlatiniform (scarlet fever-like, erythematous, wide-spread lesions) or Morbiliform (measles-like, reddish/brown macules coalesce) Usually 1w after drug exposure, resolve w/in 2 weeks after d/c Urticaria (Hives) Immediate, IgE-mediated (hypersensitivity) reactions Lesions will usually migrate until offending allergen ins topped *can be isolated or widespread ***Patients w/ urticaria are at increased risk for anaphylaxis with future exposure (do NOT re-challenge) aspirin (ASA), penicillins Angioneurotic Edema (Angioedema) Severe form of urticaries (hives penetrate deeper); involve lips, tongue, eyelids (fatal if tongue, throat, larynx); May take weeks ¡V years, can happen at any time ***ACEIs (angiotensin-converting enzyme inhibitors); patients must be warned to watch swelling TOPICAL ANTIBIOTICS (tx mild skin infections) Drug Indication ADRs/DDI/CI Bactracin (OTC) Broad G+ coverage, not for MRSA, used in combination products Topical application only due to severe nephrotoxicity with systemic use Neomycin (OTC) Common, broad-spectrum used for minor infections (abrasions, cuts, etc.), not for MRSA increased risk for hypersensitivity if in combination with other antibiotics Mupirocin (Rx) DOC for impetigo (superficial), used for multiple G+ skin infections, MRSA nasal colonization Retapamulin Topical agent used for impetigo only Silver Sulfadiazine Used in treatment/prevention of burns *caution w/ sulfa allergy SELECT VIRAL SKIN DISORDERS Condition Management General Concepts „h Antivirals have potential for DDIs „³ complete a thorough medication history before prescribing *adjustment for renal/hepatic disease „h Must also use supportive therapy/treat complications (fever, arthralgias, pain, post-herpetic neuralgia) Oral-Facial Herpes (Herpes Labialis) Most are self-limiting (10 days) and treat with respect to immune status and if prolonged disease is likely Topical *should begin w/in 1 hour of first signs/symptoms **all must be frequently applied (disadvantage) „h Acyclovir (Zovirax) cream ¡V Rx only „h Docosanol (Abreva) cream ¡V OTC „h Penciclovir (Denavir) cream ¡V Rx only Oral *can be good option for immunosuppressed **easier to take, but costly (weigh costs/benefits) „h Acyclovir (Zovirax) „h Famciclovir (Famvir) ¡V single dose „h Valacyclovir (Valtrex) Varicella-Zoster Infection Varicella (Chickenpox) „h Childhood vaccine available „h Acyclovir ¡V PO Herpes Zoster (Shingles) „h Adult vaccine available „h Acyclovir, Famciclovir (fewer doses), Valacyclovir (fewer doses Genital Herpes Acyclovir, Famciclovir (fewer doses), Valacyclovir (fewer doses) Warts Vaccine available Treat w/ cryotherapy, instrumentation (cutting or curettage) Imiquimoid (Aldara) cream or Podofilox (Condylox) gel for genital warts 7 CORTICOSTEROIDS General Concepts „h Glucocorticoids ¡V receptors widespread throughout body (cortisol) „h Mineralocorticoids ¡V receptors in kidney, colon, salivary/sweat glands, brain (aldosterone) o Regulates water volume and concentration of electrolytes ¡V acts on kidney tubules, collecting ducts, enhances Na+ reabsorption o Used less frequently than glucocorticoids Class MOA Indications/Management ADR/Patient Education Systemic Glucocorticoids „h Anti-Inflammatory „h Promotion of Metabolism (**DM patients sugar will increase) „h Increased Resistance to Stress „h Alteration of Blood Cell Levels in Plasma Acute Adrenal Insufficiency „h Dx: ACTH stimulation test; Tx: IV hydrocortisone + glucose Chronic (Addisons) Adrenal Insufficiency: „h Tx: PO hydrocortisone daily, prednisone or dexamethasone „h Some patients normalized by hydrocortisone + salt intake, many require mineralcorticoid replacement „h Fludrocortisone** mineral action Inflammatory/Autoimmune Disease: Provide sx relief only ¡V do not cure!! „h High initial dose and taper over days to allow adrenal recovery „h Tablets (#1), can also be injected to minimize systemic effects Asthma „h Inhaler administration daily *minimizes systemic effects, ADRs „h Agents: Triamcinolone, Beclomethasone, Flunisolide, Fluticasone „h PO for severe exacerbations * chronic bronchitis and emphysema Allergic Disease „h Relief delayed 12-24h, appropriate for severe/long /systemic reactions „h PO or IV, nasal spray steroids are first choice treatment for allergic rhinitis Other: „h Infectious Disease: supplemented, not 1st line „h Blood Malignancies „h Traumatic Injury/Organ Transplantation: Spinal cord injury (NOT effective w/ head injury), Organ transplantation „h Preterm labor „h Chemotherapy ADRs of Corticosteroids „h Fluid/electrolyte imbalances „h Metabolic: hyperglycemia/glucosuria (close management w/ diet, insulin) „h Immune suppression: Increased susceptibility to infection with chronic use „h GI acid production: increased risk of peptic ulcer, (esp. in conjunction w/ NSAIDs) „h Myopathy: muscle wasting, takes high dose „h Osteoporosis, Osteonecrosis „h Cataracts „h Behavioral changes ¡V ¡§steroid psychosis¡¨ „h Growth suppression in children ¡V especially systemic steroids **use of steroids in chronic asthma in children is a common concern „h Cushing¡¦s Syndrome ¡V chronic use; upper body obesity, rounded/moon face, thin arms/legs Withdrawal from Glucocorticoids: Sudden withdrawal can be life-threatening (acute adrenal insufficiency) **taper off if used > 2weeks!! Topical Corticosteroids Inflammatory skin diseases „h 1% hydrocortisone ointment +/- occlusive dressing, minimal systemic absorption „h Systemic administration for widespread/severe exacerbations (prednisone, prednisolone) „h Many preparations ¡V betamethasone (most potent), triamcinolone, clobetasol „h Fluorinated steroids should NOT be used on face (dexamethasone, triamcinolone, betamethasone, ¡§flu-sone,lone,rone) * DOC for skin inflammation and pruritus but avoid use in infectious etiologies (except when combined w/ antifungal) Ocular Inflammation „h Dexamethasone eye