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9110 APPLIED PHARMACOLOGY FALL 2012 Essential Pharmacology For Dentists A Board Preparation Study Guide Prepared By Darren M. Roesch, Ph.D. Department of Biomedical Sciences Texas A&M University Baylor College of Dentistry PAGE 1 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY Essential Drugs Drugs Affecting the Autonomic Nervous System FALL 2012 scopolamine ISOPTO HYOSCINE, SCOPACE, TRANSDERM SCOP solifenacin VESICARE tiotropium SPIRIVA HANDIHALER tolterodine DETROL trihexyphenidyl ARTANE tropicamide MYDRIACYL, TROPICACYL trospium chloride SANCTURA Cholinergic Agonists Direct Acting acetylcholine MIOCHOL-E bethanechol URECHOLINE carbachol MIOSTAT, ISOPTO CARBACHOL cevimeline EVOXAC pilocarpine SALAGEN, ISOPTO CARPINE Indirect Acting (reversible) ambenonium MYTELASE donepezil ARICEPT galantamine RAZADYNE neostigmine PROSTIGMIN physostigmine ANTILIRIUM pyridostigmine MESTINON rivastigmine EXELON tacrine COGNEX Indirect Acting (irreversible) echothiophate PHOSPHOLINE IODIDE Reactivation of Acetylcholinesterase pralidoxime PROTOPAM Cholinergic Antagonists Antimuscarinic Agents atropine ISOPTO ATROPINE benztropine COGENTIN cyclopentolate AK-PENTOLATE, CYCLOGYL darifenacin ENABLEX fesoterodine TOVIAZ ipratropium ATROVENT oxybutynin DITROPAN, GELNIQUE, OXYTROL PAGE 2 OF 63 Ganglionic Blockers mecamylamine nicotine COMMIT, NICODERM, NICORETTE, NICOTROL INHALER Neuromuscular Blockers atracurium ONLY GENERIC cisatracurium NIMBEX pancuronium PAVULON rocuronium ZEMURON succinylcholine ANECTINE, QUELICIN vecuronium ONLY GENERIC Adrenergic Agonists Direct-Acting Agents albuterol ACCUNEB, PROAIR HFA, VENTOLIN HFA clonidine CATAPRES, DURACLON dobutamine DOBUTREX dopamine INTROPIN epinephrine ADRENALIN, EPIPEN, PRIMATENE MIST fenoldopam CORLOPAM formoterol FORADIL AEROLIZER, PERFOROMIST isoproterenol ISUPREL metaproterenol ALUPENT norepinephrine LEVOPHED phenylephrine NEO-SYNEPHRINE, SUDAFED PE salmeterol SERVENT DISKUS terbutaline BRETHINE Indirect-Acting Agents amphetamine ADDERALL cocaine DR. ROESCH 9110 APPLIED PHARMACOLOGY Direct and Indirect (mixed action) Agents ephedrine pseudoephedrine SUDAFED Adrenergic Antagonists alpha Blockers alfuzosin UROXATRAL doxazosin CARDURA phenoxybenzamine DIBENZYLIN phentolamine REGITINE prazosin MINIPRESS tamsulosin FLOMAX terazosin HYTRIN yohimbine YOCON beta Blockers acebutolol SECTRAL atenolol TENORMIN betaxolol BETOPTIC-S, KERLONE bisoprolol ZEBETA carteolol CARTROL carvedilol COREG, COREG CR esmolol BREVIBLOC labetalol TRANDATE metoprolol LOPRESSOR, TOPROL-XL nadolol CORGARD nebivolol BYSTOLIC penbutolol LEVATOL pindolol VISKEN propranolol INDERAL LA, INNOPRAN XL timolol BETIMOL, ISTALOL, TIMOPTIC Drugs Affecting Neurotransmitter Uptake or Release guanethidine ISMELIN reserpine SERPASIL Drugs Affecting the Central Nervous System Neurodegenerative Diseases Anti-Parkinson Drugs amantadine SYMMETREL apomorphine APOKYN benztropine COGENTIN biperiden AKINETON PAGE 3 OF 63 FALL 2012 bromocriptine PARLODEL, CYCLOSET carbidopa LODOSYN entacapone COMTAN levodopa (w/carbidopa) SINEMET, PARCOPA pramipexole MIRAPEX procyclidine KEMADRIN rasagiline AZILECT ropinirole REQUIP rotigotine selegiline (deprenyl) ELDEPRYL, ZELAPAR tolcapone TASMAR trihyxyphenidyl ARTANE Anti-Alzheimer Drugs donepezil ARICEPT galantamine RAZADYNE memantine NAMENDA rivastigmine EXELON tacrine COGNEX Anxiolytic and Hypnotic Drugs Benzodiazepines alprazolam XANAX chlordiazepoxide LIBRIUM clonazepam KLONOPIN clorazepate TRANXENE diazepam VALIUM, DIASTAT esazolam PROSOM flurazepam DALMANE lorazepam ATIVAN midazolam VERSED oxazepam SERAX quazepam DORAL tamazepam RESTORIL triazolam HALCION Benzodiazepine Antagonist flumazenil ROMAZICON Other Anxiolytic Drugs antidepressants buspirone BUSPAR Barbiturates DR. ROESCH 9110 APPLIED PHARMACOLOGY amobarbital AMYTAL pentobarbital NEMBUTAL phenobarbital LUMINAL SODIUM secobarbital SECONAL thiopental PENTOTHAL Other Hypnotic Agents antihistamines chloral hydrate SOMNOTE, NOCTEC eszopiclone LUNESTA ethanol ramelteon ROZEREM zaleplon SONATA zolpidem AMBIEN CNS Stimulants Psychomotor Stimulants amphetamine ADDERALL armodafinil NUVIGIL atomoxetine STRATTERA caffeine CAFCIT, NO DOZ, VIVARIN cocaine dexmethylphenidate FOCALIN dextroamphetamine DEXEDRINE, DEXTROSTAT lisdexamfetamine VYVANSE modafinil RITALIN, CONCERTA, DAYTRANA nicotine COMMIT, NICODERM CQ, NICORETTE theophylline ELIXOPHYLLIN, THEO-24, THEOCHRON, UNIPHYL varenicline CHANTIX Hallucinogens dronabinol MARINOL lysergic acid diethylamide (LSD) Phencyclidine (PCP) Tetrahydrocannabional (THC) Anesthetics Preanesthetic Medications antacids anticholinergics antiemetics antihistamines PAGE 4 OF 63 FALL 2012 benzodiazepines opioids General Anesthetics: Inhaled desflurane SUPRANE halothane FLUOTHANE isoflurane FORANE nitrous oxide NITROUS OXIDE sevlflurane ULTANE General Anesthetics: Intravenous barbiturates benzodiazepines dexmedetomidine PRECEDEX etomidate AMIDATE ketamine KETALAR opioids propofol DIPRIVAN Neuromuscular Blockers cisatracurium pancuronium rocuronium succinylcholine vecuronium Local Anesthetics: Amides bupivicaine MARCAINE lidocaine XYLOCAINE mepivacaine CARBOCAINE ropivacaine NAROPIN Local Anesthetics: Esters chloroprocaine NESACAINE procaine NOVOCAINE tetracaine PONTOCAINE Antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs) citalopram CELEXA escitalopram LEXAPRO fluoxetine PROZAC fluvoxamine LUVOX CR paroxetine PAXIL sertraline ZOLOFT DR. ROESCH 9110 APPLIED PHARMACOLOGY Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) desvenlafaxine PRISTIQ duloxetine CYMBALTA venlafaxine EFFEXOR Atypical Antidepressants bupropion WELLBUTRIN, ZYBAN mirtazapine REMERON nefazodone SERZONE trazodone DESYREL Tricyclic Antidepressants (TCAs) amitriptyline ELAVIL amoxapine ASENDIN clomipramine ANAFRANIL desipramine NORPRAMIN doxepin SINEQUAN imipramine TOFRANIL maprotiline LUDIOMIL nortriptyline PALMELOR protriptyline VIVACTIL trimipramine SURMONTIL Monamine Oxidase Inhibitors (MAOIs) iscarboxazid MARPLAN phenelzine NARDIL selegiline ELDEPRYL tranylcypromine PARNATE Antipsychotic Drugs First-Generation Antipsychotic (low potency) chlorpromazine THORAZINE prochlorperazine COMPAZINE thioridazine MELLARIL First-Generation Antipsychotic (high potency) fluphenazine PROLIXIN haloperidol HALDOL pimozide ORAP thiothixene NAVANE Second Generation Antipsychotic PAGE 5 OF 63 FALL 2012 aripiprazole ABILIFY asenapine SAPHRIS clozapine CLOZARIL iloperidone FANAPT lurasidone LATUDA olanzapine ZYPREXA quetiapine SEROQUEL paliperidone INVEGA risperidone RISPERDAL ziprasidone GEODON Opioids Strong Agonists alfentanil ALFENTA fentanyl ACTIQ, DURAGESIC, FENTORA heroin hydrocodone hydromorphone DILAUDID meperidine DEMEROL methadone DOLOPHINE morphine ROXANOL, CONTIN, ORAMORPH, KADIAN, AVINZA oxycodone OXYCONTIN oxymorphone OPANA remifentanil ULTIVA sufentanil SUFENTA tapentadol NUCYNTA Moderate/Low Agonists codeine Mixed Agonist-Antagonists and Partial Agonists buprenoprhine BUPRENEX, SUBUTEX butorphanol STADOL nalbuphine NUBAIN pentazocine TALWIN Antagonists nalmefene REVEX naloxone NARCAN naltrexone DEPADE, REVIA, VIVITROL Other Analgesics DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 tramadol ULTRAM metoprolol LOPRESSOR, TOPROL-XL Epilepsy carbamazepine TEGRETOL diazepam VALIUM divalproex (valproate) DEPAKOTE ethoxuximide ZARONTIN felbamate FELBATOL gabapentin NEURONTIN lacosamide VIMPAT lamotrigine LAMICTAL levetiracetam KEPPRA lorazepam ATIVAN oxcarbazepine TRILEPTAL phenobarbital LUMINAL phenytoin DILANTIN fosphenytoin CEREBYX primidone MYSOLINE rufinamide BANZEL tiagabine GABITRIL topiramate TOPAMAX vigabatrin SABRIL zonisamide ZONEGRAN Diruetics bumetanide BUMEX furosemide LASIX hydrochlorothiazide (HCTZ) MICROZIDE metolazone ZAROXOLYN Drugs Affecting the Cardiovascular System Heart Failure ACE Inhibitors captopril CAPOTEN enalapril VASOTEC fosinopril MONOPRIL lisinopril PRINIVIL, ZESTRIL quinapril ACCUPRIL ramipril ALTACE Antiotensin-Receptor Blockers candesartan ATACAND losartan COZAAR telmisartan MICARDIS valsartan DIOVAN Beta-Adrenoreceptor Blockers atenolol TENORMIN carvedilol COREG, COREG CR PAGE 6 OF 63 Antiarrhythmics Class I (Na+ Channel Blockers) disopyramide (IA) NORPACE flecainide (IC) TAMBOCOR lidocaine (IB) XYLOCAINE mexiletine (IB) MEXITIL procainamide (IA) PRONESTYL, PROCAN propafenone (IC) RYTHMOL quinidine (IA) QUINIDEX Class II (beta-adrenoreceptor blockers) esmolol BREVILBLOC metoprolol LOPRESSOR, TOPROL-XL propranolol INDERAL Class III (K+ Channel Blockers) amiodarone CORDARONE, PACERONE dofetilide TIKOSYN dronedarone MULTAQ sotalol BETAPACE, SORINE Class IV (Ca2+ Channel Blockers) diltiazem CARDIZEM, CARTIA XT, DILACOR XR, DILTIA XT verapamil CALAN, COVERA-HS, ISOPTIN SR, VERELAN Other Anti-arrhythmic Drugs adenosine ADENOCARD, ADENOSCAN digoxin LANOXIN Antianginal Drugs Organic Nitrates DR. ROESCH 9110 APPLIED PHARMACOLOGY isosorbide dinitrate DILATRATE-SR, ISORDIL isosorbide mononitrate IMDUR, ISMO nitroglycerin NITRO-BID, NITRO-DUR Beta-Blockers acebutolol SECTRAL atenolol TENORMIN metoprolol LOPRESSOR, TOPROL-XL propranolol INDERAL Calcium-Channel Blockers amlodipine NORVASC diltiazem CARDIZEM felodipine PLENDIL nicardipine CARDENE nifedipine PROCARDIA verapamil CALAN, ISOPTIN Sodium-Channel Blocker ranolazine RANEXA Antihypertensives Alpha-Blockers doxazosin CARDIRA prazosin MINIPRESS terazosin HYTRIN Other clonidine CATAPRESS, DURACLON diazoxide PROGLYCEM hydralazine APRESOLINE labetalol TRANDATE alpha-methyldopa ALDOMET minoxidil LONITEN sodium nitroprusside NITROPRESS Renin Inhibitors aliskiren TEKTURNA Calcium-Channel Blockers amlopidine NORVASC diltiazem CARDIZEM, CARTIA, DILACOR felodipine PLENDIL isradipine DYNACIRC CR PAGE 7 OF 63 FALL 2012 nicardipine CARDENE nifedipine ADALAT, NIFEDIAC, PROCARDIA nisoldipine SULAR verapamil CALAN, ISOPTIN, VERELAN Diruretics amiloride MIDAMOR bumetanide BUMEX chlorthalidone HYGROTON eplerenone INSPRA furosemide LASIX hydrochlorothiazide MICROZIDE metolazone MYKROX, ZAROXOLYN spironolactone ALDACTONE triamterene DYRENIUM Beta-Blockers atenolol TENORMIN carvedilol COREG, COREG CR labetalol TRANDATE metoprolol LOPRESSOR, TOPROL-XL nadolol CORGARD nebivolol BYSTOLIC propranolol INDERAL LA, INNOPRAN XL timolol BLOCADREN ACE Inhibitors benazepril LORENSIN captopril CAPOTEN enalapril VASOTEC fosinopril MINOPRIL lisinopril PRINIVIL, ZESTRIL moexipril UNIVASC quinapril ACCUPRIL ramipril ALTACE Angiotensin II-Receptor Blockers azilsartan medoxomil EDARBI