drops or ointment **should always be used under Aoid overuse, use lowest potency *educate patient not to exceed recommended dosing Don¡¦t forget systemic effects: children, elderly, liver disease, thin skin, use of occlusion/high potency agents (ointments) ADRs *fewer than systemic Local ¡V with chronic, repeated use Systemic ¡V adrenal suppression can occur with high dose, long-term treatment 8 supervision of ophthalmologist „h Increase IOP, aggravate glaucoma *monitor if admistered for >2 weeks SELECT PARASITIC SKIN INFECTIONS Condition Drug MOA Indication & ADRs/DDI/CI Specific Education/Other Pediculosis/Lic e Pyrethrins & piperonyl butoxide Generally work by disruption of nerve conduction „h Many are OTC, come in various dosage forms, very specific instructions, specific age limits „h All drug tx + non-pharmacological tx (combs, disinfestation of bedding/clothes) „h Petrolatum ¡V good for eye lashes or wanting to avoid pharmaceuticals *Permethrin 1st line treatment ; Avoid use around eye, caution w/ ragweed or chrysanthemum allergy Benzyl Alcohol Spinosad Ivermctin Malathion Use if resistance Lindane NOT first line, black-box warning (CNS toxicity) Scabies Permethrin No use around eye, caution w/ ragweed or chrysanthemum allergy „h Tx bleeding, clotting and all infected persons in household/institution!! „h Itching persisting after initial eradication ¡V use topical corticosteroid Ivermectin Not FDA approved Crotamiton High failure rates ACNE MANAGEMENT Class Drug MOA Indication ADRs/DDI/CI Specific Education/Other Topical Retinoids Tretinoin* Vitamin A analogs stimulate epidermal cell turnover ¡V unplug follicles, inhibit inflammatory mediators 1st line in mild-moderate acne, combo for moderate-severe, maintain remission ADR: skin (stinging, redness, drying); Use sunscreen, moisturizer, apply at night, avoid use with benzoyl peroxide most commonly used Tazarotene more effective, but more irritation *contraindicated in pregnancy Adapalene less irritation, but less effective Benzoyl Peroxide (OTC) antibacterial and keratolytic often in combo with other antibiotics to reduce resistance, OTC so often used first-line as monotherapy Pt Ed: can bleach of skin, avoid overuse (mostly once daily), do NOT use with topical retinoids ADR: skin (dryness and peeling of skin), well tolerated Azelaic Acid (Rx) normalizes keratinization and suppresses P.acnes less irritation, 1st-line for sensitive skin, < effective than other topicals, indicated for Rosacea (specific form) Pt Ed: reported cases of hypopigmentation, $$$ ADR: local skin irritation Salicylic Acid (OTC) desquamation of hyperkeratotic epithelium, keratolytic less effective v. benzoyl peroxide, 2ndline if other comedolytics haven¡¦t worked, in combo with other agents ADR: local skin irritation Topical Abx Sulfacetamide increase turnover of epithelium failure of mild acne or moderate acne (usually in combo Sulfacetamide + with other topicals) Sulfur Erythromycin Clindamycin Oral Abx Minocycline usually for moderate-severe acne, given ~3 months/until under control Dosed with topical retinoid and/or benzoyl peroxide to improve efficacy and reduce resistance Doxycycline TMP-SMX Azithromycin 9 Erythromycin Oral Contraceptives estrogen is an anti-androgen agent moderate-severe acne (females only), specific combos have indications and/or are better for acne Isotretinoin (Accutane) Only for severe, recalcitrant, nodular acne (extremely severe, failed other tx), producing either physical/psych scarring ***ORAL ISOTRETINOIN IS A POTENT TERATOGEN*** iPLEDGE program (anyone in contact w/ drug must use) ¡V only prescribe 30 days/time, must complete monthly pregnancy test, etc. ADRs: LOTS **must look up if you see on medication list, also a list of lab tests to be ordered at baseline and during treatment „h There is no cure, ranges mild„³severe, triggered by stress/sunlight/chemicals/etc; Strategy: topical retinoid „³ topical antibiotic „³ oral antibiotic „³ isotretinoin*** „h Don¡¦t forget patient expectations, address: discomfort, appearance, long-term scarring, psychological stress „h Etiology: sebaceous gland hyperplasia, follicular hyperkeratosis, propionibcaterium acnes colonization, inflammation ALLERGIC RHINITIS Class Drug MOA Indication ADRs/DDI/CI Specific Education/Other Intranasal Antihistamines Azelastine Sneezing, rhinorrhea, nasal pruritis, Olopatadine some congestion PO 1st Gen Antihistamines *Diphenhydramine allergic/non-allergic rhinitis and sleep Allergic - photosensitivity, anaphylactic shock, drug rash, dermatitis CV - postural hypotension, palpitations, reflex tachycardia, thrombosis at injection site (IV promethazine) CNS **- drowsiness, sedation, dizziness, coordination, fatigue, confusion GI - epigastric distress, anorexia, bitter taste (nasal spray) GU - urinary frequency, dysuria, urinary retention Resp - chest tightness, wheezing, dry mouth, nose and throat, thickening of bronchial secretions, epistaxis and nasal burning (nasal spray) chlorpheniramine clemastine brompheniramine hydroxyzine PO 2nd Gen Antihistamines Desloratadine allergic/non-allergic rhinitis and sleep Allergic - photosensitivity, anaphylactic shock, drug rash, dermatitis CNS* - somnolence/ drowsiness, headache, fatigue, sedation Resp** - dry mouth, nose and throat (cetirizine, loratadine) GI** - nausea, vomiting, abdominal distress (cetirizine, fexofenadine) Fexofenadine Levocetirizine loratadine cetirizine Oral Decongestants Pseudoephedrine directly stimulate alpha- and betaadrenergic receptors nasal/ophthalmic congestion, Adjunctive/2nd Line Oral: better used intermittently to control symptoms Topical: (max length of therapy is generally 3 days due to rebound congestion) ***IMPORTANT **should not use long term Phenylephrine Topical Decongestants phenylephrine naphazoline tetrahydrozoline oxymetazoline Corticosteroids sneezing, rhinorrhea, itching, nasal congestion **1st line therapy Mast Cell Stabilizers Comolyn Na OTC add-on therapy used for prophylaxis, not for acute ADR: burning, HA, unpleasant taste CI: acute asthma attack onset 1-2 weeks Leukotriene Receptor Antagonist Montelukast Adjunctive/2nd Line ADRs: generally well tolerated 10 Intranasal Anticholinergic s Ipratropium bromide rhinorrhea, Adjunctive/2nd Line Caution: gluaucoma, myasthenia gravis, BPH (due to acetyl choline receptors), urinary issues Intranasal Saline (salt water, netti pots): help w/ congestion, moistening nasal passage Special Populations: Pregnancy ¡V ipratropium*, budesonide, cromolyn; Elderly ¡V avoid anticholingerics, decongestants SINUS/MOUTH/THROAT CONDITIONS Rhinosinusitis „h *Acute: < 4 weeks, Chronic: > 8 weeks, Recurrent: > 3x per year „h Viral: common cold is #1 pathogen** (supportive only) „h Bacterial: symptoms >10 days, 3+ days of severe fever, purulent drainage, facial pain, worsening symptoms „h Amoxicillin + clavulanate ; PCN allergy: doxycycline or FQ (levoflo/moxifloxacin) „h Adjunct therapy: decongestants, corticosteroids, mucolytics, irrigation, analgesics „h Varies due to regional resistance rates, age, recent hospitalization, recent antibiotic therapy, immune status Strep Pharyngitis „h White exudates, edema, erythema, 10 days* „h 1st Line: PO PCN V, PO amoxicillin or IM penicillin „h 2nd Line: Erythromycin (if PCN allergy), Azithromycin, Cephalosporins Cold & Flu „h Decongestant: Pseudoephedrine, Phenylephrine HCl „h Expectorant: Guaifenesin „h Cough Suppressant: Dextromethorphan HBr „h Antihistamine: Doxylamine succinate, Diphenhydramine, Brompheniramine, Chlorpheniramine „h Pain/Fever: Acetaminophen, Aspirin, Ibuprofen, Naproxen ORAL CANDIDIASIS Drug MOA Indication ADRs/DDI/CI Specific Education/Other Fluconazole 1st line Nystatin Suspension ADRs: N/V/D, poorly absorbed *swish & swallow (hold in mouth), relief in 24- 72hrs Chlorhexadine Gluconate binds to bacterial and yeast cell membranes Symptom relief ADRs: staining of teeth protection ~6hrs Magic Mouthwash MUST specify which EXACT ingredients you want to be compounded Clotrimazole Troche Tx or prophylaxis for patients on chemotherapy, steroids, other IC Needs special patient education OTIC CONDITIONS Condition Management Acute Otitis Externa „h Clean canal: either manually or with 1:1 hydrogen peroxide/water **Only if TM intact! „h Topical antibiotics: ofloxacin*, ciprofloxacin*, polymyxin B + neomycin, gentamicin, tobramycin (recall ototoxicity with AGs) „h Antiseptics: act as bacteriostatic agents; alcohol is most common product „h Glucocorticoids: hydrocortisone, dexamethasone (inflammation) „h Acidifying agents: acetic, hydrochloric, sulfuric, boric (lower pH) „h Mild: acidifying agent + glucocorticoid; Severe: antibiotic + antiseptic + glucocorticoid ** PO abx only for severe disease that extends outside of ear canal 11 „h Patient education important: fill ear canal to expose for at least 20 minutes, protect ear canal from water Malignant Otitis Externa „h 1st line IV antibiotics***(CBPs, AGs, anti-pseudomonal PCN) „³ systemic antibiotics + topical therapy „h Targets: *Pseudomonas aeruginosa, Staphylococcus aureus Acute Otitis Media (AOM) „h Treat symptoms: pain, fever + Treat Infection: 2 strategies *depends on severity and age o Tx immediately w/ antibiotics, observe for symptom improvement within 48-72 hours o Tx immediately w/ antibiotics: children <2 or >2 = appear toxic, otalgia for more than 48 hours, temperature >102, bilateral AOM, uncertain follow-up care, immuno-compromised „h First-line antibiotic choices:Amoxicillin, Amoxicillin-clavulanate (Augmentin); Alternatives: Macrolides, Clindamycin „h Length of treatment: <2 years old treat for 10 days, >2 years old 5-7 days Tinnitus Offending Medications: *Salicylates (aspirin), NSAIDs (ibuprofen, naproxen, diclofenac¡K), **Antibiotics (aminoglycosides, erythromycin, vancomycin), *Loop diuretics (furosemide, bumetadine), Chemo drugs (cisplatin, vincristine) GLAUCOMA/OPTHALMIC DRUGS Class Drug MOA Indication ADRs/DDI/CI Specific Education/Other Topical Prostaglandin Analogs*** Increases aqueous outflow 1st line glaucoma (recently) ADR: increased brown pigmentation of the iris, eyelash growth, hyperpigmentation of periorbital skin, conjunctival hyperemia, punctate epithelial keratopathy, foreign body sensation, cystoid macular edema Topical Beta- Adrenergic Receptor Reduces aqueous production Classically first choice in glaucoma ADR: potential for systemic absorption is highest (bronchoconstriction, bradycardia, depression, confusion, fatigue) CI: obstructive airway disease Topical Carbonic Anhydrase Inhibitors Reduces production of aqueous, sulfonamide derivatives Glaucoma ADR: local reactions including burning and stinging, superficial punctate keratopathy, allergic reactions of the conjunctiva, bitter after-taste is common; systemic side effects Topical Direct-Acting Cholinergic Agonists increase the outflow of aqueous through the trabecular meshwork Glaucoma ADR: local irritation, decreased vision Topical Indirect-Acting Anticholinesterase Agents Increase outflow of aqueous Glaucoma Topical Corticosteroids ADRs: exacerbation/development of microbial keratitis, reactivation of herpes simplex keratitis, ocular HTN, risk of open-angle glaucoma; cataract Any patient receiving topical corticosteroid therapy should be under ophthalmologist NSAIDS block prostaglandin synthesis through inhibition of cyclooxygenase pain and inflammation Miscellaneous Ocular Agents „h Mydriatics and cycloplegics used to dilate and paralyze muscles of accommodation for inspection and/or procedures „h Artificial tears/ocular lubricants used for symptoms of dryness „h FYI: Other agents used by ophthalmologists such as immunologic agents OPTHALMIC DRUGS & CONDITIONS Condition Management Blepharitis „h Warm compress (not hot) „h