candesartan ATARCAND eprosartan TAVETEN irbesartan AVAPRO losartan COZAAR olmesartan BENICAR telmisartan MICARDIS DR. ROESCH 9110 APPLIED PHARMACOLOGY valsartan DIOVAN Blood Drugs Platelet Inhibitors abciximab REOPRO aspirin cilostazol PLETAL clopidogrel PLAVIX dipyridamole PERSANTINE eptifibatide INTEGRILIN prasugrel EFFIENT ticlopidine TICLID tirofiban AGGRASTAT Anticoagulants argatroban ARGATROBAN dabigatran PRADAXA dalteparin FRAGMIN enoxaparin LOVENOX fondaparinux ARIXTRA heparin HEP-LOCK, HEPFLUSH-10 lepirudin REFLUDAN tinzaparin INNOHEP warfarin COUMADIN JANTOVEN Thrombolytic Agents alteplase (tPA) ACTIVASE reteplase RETAVASE streptokinase STREPTASE urokinase KINLYTIC Treatment of Bleeding aminocaproic acid AMICAR aprotinin TRASYLOL protamine sulfate tranexamic acid CYKLOKAPRON, LYSTEDA vitamin K1 (phytonadione) MEPHYTON Treatment of Anemia cyanocobalamin (B12) RUBRAMIN PC erythropoietin EPOGEN, PROCRIT folic acid FOLACIN-800 iron DEXFERRUM, INFED Treatment of Sickle Cell Anemia PAGE 8 OF 63 FALL 2012 hydroxyurea DROXIA, HYDREA pentoxifylline TRENTAL Hyperlipidemias HMG CoA Reductase Inhibitors (Statins) atorvastatin LIPITOR fluvastatin LESCOL lovastatin MEVACOR pitavastatin LIVALO pravastatin PRAVACHOL rosuvastatin CRESTOR simvastatin ZOCOR Fibrates gemfibrozil LOPID fenofibrate TRICOR, LOFIBRA, TRIGLIDE Niacin niacin NIASPAN, SLO-NIACIN Cholesterol Absorption Inhibitor ezetimibe ZETIA Bile Acid Sequestrants colesevelam WELCHOL colestipol COLESTID cholestyramine QUESTRAN, PREVALITE Omega-3 Fatty Acids docosahexaenoic and eicosapentaenoic acids LOVAZA Diuretics Thiazide Diuretics chlorothiazide DIRUIL, SODIUM DIURIL chlorthaldone HYGROTON hydrochlorothiazide MICROZIDE indapamide LOZOL metolazone ZAROLXOLYN Loop Diuretics bumetanide BUMEX ethacrynic acid EDECRIN DR. ROESCH 9110 APPLIED PHARMACOLOGY furosemide LASIX torsemide DEMADEX Potassium-Sparing Diuretics amiloride AMILORIDE HCL eplerenone INSPRA spironolactone ALDACTONE triamterene CYRENIUM Carbonic Anhydrase Inhibitors acetazolamide DIAMOX Osmotic Diuretics mannitol OSMITROLL urea CARMOL Drugs Affecting the Endocrine System Pituitary and Thyroid Hypothalmic and Anterior Pituitary Hormones human chorionic gonadotropin PREGNYL corticotropin H.P. ACTHAR cosyntropin CORTROSYN follitropin alpha GONAL-F follitropin beta FOLLISTIM gonadorelin FACTREL goserelin ZOLADEX histrelin VANTAS leuprolide LUPRON menotropins MENOPUR, REPRONEX nafarelin SYNAREL octreotide SANDOSTATIN pegvisomant SOMAVERT somatropin NORDITROPIN urofollitropin BRAVELLE Hormones of the Posterior Pituitary desmopressin DDAVP oxytocin PITOCIN vasopressin PITRESSIN Drugs Affecting the Thyroid iodine and potassium iodide LUGOL’S SOLUTION PAGE 9 OF 63 FALL 2012 liothyronine CYTOMEL levothyroxine LEVOXYL, SYNTHROID methimazole TAPAZOLE propylthiouracil (PTU) liotrix THYROLAR Insulin and Other Glucose-Lowering Drugs Insulin insulin aspart NOVOLOG insulin detemir LEVEMIR insulin glargine LANTUS insulin glusine APIDRA insulin lispro HUMALOG NPH insulin suspension HUMULIN N, NOVOLIN N Regular insulin HUMULIN R, NOVOLIN R Amylin Analog pramlintide SYMLIN Oral Agents acarbose PRECOSE glimepiride AMARYL glipizide GLUCOTROL glyburide DIABETA, GLYNASE, PRESTAB metformin FORTAMET, GLUCOPHAGE miglitol GLYSET nateglinide STARLIX pioglitazone ACTOS repaglinide PRANDIN rosiglitazone AVANDIA saxagliptin ONGLYZA sitagliptin JANUVIA tolbutamide TOLBUTAMIDE Incretin Mimetic exanatide BYETTA liraglutide VICTOZA Estrogens and Androgens Estrogens estradiol DR. ROESCH 9110 APPLIED PHARMACOLOGY estrone MANEST ethinyl estradiol mestranol (w/norethindrone) NECON 1/50, NORINYL 1+50 Selective Estrogen-Receptor Modulators (SERMs) clomiphene CLOMID, SEROPHENE raloxifene EVISTA tamoxifen TAMOXIFEN, NOLVADEX Progestogens desogestrel drospirenone (w/ ethinyl estradiol) YAZ, YASMIN levonorgestrel MIRENA, NEXT CHOICE, PLAN B ONE-STEP medroxyprogesterone PROVERA norelgestromin (w/ ethinyl estradiol) ORTHO EVRA norethindrone NOR-QD, ORTHO MICONOR norethindrone acetate AYGESTIN norgestimate norgestrel (w/ ethinyl estradiol) LO/OVRAL progesterone Antiprogestin mifepristone MIFEPREX Androgens danazol DANOCRINE fluoxymesterone ANDROXY oxandrolone OXANDRIN testosterone ANDRODERM, ANDROGEL, STRIANT, TESTIM, TESTOPEL testosterone enanthate DELASTESTRYL Adrenal Hormones Corticosteroids betamethasone CELESTONE, DIPROLENE, LUXIQ cortisone CORTISONE ACETATE dexamethasone DECADRON PAGE 10 OF 63 FALL 2012 fludrocortisone FLORINEF hydrocortisone methylprednisolone MEDROL prednisolone ORAPRED, PEDIAPRED prednisone DELTASONE triamcinolone KENALOG, NASACORT AQ, ARISTOSPAN Inhibitors of Adrenocorticoid Biosynthesis or Function eplerenone INSPRA ketoconazole NIZORAL spironolactone ALDACTONE Chemotherapeutic Drugs Cell Wall Inhibitors Penicillins amoxicillin AMOXIL ampicillin OMNIPEN dicloxacillin DYNAPEN indanyl carbenicillin GEOCILLIN nafcillin NALLPE oxacillin OXACILLIN penicillin G PFIZERPEN penicillin V VEETIDS piperacillin PIPRACIL ticarcillin TICAR Cephalosporins cefaclor CECLOR cefadroxil DURACEF cefazolin DEFZOL cefdinir OMNICEF cefepime MAXIPIME cefixime SUPRAX cefotaxime CLAFORAN cefotetan CEFOTAN cefoxitin MEFOXIN cefprozil CEFZIL ceftazidime FORTAZ Ceftbuten CEDAX ceftizoxime CEFIZOX ceftaroline TEFLARO ceftriaxone ROCEPHIN cefuroxime CEFTIN DR. ROESCH 9110 APPLIED PHARMACOLOGY cephalexin KEFLEX Carbapenems Doripenem DORIBAX Ertapenem INVANZ imipenem/cilastatin PRIMAXIN meropenem MERREM IV Monobactams aztreonam AZACTAM Protein Synthesis Inhibitors Tetracylcines demeclocycline DECLOMYCIN doxycycline VIBRAMYCIN minocycline MINOCIN tetracycline SUMYCIN Glycylcyclines tigecycline TYGACIL Aminogycosides amikacin AMIKIN gentamicin GARAMYCIN neomycin NEO-FRADIN streptomycin STREPTOMYCIN tobramycin TOBREX Macrolides/Ketolides azithromycin ZITHROMAX clarithromycin BIAXIN erythromycin E-MYCIN telithromycin KETEK Others chloramphenicol CHLOROMYCETIN clindamycin CLEOCIN linezolid ZYVOX quinupristin/dalfopristin SYNERCID Quinolones, Folic Acid Antagonists and Urinary Tract Antiseptics Fluoroquinolones, !st Gen nalidixic acid NEGGRAM PAGE 11 OF 63 FALL 2012 Fluoroquinolones 2nd Gen ciprofloxacin CIPRO norfloxacin NOROXIN ofloxacin FLOXIN Fluoroguinolones, 3rd Gen levofloxacin LEVAQUIN Fluoroguinolones, 4th Gen moxifloxacin AVELOX Inhibitors of Folate Synthesis mafenide SULFAMYLON silver sulfadiazine SILVADENE sulfasalazine AZULFIDINE sulfisoxazole GANTRISIN Inhibitors of Folate Reduction pyrimethamine DARAPRIM trimethoprim PROLOPRIM Combination of Inhibitors of Folate Synthesis and Reduction cotrimoxazole (trimethoprim+sulfamethoxazole) BACTRIM, SEPTRA Urinary Tract Antiseptics methenamine MANDELAMINE, HIPREX nitrofurantoin MACROBID Antimycobacterials Drugs Used to Treat Tuberculosis ethambutol MYAMBUTOL isoniazid NYDRAZID pyrazinamide PYRAZINAMIDE rifamycins RIFADIN Drugs Used to Treat Tuberculosis (2nd line) aminoglycosides aminosalicyclic acid PASER capreomycin CAPASTAT SULFATE cycloserine SEROMYCIN ethionamide TRECATOR fluoroquinolones DR. ROESCH 9110 APPLIED PHARMACOLOGY macrolides Drugs Used to Treat Leprosy clofazimine LAMPRENE dapsone DAPSONE rifampin (rifampicin) RIFADIN Antifungal Drugs Drugs for Subcutaneous and Systemic Mycoses amphotericin B AMBISOME anidulafungin ERAXIS caspofungin CANCIDAS fluconazole DIFLUCAN flucytosine ANCOBON itraconazole SPORANOX ketoconazole NIZORAL micafungin MYCAMINE posaconazole NOXAFIL voriconazole VFEND Drugs for Cutaneous Mycoses butenafine LOTRIMIN ULTRA clotrimazole LOTRIMIN AF ciclopirox PENLAC econazole ECONAZOLE NITRATE griseofulvin GRIFULVIN V, GRIS-PEG miconazole FUNGOID, MICATIN, MONISTAT naftifine NAFTIN nystatin MYCOSTATIN oxyiconazole OXISTAT sertaconazole ERTACZO sulconazole EXELDERM terbinafine LAMISIL terconazole TERAZOL tioconazole VAGISTAT-1 tolnaftate TINACTIN Antiprotozoal Drugs Amebiasis chloroquine ARALEN dehydroemetine DEHYDROEMETINE emetine IPECAC SYRUP iodoquinol YODOXIN metronidazole FLAGYL PAGE 12 OF 63 FALL 2012 paromomycin HUMATIN tinidazole TINDAMAX Malaira artemisinin ARTEMISININ chloroquine ARALEN mefloquine LARIAM primaquine PHOSPHATE TABLETS pyrimethamine DARAPRIM quinine/quinidine QUALAQUIN, QUINIDINE GLUCONATE Trypanosomiasis benznidazole RADANIL melarsoprol MELARSOPROL nifurtimox NIFURTIMOX pentamidine NEBUPENT suramin GERMANIN Leishmaniasis sodium stibogluconate SODIUM STIBOGLUCONATE Toxoplasmosis pyrimethamine DARAPRIM Giardiasis metronidazole FLAGYL nitazoxanide ALINIA tinidazole TINDAMAX Antihelmintic Drugs Chemotherapy of Helmintic Infections: For Nematodes diethylcarbamazine BANOCIDE ivermectin STROMECTOL mebendazole VERMOX pyrantel pamoate NEMEX thiabendazole MINTEZOL Chemotherapy of Helmintic Infections: For Trematodes praziquantel BILTRICIDE DR. ROESCH 9110 APPLIED PHARMACOLOGY Chemotherapy of Helmintic Infections: For Cestodes albendazole ALBENZA niclosamide NICLOCIDE Antiviral Drugs For Respiratory Virus Infections amantadine SYMMETEREL oseltamivir TAMIFLU ribavirin COPEGUS, REBETOL, RIBAPAK, RIBASPHERE, VIRAZOLE rimantadine FLUMADINE zanamivir RELENZA For Hepatic Viral Infections adefovir HEPSERA entecavir BARACLUDE interferon INTRON, AVONEX lamivudine EPIVIR telbivudine TYZEKA tenofovir VIREAD For Herpesvirus and Cytomegalovirus Infections acyclovir ZOVIRAX cidofovir VISTIDE famciclovir FAMVIR fomivirsen VITRAVENE foscarnet FOSCARNET ganciclovir CYTOVENE penciclovir DENAVIR valacyclovir VALTREX valganciclovir VALCYTE vidarabine VIRA-A For HIV: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors abacavir ZIAGEN didanosine VIDEX emtricitabine EMTRIVA lamivudine EPIVIR stavudine ZERIT tenofovir VIREAD zalcitabine HIVID zidovudine RETROVIR PAGE 13 OF 63 FALL 2012 Anticancer Drugs Antimetabolites capecitabine XELODA cladribine LEUSTATIN cytarabine CYTOSINE ARABINOSIDE floxuridine FUDR fludarabine FLUDARA 5-fluorouracil EFUDEX gemcitabine GEMZAR 6-mercaptopurine PURINETHOL methotrexate (MTX) TREXALL 6-thioguanine THIOGUANINE TABLOID Antibiotics bleomycin BLENOXANE dactinomycin COSMEGEN daunorubicin CERUBIDINE doxorubicin ADRIAMYCIN epirubicin ELLENCE idarubicin IDAMYCIN Alkylating Agents busulfan MYLERAN carmustine BICNU chlorambucil LEUKERAN cyclophosphamide CYTOXAN dacarbazine DTIC-DOME ifosfamide IFEX lumustine CEENU mechlorethamine MUSTARGEN melphalan ALKERAN streptozocin ZANOSAR temozolomide TEMODAR Microtubule Inhibitors docetaxel TAXOTERE paclitaxel ONOXOL vinblastine VELBAN vincristine VINCASAR PFS, ONCOVIN vinorelbine NAVELBINE Immunosuppressants Selective Inhibitors of Cytokine Production and