Antibiotics: topical &/or systemic 12 o Topical: bacitracin, erythromycin oint o Oral Tetracyclines (doxy- or mino-) o Oral Macrolide: Erythromycin, Azithromycin „h Topical anti-inflammatory agents: corticosteroids ointment, drops, cyclosporine 0.05% Corneal Abrasion „h Topical NSAIDS (reduce pain): diclofenac, ketorolac, nepafenac, bromfenac „h Topical (prophylactic) antibiotics may be used b/c infection slows healing o Discontinue contact lens use until healed o Gentamicin or Fluoroquinolone (i.e. gati- or moxifloxacin) Viral Conjunctivitis „h Antibiotics are NOT for viruses „h Self-limiting : gets worse for < 1 wk, then resolves in 2-3 wks Bacterial Conjunctivitis „h Empiric treatment is broad spectrum „h 1st line: polymixin B + bacitracin drops; erythromycin ointment ***SPECIFY EYE or OPHTHALMIC FORMULATION EENT CONDITIONS REVIEW System Conditions Management Eye Allergies Application Conjunctivitis of liquid, ointment Glaucoma Ear Otitis Media Cerumen Impaction Nose Allergies Nasal steroids: DOC, Antihistamines: 1st gen v. 2nd gen, Nasal antihistamines, LTRA, Ipratropium NS Decongestants Saline Irrigation EENT REVIEW Class Drug Comments Intranasal Corticosteroids Beclomethasone Budesonide Ciclesonide Low systemic absorption Flunisolide Fluticasone Low systemic absorption Fluticasone + Azelastine Combination of ICS and antihistamine Mometasone Low systemic absorption Triamcinolone Systemic H1 Receptor Antagonists Chlorpheniramine OTC Clemastine OTC Cyproheptadine rarely for rhinitis, used more for urticaria, off-label for migraine prophylaxis Diphenhydramine OTC Hydroxyzine very sedating Meclizine OTC formulations, used mainly for motion sickness and vertigo Promethazine used for nausea and vomiting 13 Cetirizine OTC Loratadine OTC Desloratadine Fexofenadine Levocetirizine Nasal H1 Receptor Antagonists Azelastine warn of drowsiness Olopatadine warn of drowsiness Opthalmic H1 Receptor Antagonists don¡¦t need to know individual agents 14 PHARM FALL 2013 BLOCK II: ENDOCRINE & HEME PITUITARY HORMONES „h Posterior Hormones synthesized in neurons that originate in hypothalamus; Anterior Hormones synthesized in epithelial cells, but are under neural control via portal circulation „h Most require parenteral administration because of proteolytic breakdown in the gut; newer, synthetic analogues have PO stability; Many routes: IM, IV, SubQ, IN, PO Class Drug MOA Uses/Coverage ADR/DDI Posterio r Pituitary Vasopressin ADH: Controls rate of water excretion in urine „h ¡ô = ¡ôpermeability, ¡õ water loss in urine „h ¡õ = kidneys impermeable to water, ¡õ reabsorption Kidney: binds to V2 receptor to ¡ô water permeability and reabsorption in collecting tubules; In liver, vascular SM Diabetes insipidus Esophageal varices Cardiac arrest/shock ADR: Water intoxication, hyponatremia, HA, bronchoconstriction, tremor Caution: CAD, epilepsy, asthma, vascular disease, elderly Desmopressin Molecule modified for minimal activity at the V1 receptor Diabetes insipidus and nocturnal enuresis Oxytocin (Pitocin) Oxytocin: Elicits Uterine contractions during labor, Milk expression in lactation Medical (not elective) induction of labor, adjunct in abortion, postpartum bleeding CI: fetal distress, abnormal fetal presentation, premature births Anterior Pituitary Corticotropin ACTH: Stimulates production of glucocorticoids and androgens by the adrenal cortex; maintains size of zona fasciculata and zona reticularis of cortex Dx: Diff. Cushing syndrome and ectopic ACTH-producing cells, Diff. primary (Addison disease) from secondary adrenal insufficiency Tx: MS, infantile spasms, other inflammatory ADR: like glucocorticoids (osteoporosis, hypertension, edema, hypokalemia, CNS stimulation, infection, etc.) Cosyntropin Synthetic ACTH Diagnosis of adrenal insufficiency Somatotropin GH: Stimulates body growth; secretion of IGF-1; stimulates lipolysis; inhibits actions of insulin on car/lipid metabolism GH deficiencies; is not indicated for use in elderly to increase/maintain muscle mass ADR: edema (HTN, intracranial HTN, etc.), neoplasms, bone malformations Mecasermin IGF-I analogue Tesamorelin GH secretagogue HIV-associated lipodystrophy Pegvisomant GH Receptor Antagonist; prevents binding Tx-resistant acromegaly Octreotide* Somatostatin (GH inhibitor) Analog Acromegaly, CA; diarrhea, esophageal varices Lanreotide Refractory acromegaly Pasireotide Cushing¡¦s disease Goserelin GnRH Agonist:(Luteinizing hormone-releasing hormone, gonadorelin): Endogenous GnRH undergoes pulsatile secretion, release of FSH and LH is inhibited Prostate cancer, endometriosis, precocious puberty CI: pregnancy ADR women: hot flushes, sweating, decreased libido, depression, ovarian cysts ADR men: ¡ôtestosterone (bone pain); hot flushes, *gynecomastia, edema, diim. libido Histrelin Leuprolide Nafarelin Triptorelin Degarelix GnRH Antagonist Advanced prostate cancer Cetrorelix Control ovulation CI: Preg category X Chorionic FSH: development of ovarian follicles; regulates Infertility treatment in women and men; 15 Gonadotropin spermatogenesis in testis LSH: ovulation and formation of the corpus luteum in the ovary; stimulates production of estrogen and progesterone, testosterone specialist use only Follitropin B Follitropin A Urofollitropin Prolactin Prolactin: Stimulates milk secretion and production Stimulate and maintain lactation, Decrease sex drive and reproductive function THYROID HORMONES „h Iodine is brought into glanda Thyroid hormones are made in gland a thyroid hormones and exported out of gland into circulation. Class Drug MOA Uses/Coverage ADR/DDI Antithyroi d Methimazole Inhibits thyroid hormone synthesis Hyperthyroidism/Grave¡¦s disease ADR: Dermatitis*, myalgia, arthralgia, jaundice, edema; nephritis, agranulocytosis*, hepatotoxic* CI: Preg Cat D PTU Propylthiouraci l Inhibits T3/T4 synthesis; iodination of tyrosyl groups and