Function cyclosporine NEORAL, SANDIMMUNE everolimus ZORTRESS DR. ROESCH 9110 APPLIED PHARMACOLOGY sirolimus RAPAMUNE tacrolimus PROGRAF Immunosuppressive Antimetabolites azathioprine IMURAN mycophenolate mofetil CELLCEPT mycophenolate sodium MYFORTIC Antibodies alemtuzumab CAMPATH antithymocyte globulins ATGAM, THYMOGLOBULIN basiliximab SIMULECT daclizumab ZENAPRAX muromonab-CD3 ORTHOCLONE OKT3 Adrenocorticoids methylprednisolone MEDROL prednisolone ORAPRED, PRELONE prednisone DELTASONE Respiratory Drugs Drugs Used to Treat Asthma beta2-adrenergic agonists corticosteroids cromyln CROMOLYN ipratropium ATROVENT HFA leukotriene antagonists montelukast SINGULAIR zafirlukast ACCOLATE zileuton ZYFLO CR omalizumab XOLAIR theophylline ELIXOPHYLLIN, THEO-24, THEOCHRON, UNIPHYL Drugs Used to Treat Chronic Obstructive Pulmonary Diseases beta-adrenergic agonists ACCUNEB, PROAIR HFA, PROVENTIL HFA, XOPENEX, VENTOLIN HFA corticosteroids ipratropium ATROVEN HFA tiotropium SPIRIVA FALL 2012 alpha-adrenergic agonists NEOSYNEPHRINE, SUDAFED antihistamines ALLEGRA, CLARATIN, BENADRYL, ZYRTEC corticosteroids cromolyn NASALCROM montelukast SINGULAIR Drugs Used to Treat Cough dextromethorphan DELSYN codeine Gastrointestinal and Antiemetic Drugs Antimicrobial Agents amoxicillin AMOXIL, TRIMOX bismuth compounds PEPTO-BISMOL, KAOPECTATE clarithromycin BIAXIN metronidazole FLAGYL tetracycline SUMYCIN H2-Histamine Receptor Blockers cimetidine TAGAMET famotidine PEPCID nizatidine AXID ranitidine ZANTAC Proton Pump Inhibitors (PPIs) dexlansoprazole DEXILANT esomeprazole NEXIUM lansoprazole PREVACID omeprazole PRILOSEC pantoprazole PROTONIX rabeprazole ACIPHEX Prostaglandins misoprostol CYTOTEC Antimuscarinic Agents dicyclomine BENTYL Antacids aluminum hydroxide ALTERNAGEL calcium carbonate TUMS Drugs Used to Treat Allergic Rhinitis PAGE 14 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY magnesium hydroxide MILD OF MAGNESIA sodium bicarbonate Mucosal Protective Agents bismuth subsalicylate PEPTO-BISMOL sucralfate CARAFATE Other Therapies Drugs for Erectile Dysfunction sildenafil VIAGRA, REVATIO tadalafil CIALIS, ADCIRCA vardenafil LEVITRA Drugs for Osteoporosis alendronate FOSAMAX calcitonin FORTICAL, MIACALCIN denosumab PROLIA ibandronate BONIVA risedronate ACTONEL raloxifene EVISTA teriparatide FORTEO zoledronic acid RECLAST, ZOMETA Drugs for Disorders of Bone Remodeling etidronate DIDRONEL pamidronate AREDIA tiludronate SKELID Drugs for Obesity diethylpropion TENUATE orlistat ALLI, XENICAL phentermine ADIPEX-P Anti-inflammatory Drugs and Autacoids NSAIDS aspirin BAYER, BUFFERIN, ECOTRIN celecoxib CELEBREX diclofenac CATAFLAM, FLECTOR, PENNSAID, VOLTAREN diflunisal DOLOBID PAGE 15 OF 63 FALL 2012 etodolac LODINE fenamates: meclofenamate MECLOMEN fenoprofen NALFON flurbiprofen ANSAID ibuprofen ADVIL, MOTRIN indomethacin INDOCIN ketorolac ACULAR, ACUVAIL, TORADOL ketoprofen ORUDIS meloxicam MOBIC methyl salicylate WINTERGREEN OIL nabumetone RELAFEN naproxen ALEVE, ANAPROX, NAPROSYN oxaprozine DAYPRO piroxicam FELDENE sulindac CLINORIL tolmetin TOLMETIN SODIUM Other Analgesics acetominophen (paracetamol) TYLENOL Prostaglandins mifepristone MIFEPREX misoprostol CYTOTEC H1 Antihistamines acrivastine (with pseudoephedrine) SIMPREX-D cetirizine ZYRTEC chlorpheniramine CHLOR-TRIMETON cyclizine MAREZINE deloratadine CLARINEX dephenhydramine BENADRYL dimenhydrinate DRAMAMINE doxepin SINEQUAN doxylamine UNISOM SLEEPTABS fexofenadine ALLEGRA hydroxyzine VISTARIL, ATARAX levocetirizine XYZAL loratadine CLARITIN meclizine BONINE, ANTIVERT promethazine PHENERGAN DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Drugs Used to Treat Migraine Headachea almotriptan AXERT dihydroergotamine D.H.E. 45, MICRANAL eletriptan RELPAX frovatriptan FROVA naratriptan AMERGE rizatriptan MAXALT sumatriptan IMITREX zolmitriptan ZOMIG Color Coding Key: Drugs that are representative of their class appear in red. Frequently prescribed drugs are in green. Drugs that are both representative and highly prescribed drugs are in blue. PAGE 16 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Essential Pharmacology Facts General Principles of Pharmacology o Receptor Theory Agonists An agonist is a compound that binds to receptor and produces the biological response. Partial agonist A partial agonist produces the biological response but cannon produce 100% of the biological response even at very high doses. Efficacy and Potency Efficacy Efficacy is the maximal response a drug can produce. Potency is a measure of the dose that is required to produce a response. Potency Potency is often expressed as the dose of a drug required to achieve 50% of the desired therapeutic effects. This is the ED50 (effective dose). Therapeutic Index Therapeutic Index is a measure of drug safety. A drug with a higher therapeutic index is safer than one with a lower therapeutic index. Therapeutic Index = LD50/ED50 (lethal dose, effective dose) Antagonists Antagonists block or reverse the effect of agonists. They have no effect on their own. Competitive Antagonists Competitive antagonists make the agonist look less potent by shifting the dose response curve to the right. Noncompetitive Antagonists A noncompetitive antagonist reduces the maximal response that an agonist can produce Inverse Agonists Inverse agonists have the opposite effects from those of full agonists. They are not the same as antagonists, which block the effects of both agonists and inverse agonists. o Absorption, Distribution, and Clearance First-Pass Effect The liver is a metabolic machine and often inactivates drugs on their way from the GI tract to the body. This is called the first-pass effect. How Drugs Cross Membranes Drugs cross membranes by passive diffusion or active transport. PAGE 17 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 A drug tends to pass through membranes if it is uncharged. For a weak acid, when the pH is less than the pK, the protonated form (non-ionized) predominates. When pH is greater than the pK, the unprotonated (ionized) form predominates. For a weak base, when the pH is less than the pK, the ionized form (protonated) predominates. When the pH is greater than the pK, the unprotonated (nonionized) for predominates. In the stomach (pH 2.0), weak acids are uncharged and will be absorbed into the blood-stream, whereas weak bases are charged and will remain in the GI tract. Bioavailability Bioavailability is the amount of drug that is absorbed after administration by route X compared with the amount of drug that is absorbed after intravenous (IV) administration. X is any route of drug administration other than IV. Total Body Clearance Clearance is a term that indicates the rate at which a drug is cleared from the body. It is defined as the volume of plasma from which all drug is removed in a given time. Thus the units for clearance are given in volume per unit of time. Total body clearance is the sum of clearances from the various organs involved in drug metabolism and elimination. o Pharmacokinetics Volume of distribution Volume of distribution (VD) is a calculation of the apparent volume in which the drug is dissolved. It assumes that a drug is evenly distributed and that metabolism or elimination has not taken place. In reality, it does not correspond to any real volume. VD=Dose/plasma concentration First-order kinetics Most drugs disappear from plasma by processes that are concentration-dependent, which results in first-order kinetics. With first-order elimination, a constant percentage of the drug is lost per unit time. An elimination rate constant can be described. The half-life (t1/2) is the period of time required for the concentration of a drug to decrease by one half. The half-life is constant and related to the elimination rate constant (ke) for drugs that have first order kinetics. t1/2=0.693/ke PAGE 18 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Clearance of a drug is different from the elimination rate. For drugs with first-order kinetics, the VD, t1/2, ke, and clearance are all interrelated. Zero-order kinetics Drugs that saturate routes of elimination disappear from plasma in a non-concentration-dependent manner which is zero-order kinetics. Examples: aspirin, phenytoin, and ethanol. For drugs with zero-order kinetics, a constant amount of drug is lost per unit time. The half-life is not constant for zero-order reactions, but depends on the concentration Zero-order kinetics is also known as nonlinear or dosedependent kinetics. Steady-State Concentration With multiple dosing, or a continuous infusion, a drug will accumulate until the amount administered per unit time is equal to the amount eliminated per unit time. The plasma concentration at the this point is called the steady-state concentration (CSS). Repeated dosing is associated with peak and trough plasma concentrations. Time needed to reach steady-state The time needed to reach steady state depends only on the half-life of the drug. Ninety percent of steady state is reached in 3.3 half-lives. Loading Dose A loading dose is a single large dose of drug that is used to raise the plasma concentration to therapeutic level more quickly than would occur through repeated smaller doses. o Drug Metabolism and Renal Elimination Liver Metabolism Phase I reactions frequently involve the P-450 system. Phase II reactions are conjugations, mostly with glucuronide. Renal Excretion Renal elimination of drugs involves three physiological processes: glomerular filtration, proximal tubular secretion, and distal tubular reabsorption. Reminder: When the pH is higher than the pK, the unprotonated forms (A- and B) predominate. When the pH is less than the pK, the protonated forms (HA and BH+) predominate. Drugs that Affect the Autonomic Nervous System PAGE 19 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 o Review of the Autonomic Nervous System Relevant Anatomy The autonomic nervous system is responsible for maintaining the internal environment of the body (homeostasis). Within the autonomic nervous system, two neurons are required to reach a target organ, a preganglionic neuron and a postganglionic neuron. All preganglionic neurons release acetylcholine as their transmitter. The acetylcholine binds to nicotinic receptors on the postganglionic cell. All of the parasympathetic postganglionic fibers release acetylcholine. At the target organ acetylcholine interacts with muscarinic receptors. Most of the sympathetic postganglionic fibers release norepinephrine. At the target organ norepinephrine interacts with a variety of receptors. Synthesis, Storage, Release, and Removal of Transmitters Acetylcholine is synthesized from acetyl coenzyme A (acetyl CoA) and choline. Its action is terminated by acetylcholinesterase. The effect of NE is terminated predominately by reuptake into the neuron from which it was released. Receptors There are two classes of receptors for acetylcholine, muscarinic and nicotinic. All of the parasympathetic postganglionic fibers release acetylcholine. At the target organ the acetylcholine interacts with muscarinic receptors. Nicotinic receptors are found at the motor end plate, in all autonomic ganglia, and in the adrenal medulla. Receptors for NE are divided into alpha and beta receptors. These receptors are further subdivided into alpha1 and alpha2, and beta1, beta2, and beta3, respectively. General Rules of Innervation Many organs are innervated by both the sympathetic and parasympathetic nervous systems. Most of the time the two systems have opposing effects. Important organs that receive innervation from both the sympathetic and parasympathetic nervous systems include the heart, eye, bronchial smooth muscle, GI PAGE 20 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 tract smooth muscle, and genitourinary tract smooth muscle. In the resting state (not in fight-or-flight situations), most dually innervated organs are controlled by the parasympathetic system. Most of the vascular smooth muscle is innervated solely by the sympathetic nervous system. This means that blood pressure and peripheral resistance are controlled by the sympathetic nervous system. Contraction of the radial muscle (sympathetic innervation) causes dilation, or mydriasis (expected sympathetic response), while contraction of the circular muscle (parasympathetic innervation) causes constriction or miosis (expected parasympathetic response). The heart is the main site for beta1 receptors. Activation of beta2 receptors relaxes smooth muscle. Activation of alpha receptors causes contraction or constriction, mostly vasoconstriction. Presynaptic Receptors Activation of presynaptic alpha2 receptors results in feedback inhibition of the release of norepinephrine. Inhibition of presynaptic alpha2 receptors will increase release of norepinephrine. o Cholinergic Agonists Organization of the Class Direct-acting cholinergic agonists have a direct action on the receptor for acetylcholine. Some drugs are specific for the muscarinic receptor; others are specific for the nicotinic receptor. The indirect-acting cholinomimetic act by blocking the metabolism of acetylcholine by cholinesterases. These drugs effectively increase the concentration of acetylcholine at all cholinergic synapses. Effects of Activation of Muscarinic Receptors o Eye: Miosis (constriction of the pupil) o Cardiovascular: Decrease in heart rate o Respiratory: Bronchial constriction and increased secretions. o Gastrointestinal: Increased motility, relaxation of sphincters PAGE 21 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 o Genitourinary: Relaxation of sphincters and bladder wall contraction. o Glands: Increased secretions Activation of nicotinic receptors results in muscle contraction (fasciculations and weakness). Direct Cholinergic Agonists Esters o bethanechol o carbachol o cevimeline o methacholine Alkaloids o arecoline o muscarine o pilocarpine The effects of all of these agents are exclusively muscarinic. Bethanechol is used in the treatment of urinary retention. The side effects of these drugs are directly related to their interaction with muscarinic receptors. Nicotine is a direct agonist at nicotinic receptors. used therapeutically to help patients stop smoking Cholinesterase Inhibitors Reversible Inhibitors o Myasthenia Gravis Edrophonium Neostigmine Pyridostigmine ambenonium demecarium physostigmine o Alzheimer Disease Donepezil galantamine rivastigmine tacrine Irreversible Inhibitors o diisopropyl fluorophosphate o echothiophate o isoflurophate o malathion PAGE 22 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 o parathion o sarin o soman These drugs all have the same actions (and side effects) as the direct-acting drugs (muscarinic). In addition, because they increase the concentration of acetylcholine, they have effects at the neuromuscular junction (nicotinic). Edrophonium is used in the diagnosis of myasthenia gravis. Neostigmine, Pyridostigmine, and ambenonium are used in the treatment of myasthenia gravis. Other uses of the reversible cholinesterase inhibitors: treatment of open-angle glaucoma, treatment of alzheimer disease and the reversal of nondepolarizing neuromuscular blockade after surgery. There are no therapeutic uses for the irreversible cholinesterase inhibitors. Pralidoxime and atropine are used to treat poisoning with organophosphates. Dental considerations o muscarinic receptor agonists may be useful in stimulating salivary flow when there is functional salivary gland tissue and when there is no contraindication for their use. muscarinic receptor agonists are contraindicated in urinary tract obstruction, hyperactive airway disease, chronic obstructive pulmonary disease, acute heart failure, gastrointestinal spasms, hyperthyroidism, and acute iritis o Pilocarpine is usually taken at doses of 5mg or 10mg three times a day, 30 minutes before each meal o Cevimeline is given at dose of 30 mg three times daily o Physostigmine may be valuable in treating certain adverse reactions to antimuscarinic drugs used for intravenous sedation o Cholinergic Antagonists Muscarinic Antagonists The prototypic muscarinic antagonist is Atropine PAGE 23 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 All of the muscarinic antagonists are competitive antagonists for the binding of acetylcholine to the muscarinic receptor. Effects of muscarinic antagonists o eye: mydriasis, cycloplegia (blurred vision) o Skin: reduced sweating, flushing o Gastrointestinal: reduced motility and secretions o Cardiovascular: increased heart rate (high doses) o Respiratory: bronchial dilation and decreased secretion o Genitourinary: Urinary retention o Central nervous system: Drowsiness, hallucinations, coma Muscarinic antagonists o atropine o ipratroprium o scopolamine Muscarinic antagonists are used preoperatively to reduce secretions. Scopolamine is used to treat motion sickness. Ipratropium is used in the treatment of chronic obstructive pulmonary disease (COPD) to produce bronchodilation. Muscarinic antagonists are used for urinary frequency, urgency, and urge incontinence caused by bladder (detrusor) overactivity. Ganglionic Blockers Ganglionic blockers works by interfering with the postsynaptic action of acetylcholine. They block the action of acetylcholine at the nicotinic receptor of all autonomic ganglia. These drugs are very rarely used clinically. Neuromuscular Blockers The competitive neuromuscular blocking drugs are used to produce skeletal muscle relaxation. Succinylcholine is a depolarizing neuromuscular blocker. Nondepolarizing blockers o d-tubocurarine o pancuronium Botulinum toxin blocks the release of acetylcholine at all cholinergic synapses. Dantrolene is used to treat malignant hyperthermia. PAGE 24 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 interferes with release of calcium from the sarcoplasmic reticulum in skeletal muscle. Therapeutic Uses in Dentistry o anticholinergic drugs in dentistry are used to decrease salivary flow during dental procedures. During general anesthesia, anticholinergics also diminish secretions in the respiratory tract, reducing the likelihood of laryngospasm and help prevent reflex vagal slowing of the heart Implications for Dentistry o antimuscarinic drugs cause xerostomia and associated deterioration of oral health o antimuscarinic drugs should be avoided in patients with prostate hypertrophy and patients with atony in the urinary or gastrointestinal tract o Adrenergic Agonists Organization of the Class alpha1=most vascular smooth muscle; agonists contract beta1=heart; agonists increase rate beta2=respiratory and uterine smooth muscle; agonists relax Direct-Acting Agonists only epinephrine and norepinephrine activate both alpha and beta receptors. Norepinephrine has a relatively low affinity for beta2 receptors. Alpha1 agonists o phenylephrine; used as a nasal decongestant alpha2 agonists o clonidine; decreases blood pressure through a central action B1 agonists o dobutamine increases heart rate and cardiac output Agonists with equal affinity for beta1 and beta 2 o isoproterenol beta2 agonists o albuterol used to relieve bronchoconstriction Dopamine PAGE 25 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 at low doses, dopamine causes renal and coronary vasodilation. It also activates beta1 receptors in the heart. Indirect-acting agents The indirect acting sympathomimetic agents act by releasing previously stored norepinephrine. Amphetamine and is its relatives, dexmethylphenidate and methylphenidate, are central nervous system stimulants used to treat attention deficit hyperactivity disorder in children. Cardiovascular Effects of Norepinephrine, Epinephrine, and Isoproterenol Norepinephrine increases total peripheral resistance and mean arterial pressure. Epinephrine predominately affects the heart through beta1 receptors, causing an increase in heart rate and cardiac output Isoproterenol causes a marked decrease in total peripheral resistance and an increase in heart rate and cardiac output. Therapeutic Uses in Dentistry Epinephrine is the most common vasoconstrictor used in dentistry with levonordefrin being used less frequently, usually with mepivacaine. Vasoconstrictors serve several useful purposes when used with local anesthetic solutions o they prolong duration of local anesthesia several fold and may improve the frequency of nerve block o systemic toxicity of the local anesthetic may be minimized by reducing the peak blood concentration of the local anesthetic o they tend to reduce blood loss associated with surgical procedures o the question is often faced of whether to use vasoconstrictor-containing anesthetics in patients with cardiovascular disease; consult guidelines o Adrenergic Antagonists Organization of Class the sympathetic nervous system can be blocked either by decreasing sympathetic outflow from the brain, suppressing the release of norepinephrine from terminals, or by blocking postsynaptic receptors PAGE 26 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Central Blockers