condensation of iodotyrosines to form T3 and T4 Hyperthyroidism/Graves disease BBW: hepatotoxicity ADR: Derm, GI, arthritis; Granulocytopenia, leukopenia CI: Preg Cat D, max 200mg/d Iodide Inhibits the iodination of tyrosines; inhibits T3/T4 release from thyroglobulin Only for short term/3rd line (thyroid storm, presurgery) Potassium Iodide iIhibits thyroid hormone synthesis and release Hyperthyroidism ADR: metallic taste, GI; arrhythmias, GI bleed, goiter, angioedema CI: Hyperkalemia, severe dehydration, hypothyroidism, renal impairment Preg Cat D Beta Blocker Propanolol Non-selective beta antagonist (B1 & 2); Partially block conversion of T4 to T3 Graves symptomatic tx ADR: dizzy, bradycardia, hypoTN, impotence; bronchospasm BBW: Abrupt D/C„³ angina exacerbation, MI, arrhythmias CI: cardiogenic shock, sinus bradycardia; Pregnancy precaution Precaution: Bronchial asthma, DM, uncompensated HF; Abrupt withdrawal CCB Diltiazen Calcium channel blocker Graves 2nd line symptomatic Thyroid Hormone Levothyroxine Hypothyroidism CI: acute MI, thyrotoxicosis, adrenal insufficiency ADR: appetite increase, tachycardia, wt loss, nervousness, insomnia, heat intolerance, tremor; arrhythmias, CHF, HTN, angina 16 INSULIN „h Standard insulin concentration is 100 units/mL *This is done to reduce confusion and chance for errors in dosing Class Drug Uses/Coverage ADR PK/Education Rapid Acting Insulin Lispro Diabetes ADR: „h Most common and potentially most lifethreatening: hypoglycemia*** „h Other common: Weight gain, Lipodystrophy, Allergic reactions, Injection site reactions Combine with basal, can be IV or pump. MUST eat, Insulin Aspart use 15 ac¡V15 min pc Insulin Glulisin Short Acting Regular Insulin (Novolin) Diabetes 30-60min ac, coordinate meals in advance Intermediat e Acting NPH Basal control, never IV, not for emergencies Protamine Diabetes Long Acting Glargine Diabetes Avoid mixing, never IV Detemir NON-INSULIN Class Drug MOA Uses/Coverage ADR/DDI PK/Education/Other Sulfonylureas Glimepride Stimulate insulin secretion by blocking K channels „³ „^Ca+ Diabetes ADR: Hypoglycemia, weight gain, hepatic/renal Serum protein bound, P450 Glipizide metabolism Glyburide Meglitinides Nateglinide Same as SU with rapid action, short duration Diabetes post-prandial ADR: Hypoglycemia, hepatic/renal PO ac 1-30 min, P450 metabolism Repaglinide Metformin Reduce gluconeogenesis Diabetes 2 DOC ADR: GI!!! BBW: Lactic acidosis, Cr >1.5 PO TZD Pioglitazone Increase insulin sensitivity Diabetes 2nd/last line ADR: Edema, liver failure, anemia BBW: Heart failure PO, „^serum bound, „^P450 metabolism 17 ƒÑGlucosidase Inhibitor Acarbose Delay carb digestion Diabetes ADR: GI!!! Flatulence Take with first bite Miglitol DPP4 Inhibitors Gliptins Block incretin break down Diabetes ADR: Hypersensitivity, pancreatitis, $$$ PO + combo, adjust dose if renal/hepatic SLGT2 Inhibitor Invokana „` glucose reabsorption in renal tubules Diabetes ADR: Glucosuria, CI in renal, lots of DDIs (kidneys) BBW: Avoid in diabetes gastroparesis Amylin Analog Pramlintide „` gastric emptying and „` glucose Diabetes ADR: Hypoglycemia, GI *do not mix in syringe BBW: Thyroid tumors in animals GLP-1 Analogs Exenatide Incretin mimics, „` gastric emptying Diabetes ADR: GI, pancreatitis Liraglutide ANEMIA TREATMENT Anemia Goal Class/Type Drugs ADR/DDI Education/Other Iron Deficiency Replenish iron stores (measure Hgb and Hct in about 2-4 weeks to check trend) ****First treat cause Oral Iron Ferrous gluconate ADR: dyspepsia, NVCD, dark stools DDI: ¡E H2 Blockers, PPIs, antacids ¡õ absorption (take 1hr pre or 4h post antacid ¡E Tetracyclines & Quinolones¡õ absorption ¡E ¡õ absorption of thyroid hormones ¡E Ca salts: ¡õ absorption ¡E Vitamin C: ¡ô absorption ¡E Take on empty stomach (~1hr ac) ¡E Continue 3-6mo after to build up stores Ferrous sulfate ¡E DFI: food ¡õ absorption Ferrous fumerate Carbonyl iron Parenteral Iron *just need to know IV exists! ADR: ¡E **Anaphylactoid reactions: give test dose prior to infusion ¡E Delayed reactions (2-7 days) can occur: Fever, urticaria, arthralgias, lymphadenopathy ¡E Others: chest pain, headache, hypotension, n/v/d, abdominal cramping Indications: Fail PO iron, Intolerance to PO iron, Required antacid therapy, Significant blood loss but patient refuse blood transfusion, Chronic hemodialysis Vit B12 Deficiency Replenish B12 Diet High Vit B12: Beef liver, cereal, trout, salmon, beef Low Vit B12: clams, oysters, tuna, milk Oral B12 OTC Cobalamin ADR: HA, NVD, hypoK Monitor: 1-2mo post initiation, then Q6-12mo For pt w/o neurologic sxs SubQ/IM For pt w/ neurologic sxs 18 QD x 1wk, then Qwk x 1mo, then Qmo Folic Acid Deficiency Replace body stores Folic Acid 1mg QD Pregnancy Folic Acid 0.8mg QD Replenish diet Diet Liver, cereal, lentils, chickpeas, asparagus, spinach, black beans, pasta¡K. Anemia of Chronic Disease Epoetin alpha BBW: ¡ô CV risk (death) in CRF pts, ¡ô risk of death & tumor progression in CA pts, ¡ô risk of thromboembolic events in surgery pts CI: uncontrolled HTN, Ab-mediated anemia ADR: HTN, edema, tachycardia, NVD, thrombosis Serious ADR: tumor progression, ¡ômortality, CHF, stroke, MI, seizure, embolism Subcutaneous or IV; Dose depends on Dz (CRF, HIV, Chemo, surgery¡K), Hospital formulary Target Hgb 10-12gm/dL „h ¡ô dose 25% if Hgb response <1gm/dL after 4wk or Hgb <10gm/dL „h ¡õ dose 25% if Hgb response >1gm/dL within 2wks or Hgb nears 12gm/dL & still ¡ô¡Khold Darbepoetin alpha ANTIPLATELETS Platelet Aggregation Inhibitors: „h Prevention and treatment of occlusive cardiovascular disease „h Maintenance of vascular grafts and arterial patency „h Adjuncts to thrombin inhibitors or thrombolytic therapy in myocardial infarction Class Drug MOA Uses/Coverage ADR/DDI PK/Education/Other COX-1 Inhibitor Aspirin Inhibits thromboxan e A2 synthesis from arachidonic acid by irreversible acetylation of a serine