Alpha 2 agonists reduce sympathetic nerve activity and are used to treat hypertension Alpha Blockers Most of the alpha antagonists allow vasodilation and, thus, decrease blood pressure. The side effects of the alpha blockers are directly related to their alpha-blocking activity. Tamsulosin and silodosin are specific antagonists of the alpha1A receptor and are used in the symptomatic treatment of benign prostatic hyperplasia. All of the alpha-blockers are reversible inhibitors of the alpha receptor, except phenoxybenzamine, which is irreversible. The "-azosins," such as Prazosin are used in the treatment of hypertension. Beta Blockers beta1=heart, antagonists decrease rate beta2=smooth muscle; antagonists contract; antagonists may be dangerous in asthmatics The beta-blockers have widespread use in the management of cardiac arrhythmias, angina, and hypertension. Beta-blockers should be used with caution in diabetics (interferes with recovery from hypoglycemia). Beta1 selective antagonists are often referred to as cardioselective. The adverse effects of these drugs are, for the most part, directly related to their beta blocking abilities. Some beta-blockers are said to have intrinsic sympathomimetic activity. This means they have partial agonist activity, even though they are classified as betablockers. Mixed Alpha and Beta Blockers Labetalol has both alpha- and beta-blocking activity Implications for Dentistry syncope can be a problem in patients taking antihypertensives in patients taking beta blockers there is increased risk of hypertension after use of local anesthetic agents that contain vasoconstrictors due to blockage of the beta2associated vasodilation PAGE 27 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Clonidine is well known to cause xerostomia and is associated with higher incidence of oral candidiasis and dental caries Patients taking MAO inhibitors must not be given drugs that have indirect sympathomimetic activity or are inactivated by MAO Opioids and other CNS depressants should be used captiously and usually at lower doses in patients taking MAO inhibitors. Meperidine is absolutely contraindicated. Drugs that Act on the Central Nervous System o Drugs Used in Dementia Organization of Class None of the drugs available for dementia alter the underlying pathology. They produce only a marginal improvement in symptoms. Cholinesterase Inhibitors Donepezil Galantamine Rivastigmine Tacrine NMDA Blocker Memantine is a noncompetitive antagonist at the NMDA subtype of glutamate receptor. o Anxiolytic and Hypnotic Drugs Tolerance and Dependence Tolerance is a physiological state characterized by a reduced drug effect with repeated use of the drug. Higher doses are needed to produce the same effect. Cross-tolerance means that individuals tolerant to one drug will be tolerant to other drugs in the same class, but not to drugs in other classes. Dependence is characterized by signs and symptoms of withdrawal when drug levels fall. Organization of Class Cross-tolerance and cross-dependence occur between all of the CNS sedatives, including the barbiturates, benzodiazepines, and ethanol. Barbiturates Barbiturates enhance the function of GABA in the CNS Barbiturates will o produce sedation, hypnosis, coma, and death o suppress respiration (overdose can lead to death) o induce the liver P-450 system PAGE 28 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY PAGE 29 OF 63 FALL 2012 Any other drug that is metabolized by the P-450 system will be altered by the presence of barbiturates. The selection of a particular barbiturate depends on the duration of action of the agent, which in turn depends on its lipid solubility. Symptoms of withdrawal in a person dependent on barbiturates include anxiety, nausea and vomiting, hypotension, seizures, and psychosis. Cardiovascular collapse may develop leading to death. Benzodiazepines Benzodiazepines bind to a specific site associated with the GABA-A receptor results in increased inhibition. Most benzodiazepines are metabolized in the liver to active metabolites. In general the metabolites have slower elimination rates than the parent compound. Elimination half-life is not the same as duration of action for the benzodiazepines. Physical and psychological dependence to benzodiazepines can occur. FLUMAZENIL is a benzodiazepine antagonist. Some specific benzodiazepines have special uses. DIAZEPAM and LORAZEPAM are used in the treatment of status epilepticus. CHLORDIAZEPOXIDE is used in cases of alcohol withdrawal. Buspirone Buspirone is a non-benzodiazepine that is used to treat generalized anxiety disorders. Benzodiazepine receptor agonists Zaleplon, zolpidem, and eszopiclone are not structurally related to the benzodiazepines but act as agonists on the benzodiazepine receptor and are used in the treatment of insomnia. Melatonin receptor agonists Ramelteon is a melatonin receptor agonist that will help one fall asleep faster. Implications for Dentistry Many concerns associated with sedative-hypnotics such as tolerance, sedation, addiction, abuse, rebound sleep disturbances, and the induction of hepatic microsomal enzymes are minimized in short-term therapy relevant to dentistry DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Patients should be warned of using other CNS depressants, particularly alcohol Elderly patients and patients with impaired liver function are at risk for impaired cognitive and motor function after administration of sedative-hypnotics Sleep apnea (more common in obese and elderly (especially men) may be exacerbated by sedativehypnotics Sedative hypnotics are generally contraindicated in pregnancy o Drugs Used in Mood Disorders Organization of Class Serotonin-Specific Reuptake Inhibitors (SSRIs) SSRIs ar antidepressants that block the reuptake of serotonin. SSRIs are not cholinergic antagonists or alpha-blockers. Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine is an effective antidepressant that block reuptake of both serotonin and norepinephrine. A related drug, atomoxetine, which is a selective norepinephrine reuptake inhibitor is used to treat attention-deficit/hyperactivity disorder. Heterocyclic/TCAs The precise mechanism of action of the tricyclic drugs is unknown. These drugs block the reuptake of biogenic amines, including norepinephrine and serotonin. Heterocyclic antidepressants are o potent muscarinic cholinergic antagonists o weak alpha antagonists o weak histamine antagonists o These actions account for the major side effects of the drugs Monoamine Oxidase Inhibitors MAO inhibitors increase levels of norepinephrine, serotonin, and dopamine by inhibiting their degradation. MAO inhibitors can cause a fatal hypertensive crisis. Other Antidepressants Bupropion is an effective antidepressant that is also approved for use (in combination with behavioral modification) in smoking-cessation programs. Mirtazapine is an effective antidepressant that antagonizes central presynaptic alpha-2 receptors. PAGE 30 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Sibutramine is a norepinephrine, 5-HT and dopamine reuptake inhibitor that is used as a weight loss agent. Drugs Used in Bipolar Disorder Lithium, carbamazepine, and valproate are drugs used for the treatment of bipolar disorder. Lithium has a low therapeutic index and the frequency and severity of adverse reactions is directly related to the serum levels. NSAIDs may decrease renal excretion of lithium and lead to toxic plasma concentrations after several days of combined therapy The combination of lithium and pilocarpine must be avoided because of risk of seizures Lithium commonly alters palpability of food and decreases salivary flow Implications for Dentistry Depression is associated with changes associated with increased risk for oral disease o reduced salivary flow o increased preference for carbohydrates o higher oral lactobacillus counts o decreased motivation and interest in oral health o periodontitis o facial pain and temporomandibular joint disorders may be comorbid amitriptyline and duloxetine may be useful for facial pain drugs that inhibit norepinephrine reuptake may produce exaggerated cardiovascular response to vasoconstrictors o Antipsychotics or Neuroleptics Organization of Class All of the neuroleptics are o alpha blockers o muscarinic antagonists o histamine antagonists o These actions produce the side effects of the drugs o All neuroleptics are dopamine blockers (D2), but the atypical drugs (second generation) also block 5-HT2A receptors. Typical Antipsychotics (First Generation) PAGE 31 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 All of these drugs produce extrapyramidal effects, including parkinsonism, akathisia, and tardive dyskinesia Serotonin-Dopamine Antagonists (Second Generation) Second-generation neuroleptics reduce both the positive and negative symptoms of schizophrenia, while causing minimum of extrapyramidal side effects. Risperidone is the drug of choice for new onset schizophrenia. Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome is a rare, potentially fatal neurological side effect of antipsychotic medication. Implications for Dentistry anti-psychotics can enhance CNS depression Tardive dyskinesia of the orofacial musculature can occur in patients taking anti-psychotics Xerostomia and associated oral problems can be a side effect of anti-psychotics o Drugs Used in Parkinson's Disease Organization of Class Therapy for Parkinson Disease o dopamine replacement therapy o dopamine agonist therapy o anticholinergic therapy Dopamine Replacement Therapy LEVODOPA (L-dopa) is a metabolic precursor of dopamine that crosses the blood-brain barrier. Carbidopa is a dopamine decarboxylase inhibitor that does not cross the blood-brain barrier. It reduced peripheral metabolism of levodopa, thereby increasing the amount of levodopa that reaches the brain. Selegiline (also known as deprenyl) is an inhibitor of monoamine oxidase (MAO-B), the enzyme that metabolizes dopamine in the central nervous system. Dopamine Agonist Therapy Anticholinergic Therapy Trihexyphenidyl, benztropine, and biperiden are muscarinic antagonists used in Parkinson disease. Implications for Dentistry Parkinson symptoms may make oral health care difficult PAGE 32 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Patients may experience xerostomia or less often sialorrhea and experience nausea and vomiting Scheduling treatment within 60 to 90 minutes of a levodopa dose may help with symptoms Orthostatic hypotension can be a problem Levodopa may sensitize the heart to epinephrineinduced arrhythmias o Antiepileptic Drugs Organization of Class Generalized convulsive seizure: drugs of choice: valproate, lamotrigine, levetiracetam partial, including simple, complex, and secondarily generalized seizures: drugs of choice: Carbamazepine, lamotrigine, oxcarbazepine, levetiracetam generalized nonconvulsive: ethosuximide, valproate Important Details About the Most Important Drugs Valproate is associated with elevated liver enzymes, nausea and vomiting, and weight gain. It can also produce a tremor. Carbamazepine causes auto induction of its own metabolism. Ethosuximide is the drug of choice for absence seizures. It is associated with stomach-aches, vomiting, and hiccups. Other Drugs to Consider Phenytoin has zero-order kinetics. Phenytoin causes ataxia and nystagmus at high doses. It has been associated with hirsutism, coarsening of facial features, and gingival hyperplasia. Clonazepam is an alternative drug for the treatment of generalized nonconvulsive seizures. It is a benzodiazepine and tolerance develops to its antiepileptic effects. Implications for Dentistry Dentists should be prepared to manage a seizure, knowing and avoiding triggers can help careful attention should be made to local anesthetic dosing and administration Dentists should be aware of additive effects of CNS depressants PAGE 33 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Anti-epileptics may induce blood dyscrasias that may increase the patients susceptibility to infection, gingival bleeding, or oral mucosal lesions phenytoin induces gingival overgrowth that can be diminished by proper oral hygiene some anticonvulsants increase hepatic enzyme activity and my impact agents used in dental practice such as tetracycline, midazolam or triazolam. Erythromycin can lead to anti-convulsant toxicity thought a CYP3A4 interaction Carbamazepine induces short term taste disorders and Xerostomia Primidone causes localized gingival pain Clonazepam produces hypersalivation Anticonvulsants may be used in the treatment of chronic orofacial pain problems such as trigeminal neuralgia or burning mouth syndrome. Carbamazepine is a firstchoice drug for trigeminal neuralgia. o Narcotics (Opiates) Organization of Class Divide the narcotics into four groups: o Agonists; use morphine as the prototype o Weak agonist/reuptake inhibitors o Mixed agonist-antagonist o Antagonists o Remember the names of the antagonists (naloxone and naltrexone) and the most important mixed agonist-antagonist (pentazocine). Everything else is an agonist. Actions of Morphine and the Other Agonists Morphine causes o analgesia o respiratory depression o spasm of smooth muscle of the gastrointestinal (GI) and genitourinary (GU) tracts, including the biliary tract o pinpoint pupils withdrawal from narcotics in a dependent person consists of autonomic hyperactivity, such as diarrhea, vomiting, chills, fever, tearing, and runny nose. Tremor, abdominal cramps, and pain can be severe. Distinguishing features of Some Agonists PAGE 34 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Codeine is used for suppressing cough and for pain. It is much less potent than morphine. Heroin is more lipid soluble than morphine and, therefore, rapidly crosses the blood-brain barrier. It is hydrolyzed to morphine in the brain; thus it is a prodrug. Meperidine is less potent than morphine and less spasmogenic. It has no cough suppressive ability. Fentanyl is 80 times more potent than morphine but has a short duration of action. It is used by anesthesiologists. Methadone is a highly effective analgesic after oral administration and has a much longer duration of action than morphine. The weak agonist/reuptake inhibitors are mu-agonists and norepinephrine (and serotonin) reuptake inhibitors. Opioid Antagonists Opioid antagonists have no effect when administered alone. When given after a dose of agonist, they promptly reverse all of the actions of the agonist. Naloxone is the drug of choice for narcotic overdose. Opioid Agonist-Antagonists Pentazocine produces effects that are qualitatively similar to morphine. Pentazocine causes acute withdrawal in patients who have received regular doses of morphine or other agonists. Implications for Dentistry meperidine is contraindicated with monoamine oxidase use; severe and immediate reaction includes excitation, rigidity, hypertension, and sometimes death o General Anesthetics Organization of Class Inhaled drugs: enflurane, halothane, isoflurane, nitrous oxide IV drugs: propofol, thiopental Uptake and Distribution of Inhalation Anesthetics When a constant tension (concentration) of anesthetic gas is inhaled, the tension (concentration) in arterial blood approaches that of the agent in the inspired mixture. The tension (concentration) in the brain is always approaching the tension (concentration) in arterial blood. PAGE 35 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 The solubility of an agent is expressed as the blood:gas partition coefficient. The more soluble an anesthetic is in the blood, the more of it must be dissolved in blood to raise its partial pressure in blood. The speed of onset of anesthesia is inversely related to the solubility of the gas in blood: More soluble (high blood:gas partition coefficient)= slower onset. Less soluble (low blood:gas partition coefficient)=faster onset. Elimination of Inhalation Anesthetics Elimination of anesthetics is influenced by pulmonary ventilation, blood flow, and solubility of the gas. Potency of General Anesthetics Minimum alveolar concentration (MAC) is defined as the alveolar concentration at one atmosphere the produced immobility in 50% of patients exposed to a painful stimulus. Specific Gases and Volatile Liquids Nitrous oxide is a relatively insoluble gas, with a MAC of about 105%, that has little effect on blood pressure or respiration. It does produce analgesia. Specific Intravenous Agents Propofol and etomidate are two drugs used intravenously to produce general anesthesia. o Local Anesthetics Organization of Class Adverse effects of the local anesthetics result from systemic absorption of toxic amounts of the drugs. Mechanism of Action Local anesthetics block the sodium channel in the nerve membrane. Special Features about Individual Agents Lidocaine is a local anesthetic used intravenously in the treatment of cardiac arrhythmias. Cocaine is better known as a drug of abuse, but it also an effective local anesthetic. Drugs that Affect the Cardiovascular System o Antihypertensive Drugs Organization of Class Mean arterial pressure = cardiac output X peripheral resistance PAGE 36 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Diuretics The thiazide diuretics inhibit sodium and chloride reabsorption in the thick ascending loop of Henle and early distal tubule. This loss of ions increases urine volume. The thiazide diuretics are the drugs of choice in the treatment of primary hypertension. The thiazide diuretics can cause hypokalemia. The loop diuretics inhibit chloride reabsorption in the thick ascending loop of Henle. The loop diuretics are commonly used to reduce pulmonary edema in patients with congestive heart failure. The major side effect of the loop diuretics is hypokalemia. Implications for Dentistry for Diuretics o thiazide and loop diuretics cause low potassium, combined use of epinephrine in gingival retraction cords and local anesthetic solutions can further drop potassium and induce arrhythmias o anti-inflammatory doses of corticosteroids can promote hypokalemia o there is increased risk of syncope in patients taking diuretics, and combination with sedative hypnotics and opioid analgesics can make this risk worse o NSAIDs used for dental pain may antagonize the antihypertensive effect of diuretics, this is more significant in chronic NSAID use Drugs that Interfere with the Renin-Angiotensin System Angiotensin-Converting Enzyme (ACE) inhibitors o ACE inhibitors block the synthesis of angiotensin II. Angiotensin II Receptor Blockers o The ARBs interfere with the binding of angiotensin II with its receptor. Selective Aldosterone Receptor Antagonists Spironolactone and eplerenone are antagonists of aldosterone at the mineralocorticoid receptor and can be used to treat hypertension. Direct Renin Inhibitor Aliskiren is the first direct renin inhibitor available. PAGE 37 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Calcium Channel Blockers Calcium channel blockers inhibit the entry of calcium into cells. They cause a decrease in afterload. The most common side effects of the calcium channel blockers (headaches, dizziness, hypotension, etc.) are related to vasodilation. Nitrates The nitrates dilate blood vessels and reduced cardiac preload. Nitroglycerin is the most commonly used antianginal agent. It is the drug of choice for relieving acute coronary spasm. Nitroprusside is a vasodilator given by continuous IV infusion. It is rapidly metabolized to cyanide. Headaches and postural hypotension are common side effects of the use of nitrates. Other Vasodilators Hydralazine and minoxidil directly relax arterioles. Fenoldopam is a dopamine agonist used for the acute treatment of severe hypertension. alpha and beta blockers The alpha-1 antagonists, such as prazosin, terazosin, and doxazosin, dilate arteries and veins. Beta-blockers prevent sympathetic stimulation of the heart. Beta blockers may particularly useful in patients with angina or those with migraines. Clonidine Clonidine is an alpha-2 agonist that reduced central sympathetic outflow. Implications for dentistry in patients with angina, stress can precipitate attacks o nitroglycerin should be available o the use of epinephrine in gingival retraction cords is contraindicated in patient with angina because of the potential for excessive work load of the heart o local anesthetics with adrenergic vasoconstrictors should be used with caution orthostatic hypotension may occur in patients taking calcium channel blockers PAGE 38 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 gingival inflammation and overgrowth can occur in patients taking calcium channel blockers, particularly when combined with other gingival enlarging drugs (phenytoin, cyclosporine). Regular dental prophylaxis should be used to prevent this problem. Aspirin and other NSAIDs antagonize many antihypertensive drugs; through inhibition of prostaglandin synthesis which is particularly important in maintaining renal blood flow and urine