on COX-1 „h Prophylactic treatment of transient cerebral ischemia „h Reduce the incidence of recurrent MI „h Decrease mortality in pre- and post-MI „h Other (anti-inflammatory) Warning/caution uses: „h Salicylate sensitivity (avoid ASA); Increased in patients with asthma and nasal polyps „h EtOH/elderly/surgical: increase bleeding risk „h Peds: avoid ASA with viral illnesses (Reyes) ADRs (all increase with higher doses): ¡ôbleeding time: ¡ôrisk for hemorrhagic stroke, ¡ôrisk for GI bleeding; GI upset/ulcers, Anaphylaxis, urticaria, hypersensitivity; CNS: confusion, MS changes, coma (toxic doses); Tinnitus; Renal impairment (ALL NSAIDs) DDI: NSAIDs (dose ASA at least 30 min before or 8 h Effects of ASA lasts for the life of the platelet (7-10 d); Repeated admin of ASA has a cumulative effect on the function of platelets *Most common dose in US is 81 mg/d (formerly ¡§baby aspirin¡¨) and is often called ¡§low-dose aspirin¡¨ 19 after), **Many other (anything that can affect bleeding will increase risk and thus cause a DDI) *NOTE: ASA is only NSAID with irreversible antithrombotic efficacy ADP Receptor Inhibitor s Ticlopidine Irreversibly inhibit the binding of ADP to receptor on platelets thus inhibiting GP IIb/IIIa receptor activation Prevention of TIAs and strokes for pts with prior cerebral thrombotic event, Adjunct therapy with ASA following coronary stent *Reserve use in patients who are intolerant to other therapies BBW: May cause life-threatening hematologic reactions, including neutropenia, agranulocytosis, thrombotic thrombocytopenia purpura (TTP), and aplastic anemia Caution/warning uses: Increases bleeding risk; Elderly avoid if possible ¡E Food interferes with ticlopidine ¡E All are extensively bound to plasma proteins ¡E They undergo hepatic metabolism by CYP450 to active metabolites ¡E Max effect in 3-5 days and effect can persist* if drug is dc¡¦d ¡E Elimination of the drugs and active metabolites occurs by both renal and fecal routes ¡E All these drugs increase risk for prolonged bleeding for which there is no antidote PLAVIX Clopidogrel Atherosclerosis prevention after MI, stroke, PAD; Thrombotic prophylaxis in ACS and events associated w/ PCI with or without stent; Preferred over ticlopidine in ischemic disease ADRs: Fewer than ticlopidine but still slight risk of same hematologic reactions BBW: higher rate of cardiovascular events following MI or stent thrombosis following PCI. Prasugrel Reduces rate of thrombotic cardiovascular events in patients managed with PCI for UA, STEMI, or NSTEMI BBW: Fatal bleeding risk, Use in patients 75+ years old due to risk of intracranial bleeding, Do not initiate in those likely to undergo coronary artery bypass graft (CABG) and stop at least 7 days prior to other surgeries Ticagrelor Conjunction w/ ASA for secondary prevention of thrombotic events UA, NSTEMI, STEMI managed medically or with PCI and/or CABG BBW: Fatal bleeding risk, Avoid high-dose ASA use due to inactivation of ticagrelor, Avoid initiation of when urgent CABG surgery is planned; when possible, discontinue use at least 5 days before any surgery DDI: major CYP3A4 substrate GP IIb/IIIa Inhibitor s Abciximab Blocks binding of fibrinogen and von Willebrand factor Prevention of cardiac ischemic complications in PCI patients or UA/NSTEMI unresponsive to conventional therapy when PCI is scheduled within 24 hours ADR: Bleeding risk, anaphylaxis (has mouse bits!) Dosed IV along with ASA or heparin Antiplatelet effects persist up to 72 hours Eptifibatide Cyclic peptide blocks receptors Treatment of ACS, including patients managed medically and PCI ADRs: bleeding risk Dosed IV Duration of action: ~4h Tirofiban Blocks receptors Treatment of ACS ADRs: bleeding risk Dosed IV with heparin Duration: 4-8h Phosphodiesterase Inhibitors Dipyridamole Causes an accumulatio n of adenosine, Labeled Indications: Oral: Used with warfarin to decrease thrombosis in patients after artificial heart valve ADRs: bleeding risk, orthostasis (especially elderly) Use of aspirin/extended release dipyridamole is recommended 20 adenine nucleotides, and cAMP; stimulate release of prostacyclin ; Causes coronary vasodilation replacement I.V.: Diagnostic agent in CAD (Persantine Stress Test) Unlabeled: Stroke prevention Cilostazol Sx management of peripheral vascular disease, primarily intermittent claudication BBW: use in HF DDI: many w/ hepatic metabolism ANTICOAGULANTS Class Drug Uses/Coverage ADR/DDI PK/Education/Other Unfractioned Heparin UFH Binds to antithrombin and accelerates its action to irreversibly inactivate the following: ***Factor IIa (thrombin), ***Factor Xa, Factor IX, Factor XI, Factor XII; Inhibits platelet function, Increases vascular permeability ADR: ¡E Bleeding complications: Hemorrhage ¡V requires careful monitoring * Antidote for heparin is protamine sulfate ¡E Hypersensitivity ¡V heparin isolated from animal sources so can be antigenic ¡E Thrombosis ¡V chronic or intermittent administration can lead to reduction in antithrombin III activity a thrombosis ¡E Thrombocytopenia ¡V associated with UFH much more than LMWHs (HIT, monitor platelet count frequently) ¡E Other: abnormal liver function testing; Osteoporosis with long-term CI: Hypersensitivity, Bleeding disorders, Alcoholics, Having or have had recent surgery of the brain, eye, or spinal cord Dosing: Continuous IV infusion preferred, or SubQ Monitoring: aPTT is used to titrate doses LMWH Dalteparin Differences vs. UFH: ¡E Molecular wt ¡E Antithrombotic properties ¡E PK properties ¡E ADRs (fewer thromboembolic) ¡E Monitoring requirements Enoxaparin Tinzaparin Factor Xa Inhibitors Fondaparinux ¡E IV & SubQ ¡E Prophylaxis of DVT after hip/knee replacement, hip fracture surgery, or abdominal surgery ¡E Treatment of acute PE ¡E Treatment of acute DVT without PE ¡E Off-label: treatment of HIT ADR: Bleeding is main problem BBW: Discontinuation leads to risk of stroke so need to add other anticoagulant therapy; Neuraxial anesthesia: spinal or epidural hematomas (bleeding into spinal cord with procedures) Warnings: Renal impairment, Liver disease, Elderly Advantages: ¡E Well absorbed via SubQ route ¡E Predictable PK profile (F, elimination) ¡E Less monitoring (often none) Rivaroxaban ¡E PO** ¡E Post-op thromboprophylaxis after hip/knee replacement ¡E Prevention of stroke and systemic embolism in patients with nonvalvular Afib Apixaban ¡E PO ¡E Nonvalvular Afib to prevent stroke and systemic 21 embolism Direct Thrombin Inhibitors Argatroban IV to treat HIT, adjunct in PCI in pt with risk or h/o HIT Bivalirudin + ASA in UA undergoing PCTA or PCI w/ GP IIb/IIIa inhibitor or patient undergoing PCI with (or risk of) HIT Dabigatran 1 s t PO anticoagulant since warfarin; stroke prevention ADR: Bleeding, GI upset Advantages: No routine monitoring, Fewer DDI v. warfarin, Predicable PK Desirudin DVT prophylaxis in pts undergoing hip replacement Lepirudin IV to treat HIT, adjunct in PCI in pt with risk or h/o HIT Vitamin K Antagonist Warfarin MOA: Hepatic synthesis of coagulation factors II, VII, IX, and X, as well as proteins C and S, requires the presence of vitamin K. Prophylaxis and tx of thromboembolic disorders and complications from Afib or valve replacement, adjunct to reduce risk of systemic embolism after MI CI: Hemorrhagic tendencies; Recent eye/CNS surgery; uncontrolled malignant HTN; Pericarditis/PE, bacterial endocarditis; Unsupervised patients, high potential for noncompliance; Preeclampsia/ eclampsia BBW: fatal bleed (> 65yo, INR > 4, HTN, DM, open wounds) Preg: X DDI: ¡ô Bleed: ASA, clopidogrel, dipyridamole, NSAIDs, heparins; ¡õ INR: Vit K, sucralfate, barbitals, rifampin, phenytoin, nafcillin, griseofulvin, cholestyramine, carbamazepine; ¡ô INR: APAP, EtOH, allopurinol, amiodarone, chloral hydrate, cimetidine, fenofibrate; FQs, Cephalosporins, , -azole antifungals, omeprazole, sulfamethoxazole, Influenza vaccine, vitamin E ¡E ID of dose/tablet/brand ¡E Need for regular monitoring (danger if missed) ¡E Inform all healthcare providers of use ¡E S/Sx of bleeding ¡E Missed doses ¡E Diet/EtOH ¡E OTC meds/herbals ¡E Dose same time daily Thrombolytics Alteplase MOA: Modified forms of tPA that bind to fibrin and covert plasminogen to plasmin; used in STEMI Other use: Massive PE, Ischemic stroke, Open central venous access devices Reteplase Tenecteplase * Might offer advantages due to fewer noncerebral bleeding events and ease of use (single bolus dose) 22 PHARM FALL 2013 BLOCK III: CARDIOLOGY ANTIARRYTHMIA DRUGS Goal: decrease HR by interrupting ion channel function (Decrease phase 4 slope, Increase threshold potential, Increase max diastolic potential, Increase AP duration) Proarrhythmic by nature** Class Drug Comment (I) Sodium Channel Blockers MOA: „`phase 0, prolong phase 3 (II) Beta Blockers Propanolol MOA: Inhibit Metoprolol sympathetic activity Esmolol (III) Potassium Channel Blockers Amiodarone MOA: Prolong phase 3 Dofetilide Dronedarone Sotalol (IV) Calcium Channel Blockers Diltiazem Verapamil MOA: Slow conduction at SA/AV nodes, prolong phase 3 Other Adenosine Used for SVT (IV w/ very short . life) Digoxin Used for AFib, „^vagal tone HYPERLIPIDEMIA DRUGS PATIENTS WHO NEED A STATIN: 1. <75YO W/ CLINICAL ASCVD W/ HIGH-INTENSITY OR >75YO W/ CLINICAL ASCVD W/ HIGH-MODERATE INTENSITY 2. ANY AGE LDL >190 W/ HIGH-INTENSITY 3. 40-75YO W/ DM & LDL >70 BUT NO ASCVD W/ MODERATE INTENSITY OR HIGH FOR THOSE WITH 10 YR ASCVD RISK >7.5% 4. 40-75YO W/O DM OR ASCVD AND LDL >70 & HAVE 10 YR RISK OV ASCVD > 7.5% W/ MODERATE TO HIGH INTENSITY Class Drug MOA Uses/Coverage ADR/DDI PK/Education/Other Statins Atorvastatin or Rosuvastatin for high intensity Inhibit cholesterol synthesis in liver leading to increased LDL receptors and increased cholesterol uptake in the blood *DOC for Hyperlipidemia ADR: Hepatic, MSK (strains, sprains, myalgias), CNS, Cataracts DDI: CYP3A4 Substrate (Warfarin, Protease inhibitors, Macrolides, Fibrates, Azoles) CI: Pregnancy, Breastfeeding, Active Liver Disease Monitor: Baseline (CK, LFT, Lipid, Renal) + Lipid q4-8w until stable + Lipid q6m Dose: qhs, alternate date dosing to reduce myalgias Niacin Niacin Rx Inhibits lipolysis in adipose tissue (liver cannot make LDL) and also increases tPA and decreases plasma fibrinogen *Most potent to raise HDL ADR: cutaneous flushing + pruritus (Dose qhs + ASA); N/V, impaired glucose tolerance, Hepatic Caution using with (*Statin) Fibrates Fenofibrate Decrease VLDL/TG, Increase HDL * Works best on TG ADR: N/V/D/C, gallstones DDI: Statin (myopathy, rhabdomyolysis), Warfarin, all cardiac Rx CI: kidney/liver disease, gallbladder disease, biliary disease, pregnancy, breastfeeding Basically CI in pts with HTN or any cardiac dz due to DDI Fenofibric Acid Gemfibrozil Bile Acid Cholestyramine Resins bind bile acids and cholesterol ADR: GI (N/V/C/F), impaired absorption 23 Sequestrant s complex is excreted in feces DDI: Impaired drug absorption (Dose 1-2h pre- or 4-6h post- other meds) Colesevelam Colestipol PCSK9 Inhibitors Alirocumab Evolocumab Rx revents PC5K9from degrading LDL receptors in liver increasing # of LDLR¡¦s available to clear LDL Familial Hyperlipidemia & have failed max dose of statin Mouse bits! $$$$$, SubQ only Cholesterol Absorption Inhibitors Ezetimibe Inhibit cholesterol absorption at brush border of small intestine *Adjunct Use Only ADR: GI, Heptatic (caution w/ Statin) Omega 3 Fatty Acids Icosapent ethyl O3 ethyl ester O3 carboxylic acid Decrease synthesis of VLDL-TG *Adjunct Use Only Rx Omega 3 $$$$ ANTIANGINAL DRUGS Angina Management: *Determine Type ¡E Antianginal + ASA + Clopidogrel + Others ¡E Lifestyle modification Acute Coronary Syndrome Management: ¡E ER Treatment: Morphine, Oxygen, NTG, ASA, BB ¡E Long-term management: BB, ASA, Statin, Antiplatelet + Lifestyle modification Class Drug MOA Uses/Coverage ADR/DDI PK/Education/Other Organic Nitrates NTG Release NO to induce systemic vasodilation *DOC for Acute Angina IV: acute angina, acute MI, perioperative HTN SL: acute angina, prophylaxis Transdermal/Ointment: prophylaxis ADR: HA, HypoTN, facial flushing; Patient education on 12-14h/d of nitrate free intervals DDI: PDE-5 Inhibitors (Sildenafil, Tadalafil, Vardenafil) Isosorbide mononitrate Isosorbine dinitrate Beta- Adrenergic Antagonists Block sympathetic stimulation *DOC in prophylaxis of Chronic Stable Angina unless CI (adjunct use for Variant Angina) CI: asthma, COPD, severe bradycardia, PVD/vasospastic disease, DM, depression 24 Calcium Channel Blockers Diltiazem Slow contraction in smooth muscle of heart *Adjunct for Stable/Variant if uncontrolled or CI Verapamil *Verapamil: CI in AV conduction abnormality Amiodipine Felodipine Sodium Channel Blockers Ranolazine PO prolong phase 3 (repolarization) *Last line for Chronic Angina DDI: Lots! ANTI-CHOLINERGIC DRUGS Class Drug MOA Antimuscarini c Atropine MOA: Bind to ACh receptors but do not trigger usual response; Blocks parasympathetic system to „^HR **drugs have many more therapeutic uses CV Use: blocks parasympathetic activity to cause HR increase (dose-dependent reaction) Other Use: eye (mydriasis, unresponsiveness to light), OP poisoning, pre-anesthesia secretion drying ADR: Anti-SLUDGEMM, Anti-DUMBBELSS Ganglionic Blocker Neuromuscular Blocker ADRENERGIC/CHOLINERGIC AGONIST DRUGS Class Drug MOA Uses/Coverage ADR/DDI/CI Direct-Acting Adrenergic Agonists Epinephrine MOA: ƒÒ1, ƒÒ2 low doses, ƒÑ1, ƒÑ2 at high doses Action: „^BP/HR/contractility, bronchodilation Use: bronchospasm, anaphylactic shock, cardiac arrest, anesthesia adjunct; Rapid onset, brief duration (IV in ER) ADR: CNS, hemorrhage, arrhythmia, pulmonary edema CI: hyperthyroid, cocaine, DM, BB use Norepinephrine (Levophed) MOA: some ƒÒ1, mostly ƒÑ1 & ƒÑ2 Action: „^BP, baroreceptor reflex Use in shock **do NOT use in allergic reaction! ADR: similar to Epi + skin blanching/sloughing along injected vein Isoproterenol MOA: predominantly ƒÒ1 & ƒÒ2 effects (nonselectivity is major drawback) Use: some cardiac testing or ER heart stimulation, rare Dopamine MOA: ƒÒ1 at low doses, ƒÑ1 at high doses, Use: cardiogenic/septic shock in CKD, CHF, 25 dopaminergic HOTN *Good if increased flow to kidneys needed Dobutamine MOA: stimulates ƒÒ1 receptors to „^HR and CO (few vascular effects) Use: cardiac decompensation, cardiac surgery, acute HF ADR: same as Epi, *caution in AFib due to „^AV conduction Clonidine MOA: CNS acting ƒÑ2 agonist (blocks NE) Use: chronic HTN Fenoldopam MOA: ƒÑ2 & peripheral D-1 Dopamine receptor agonist Use: severe HTN (ER); 6x more potent than Dopamine Oxymetazoline MOA: ƒÑ1 agonist Use: eye/nasal vasoconstriction Phenylephrine MOA: ƒÑ1 agonist Use: nasal vasoconstriction ƒÒ2 Agonists (- erols) MOA: ƒÒ2 agonists (bronchodilation) Use: bronchospasm Indirect- Acting Amphetamine Cocaine Mixed-Action Ephedrine Pseudoephedrine ADRENERGIC ANTAGONISTS Class Drug MOA Uses/Coverage ADR/DDI ƒÑ-Antagonists (Sympatholytics ) Doxazosin MOA: block ƒÑ receptors to reduce sympathetic („`PVR, reflex tachycardia) Action: SM vasodilation, profound orthostatic HOTN („`1st dose, dose qhs) Profoundly „`BP, use in HTN+BPH and pheochromocytoma ADR: HOTN, dizziness, fatigue, nasal congestion, Prazosin HA, sexual dysfunction Terazosin Nonselective ƒÒ-Antagonists Propanolol Action: „`HR/contractility, „`SA/AV conduction, „`CO/O2 consumption, peripheral vasoconstriction (paradox), bronchoconstriction, „^Na+ retention BC OF DROP IN BP Use: HTN, migraine, hyperthyroid, angina, MI ADR: bronchoconstriction (COPD), arrhythmia, sexual, metabolic, CNS DO NOT USE IN PTS WITH RESP DZ! CAN ALSO MASK SSX OF HYPOGLYCEMIA!! Do not stop Dx suddenly- may cause arrhythmia! Nadolol- potent, used by Cardio MD Timolol- topical for glaucoma Selective ƒÒ1-Antagonists Atenolol Developed to eliminate unwanted bronchoconstriction, BUT selectivity is lost at high doses! Use in HTN with impaired pulmonary, DM Educate pts with respiratory dz! Bisoprolol, Metoprolol succinate Nonselective w/ ISA Penbutolol MOA: stimulate ƒÒ receptor but inhibit stimulation by catecholamines and result in diminished effect of HR/CO Use: HTN with bradycardia or DM Pindolol Selective w/ ISA Acebutolol ƒÑ&ƒÒ Antagonists Carvedilol MOA: concurrent blocking produces peripheral vasodilation Use: HTN if vasoconstriction is undesirable (CHF) Does not alter lipid or glucose levels due Labetalol to B1 selectivity 26 DIURETICS Class Drug MOA Uses/Coverage ADR/DDI PK/Education/Other Thiazide Diuretics Hydrochlorothiazid e MOA: block Na/Cl symporter in DCT to cause Na/H2O retention (loss) *DOC in HTN, most widely used Use: HTN, HF, hypercalciuria, DI („^K/Mg excretion, „`Ca/UA excretion) ADR: HOTN, hypokalemia, hyponatremia, hyperuricemia, hypercalcemia, hyperglycemia, hypersensitivity, volume depletion PK: PO, sulfa derivative (CI if allergy), ceiling effect, renal Chlorothiazide activation Chlorthalidone Indapamide Metolazone Loop Diuretics Bumetanide MOA: block Na/K/Cl uptake in TALH to cause Na/H2O retention (loss) STRONGEST DIURETIC Use: edema, hypercalcemia, hyperkalemia („^K/Mg/Ca/H/UA excretion) *DOC in edema, remove lots of fluid! ADR: HOTN, hypokalemia, hyponatremia, hypocalcemia, alkalosis, ototoxicity (AG), GI, hypersensitivity, DDI w/ diuretics, digoxin, BB, AG PK: IV/PO, fast onset (ER), high ceiling= INCREASE DOSE = MORE DIURESIS, renal excretion Furosemide Torsemide K+ Sparing Diuretics Amiloride MOA: block aldosterone (S/E) and block Na channel (A/T) in DCT Use: HTN, CHF, ascites (cirrhosis), aldosteronism, hypokalemia, remodeling *Always adjunct use in anti- HTN ADR: hyperkalemia, sexual Eplerenone dysfunction (S) Spironolactone Triamterene Carbonic