output; if blood pressure problems develop in patients prescribed NSAIDs, acetominophen should be substituted xerostomia is particularly prevalent in patients taking centrally acting antihypertensive drugs like clonidine o Drugs used in ischemic heart disease and congestive heart failure Ischemic Heart Disease Pharmacologically, the treatment of coronary artery disease focuses on the reduction of myocardial oxygen demand. Congestive Heart Failure Treatment of heart failure is targeted toward decreasing cardiac workload, controlling excess fluid, and enhancing myocardial contractility. Reduction of Cardiac Workload Angiotensin-converting enzyme (ACE) inhibitors lessen the symptoms of heart failure by reducing cardiac workload. Control of Excessive Fluid Diuretics are almost always used to control excess fluid accumulation in heart failure. Enhancement of Contractility Cardiac Glycosides o The cardiac glycosides (Digoxin and Digitoxin) improve myocardial contractility. They inhibit Na+, K+, ATPase. o Digoxin has a shorter half-life, no (the ultimate fewer) metabolites), is less completely absorbed from the GI tract, and is less protein bound the digitoxin. o The cardiac glycosides have low therapeutic index. PAGE 39 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 o Toxicity resulting from cardiac glycosides can be manifested by: arrhythmias anorexia, nausea, and diarrhea drowsiness and fatigue visual disturbances Sympathomimetics o Dobutamine is a beta-1 agonist. At moderate doses it increases contractility of the heart without changing blood pressure or heart rate. Phosphodiesterase Inhibitors Ranolazine Implications for Dentistry Stress Factor o stress can precipitate problems in heart failure patients o stress can lead to arrhythmias or CNS reactions in patients taking digoxin o antianxiety therapy or analgesics should be considered when stress or pain is likely Drug Interactions o catecholamines in local anesthetic are not contraindicated but should be used with caution avoid intravascular injection there is an increased risk of arrhythmias in patients taking digoxin o gingival retraction cords impregnated with epinephrine are not recommended in patients taking digoxin o antisialagogue such as atropine and methantheline should not be used in patient taking digoxin because they tend to reduce the effects of digoxin o Erythromycin and other macrolide antibiotics should be used with the knowledge that may increase the absorption of digoxin o excessive salivation may be a sign of toxicity owing to digoxin o Antiarrhythmic Drugs Organization of Class Class I Drugs (Sodium Channel Blockers) The class I drugs are essential sodium channel blockers PAGE 40 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 o o o o PAGE 41 OF 63 Class IA: Procainamide Class IB: Lidocaine Class IC: flecainide, propafenone The class IA drugs are useful in treatment of atrial and ventricular arrhythmias. o The class IB drugs (Lidocaine) are used for the treatment of ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation, and ventricular ectopy). o The class IC agents are useful in suppressing ventricular arrhythmias. Class II Drugs (Beta-Blockers) The Class II antiarrhythmics ar Beta Blockers These drugs are particularly useful in suppressing the tachyarrhythmias that result from increased sympathetic activity. Propanolol is the beta blocker most commonly used to treat patients with arrhythmias. Class III Drugs (Potassium Channel Blockers) The class III antiarrhythmics prolong repolarization. They are sometimes designated as potassium channel blockers. The class III agents are useful in treating intractable ventricular arrhythmias. Class IV Drugs (Calcium Channel Blockers) The class IV antiarrhythmics are calcium channel blockers. These drugs slow conduction through the AV node and increase the effective refractory period in the AV node. The calcium channel blockers are more effective against atrial then ventricular arrhythmias. Other antiarrhythmic Drugs Adenosine is highly effective in terminating paroxysmal supraventricular tachycardia. Digoxin is used to control the ventricular rate in atrial fibrillation or flutter. Drugs that increase heart rate Drugs that can be used to increase heart rate include Atropine, Isoproterenol, and Epinephrine. Implications for Dentistry DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 because some anti-arrhythmic agents may depress cardiovascular function, there is a potential for increased risk of orthostatic hypotension stressful treatment may induce arrhythmias the dentist may want to consult with the cardiologist regarding epinephrine or other vasoconstrictors o vasoconstrictors combined with propanolol may lead to hypertensive reactions o quinidine, disopyramide, procainamide have antimuscarinic activity and may interact additively with antimuscarinic antisialagogue o quinidine blocks CYP2D6 and may limit the effectiveness of certain oral opioids like codeine o there is an additive effect of lidocaine as a local anesthetic in patients who are taking it as an antiarrhythmic agent o Drugs that Affect Blood Organization of the Class Antiplatelet Agents Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, inhibit platelet aggregation and prolong bleeding time. Platelet glycoprotein IIb/IIa receptor antagonists prevent platelet aggregation by blocking the binding of fibrinogen and von Willebrand factor to the glycoprotein IIb/IIIa receptor on the surface of the platelet. Anticoagulants The major side effect of all anticoagulants is hemorrhage. Heparin interferes with clotting factor activation in both the intrinsic and extrinsic pathway. Protamine is a specific heparin antagonist that can be used to treat heparin-induced hemorrhage. Warfarin, a vitamin K antagonist, is the oral anticoagulant of choice. Administration of vitamin K can overcome the anticoagulant effects of the oral agents but the effect takes about 24 hours. There are a large number of drug interactions with the oral anticoagulants. Direct thrombin inhibitors are also effective anticoagulants. PAGE 42 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Implications for Dentistry: Anti-Coagulants o anticoagulants pose three kinds of problems for the dentists excessive bleeding may occur unless there is appropriate therapeutic modification modification of their therapeutic regimen in preparation for oral surgery may predispose them to thromboembolic events there may be interactions with analgesics, antibiotics, and sedatives o A high INR (usually greater than 3) increases the risk for bleeding; physician should be consulted about lowering INR; this may take several days to accomplish Thrombolytic Drugs Anticoagulant and antiplatelet drugs are administered to prevent the formation or extension of clots. Thrombolytic drugs are used to lyse already formed clots. The thrombolytic drugs are plasminogen activators. Clot dissolution and reperfusion are more likely if therapy is initiated early after clot formation. Clots become more difficult to lyse as they age. The main side effect of thrombolytic drugs is bleeding. Streptokinase is a foreign protein and is antigenic. t-PA is not antigenic. Phosphodiesterase Inhibitors Phosphodiesterase III inhibitors (pentoxifylline and cilostazol) are used to treat intermittent claudication. Drugs Used in the Treatment of Anemia Iron salts, such as ferrous sulfate, are used as iron supplements to treat iron deficiency anemia. Epoetin alfa and darbepoetin alfa are human recombinant erythropoietins. o Lipid-lowering Drugs Lovastatin: Inhibits HMG-CoA reductase Cholestyramine: Bile acid-binding resins Ezetimibe: inhibits absorption of cholesterol Chemotherapeutic Agents o Introduction to Chemotherapy Approach to the antimicrobials General Principles of Therapy PAGE 43 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 To be a useful antibiotic, a compound should inhibit the growth of bacteria without harming the human host. The drug should penetrate body tissues in order to reach the bacterium. Definitions Spectrum--as in narrow, broad, and extended--is a term used to convey an impression of the range of bacteria that a drug is effective against. Bacteriostatic versus bacteriocidal--be sure you know the difference. Important Concepts to Understand Resistance of bacteria to an antibiotic can occur by mutation, adaptation, or gene transfer. Adverse effects can be allergic, toxic, idiosyncratic, or related to changes in the normal body flora. Combinations of antimicrobial agents can take advantage of the mechansisms of action to produce a synergistic effects. Culture and sensitivity testing will determine the MIC for the bacteria. Classification of Antimicrobials o Inhibitors of Cell Wall Synthesis General Features The penicillins, cephalosporins, vancomycin, imipenem, and aztreonam all work by inhibiting the synthesis of the bacterial cell wall. Beta-Lactams All of the drugs in this group contain a beta-lactam ring in their structure Some bacteria inactivate the beta-lactam antibiotics by an enzyme that opens the beta-lactam ring. The inactivation of these drugs by the beta-lactamases can be dealt with by two approaches: o Give a beta-lactamase inhibitor at the same time. o Make chemical modifications in the structure of the drug to make it more resistant to inactivation. o Clavulanic acid and sulbactam are betalactamase inhibitors that are given together with the beta-lactam drugs to increase their effectiveness. Penicillins PAGE 44 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 o Penicillins are excreted by tubular secretion that can be blocked by probenecid. o The most important adverse effect of penicillins as a group is the hypersensitivity reaction. It can be fatal. Cephalosporins o Therapeutic Uses in Dentistry good activity against many orofacial pathogens, but limited activity against oral anaerobes Carbapenems o Imipenem with Cilastatin is a broad spectrum beta-lactam antibiotic. Monobactams (Aztreonam) o Aztreonam is an excellent drug for aerobic gramnegative bacteria, including pseudomonas, but is ineffective against gram-positive organisms. Therapeutic Uses of Beta-Lactams in Dentistry o penicillin V is the most frequently prescribed antibiotic for chemotherapy of infections of dental origin; amoxicillin has significantly superior pharmacokinetics; Parenteral penicillin G is reserved for severe infections or in situations in which the oral route is impaired o some dental infections are caused by betalactamase producing organisms; in this case a penicillinase resistant penicillin derivative, erythromycin, or clindamycin is used Other inhibitors of Cell Wall Synthesis Vancomycin o Vancomycin is only effective against the grampositive organisms. It is very poorly absorbed orally. o Vancomycin has no uses in the management of acute or chronic orofacial infections unless dictated by laboratory culture and sensitivity tests. Bacitracin o Bacitracin is a mixture of polypeptides that inhibit cell wall synthesis. It is used topically. Fosfomycin Daptomycin o Protein Synthesis Inhibitors PAGE 45 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 General Features Aminoglycosides The aminoglycosides are broad-spectrum antimicrobials. However, anaerobic bacteria are generally resistant to them. Aminoglycosides are poorly absorbed from the GI tract. Aminoglycosides have ototoxicity, nephrotoxicity, and neuromuscular toxicity. Aminoglycosides have no uses in orofacial infections unless dictated by culture and sensitivity tests. Tetracyclines Tetracyclines are broad-spectrum antibiotics Tetracyclines have also found use in rickettsial disease (Rocky Mountain spotted fever), chlamydial disease, cholera, Lyme disease (spirochetes), and in mycoplasma pneumonia. Food impairs the absorption of the tetracyclines. Tetracyclines are associated with staining of the teeth, retardation of bone growth, and photosensitivity. Therapeutic Uses in Dentistry o The use of tetracyclines in the management of acute orofacial infections is widely considered inappropriate because of their bacteriostatic activity and extensive microbial resistance, but with the advent of oral microbial pathogens increasingly resistant to beta-lactams, macrolides, and clindamycin, this concept may have to be reconsidered Macrolides Erythromycin and its relatives are of particular use in the treatment of patients with mycoplasma infections, pneumonia, legionnaires disease, chlamydial infections, diphtheria, and pertussis Streptogramin and oxazolidinones Chloramphenicol Chloramphenicol is associated with bone marrow depression and aplastic anemia that is usually fatal. Chloramphenicol can produce gray baby syndrome, which is often fata. Clindamycin Clindamycin penetrates most tissues, including bone. It has activity against anaerobes. PAGE 46 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Therapeutic Uses in Dentistry o Clindamycin may be appropriate for oral infections resistant to beta-lactams o Folate Antagonists Mechanism of Action Sulfonamides and trimethoprim inhibit synthesis of folate at two different sites. Selected Features These folate antagonists are broad-spectrum agents that are effective against gram-positive and gramnegative organisms. o Quinolones and Urinary Tract Antiseptics Drugs in the Group Quinolones The quinolones inhibit DNA synthesis through a specific action on DNA gyrase Quinolones are rarely first-line agents. They are used to treat genitourinary, respiratory, GI, and some skin and soft tissue infections. Fluoroquinolones are not indicated for any acute orofacial infections unless dictate by culture and sensitivity tests. Methenamine Methenamine is metabolized to formaldehyde and ammonia and is used in urinary tract infections. o Drugs Used in Tuberculosis and Leprosy Organization of Class Isoniazid Isoniazid inhibits synthesis of mycolic acids There are fast and slow acetylators of isoniazid Isoniazid is associated with hypotoxicity and peripheral neuropathy. Isoniazid is the drug of choice for chemoprophylaxis in recent converters. Rifampin Rifampin inhibits RNA synthesis by formation of a stable complex with the DNA-dependent RNA polymerase. Rifampin is metabolized in the liver and is a potent inducer of the P-450 enzymes. It can cause hepatitis and may color secretions red-orange. Pyrazinamide PAGE 47 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Pyrazinamide is only effective against M tuberculosis. It increases levels of serum uric acid. Ethambutol Ethambutol can cause optic neuritis Dapsone Dapsone is the mainstay in the treatment of leprosy. o Antifungal Drugs Organization of Class Azole Antifungals The azoles are broad-spectrum fungistatic agents that inhibit the synthesis of ergosterol by inhibiting the 14alpha-demethylase enzyme. Candidiasis is the most common type of oral fungal infection. Regardless of which drug is used, therapy for 2 weeks is required. More extended therapy may be needed. Clotrimazole in the form of oral troches is highly effective in most cases. Clotrimazole if swallowed can increase hepatic enzymes, so for patients who are at greater risk of hepatic toxicity, nystatin oral pastilles or rinses instead. Oral fluconazole is a major systemic drug useful for oral candidiasis. If the infection is resistant to fluconazole, itraconazole is an alternative. Ketoconazole has increased risk of liver abnormalities. Polyene Antifungals The polyene antifungals, amphotericin B and nystatin, work by binding to ergosterol, the principal fungal membrane sterol. Amphotericin B is most commonly used to treat serious disseminated yeast and fungal infections, particularly in immunocompromised patients. The most serious and most common toxicity of amphotericin B is nephrotoxicity. Amphotericin B is not absorbed from the GI tract, so it must be given intravenously or topically. Echinocandins Terbinafine Terbinafine is administered orally for treatment of superficial fungal infections. Terbinafine prevents ergosterol synthesis by inhibiting squalene epoxidase. o Anthelmintic Drugs PAGE 48 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Organization of Class Drugs Used Against Cestodes and Trematodes Praziquantel is the drug of choice for most trematode (fluke) and many cestode infections. Drugs Used Against Nematodes Treatment of nematodes (roundworms) consists of (for the most part) albendazole, mebendazole, or pyrantel. The exception is filaria. Albendazole and mebendazole inhibit tubulin polymerization in the worms. Pyrantel causes paralysis of the worms. Drugs Used Against Filaria Filariasis is treated (for the most part) with diethylcarbamazine or ivermectin. Diethylcarbamazine is the drug of choice for lymphatic filariasis. Ivermectin paralyzes the worm muscle and is the drug of choice for onchocerciasis (cutaneous filariasis). o Antiviral Drugs Organization of Class Anti-HIV Drugs The nucleoside (NRTIs) nucleotide, and nonnucleoside (NNRTIs) reverse transcriptase inhibitors (RT inhibitors) all inhibit the formation of viral DNA from RNA by reverse transcriptase. The protease inhibitors interfere with processing of the viral protein, thus preventing formation of new viral particles. Enfuvirtide blocks the fusion of the viral particle to the target cell, while maraviroc inhibits entry of the viral particles into cells. Raltegravir is the first available integrase inhibitor. Therapy for HIV is either based on inhibition of RT using one NNRTI+two NRTIs or based on use of a protease inhibitor using one or two PIs+two NRTIs. Drugs Used in Influenza amantadine is used for the prevention and treatment of influenza type A infections. Neuraminidase inhibitors block release of influenza virus from infected cells. Other Antivirals PAGE 49 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Acyclovir is used to treat patients with herpes infections. To be effective, it must activated by phosphorylation. Ribavirin is used in the treatment of respiratory syncytial virus (RSV) in infants and young children. Antiviral Therapy in the Oral Cavity Herpes simplex virus (HSV) causes various oral mucosal lesions, including herpetic gingivostomatitis, recurrent intraoral herpes simplex, herpes labialis, and life-threatening eczema herpeticum. Most HSVassociated viral lesions are routinely treated by oral acyclovir with intravenous administration in some severe cases. Acyclovir is best used as soon as symptoms begin to appear. Supportive therapies for herpetic lesions include antipyretic analgesics, antibacterial antibiotics, and antifungals that help control secondary infections o Topical 1% penciclovir cream is the drug of choice for the control of recurrent herpes labialis, and it may be applied to the lesion every 2 hours while awake for 4 days. It reduces the discomfort of the infection and can shorten the period of lesions by 1 to 2 days. o Antiprotozoal Drugs Organization of Class Metronidazole Metronidazole is effective in the treatment of vaginal trichomoniasis, giardiasis, and all forms of amebiasis. Therapeutic Uses in Dentistry o metronidazole is also highly effective against gram-negative anaerobic pathogens responsible for acute orofacial infections and chronic periodontitis. Combination of metronidazole with a beta-lactam antibiotic for oral infections may be indicated for serious acute orofacial infections and in the management of aggressive periodontitis Antimalarial Agents Therapeutic Considerations Artemether-lumefantrine is highly effective for the treatment of uncomplicated malaria, including multidrug resistant infections. Special Features PAGE 50 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Primaquine is effective against liver forms (exoerythrocytic) and kills gametocytes. Primaquine can cause hemolytic anemia in glucose-6phosphate dehydrogenase (G6PD)-deficient patients. o Anticancer Drugs Organization of Class Many anticancer drugs have had several names over the years. Terminology and General Principles of Therapy Anticancer therapy is aimed at killing dividing cells. There are normal host cells that are also dividing. Effects on these cells cause side effects. The log kill is an important concept to understand. The anticancer drugs kill a constant fraction of cells instead of an absolute number. Drug resistance to anticancer drugs is analogous to resistance to antimicrobials. Combinations of drugs are frequently used in the treatment of cancer. Adverse Effects Bone marrow toxicity is caused by destruction of proliferating hematopoietic stem cells. This results in a decrease in all blood elements, including white cells and platelets. Gastrointestinal toxicity takes two forms. The nausea and vomiting associated with cancer chemotherapy is felt due to a central effect. These drugs can also directly damage the proliferating mucosa of the GI tract. Most anticancer drugs damage hair follicles and produce hair loss Renal tubular damage is the major side effect of cisplatin and high dose methotrexate. Cyclophosphamide can cause hemorrhagic cystitis. Cardiotoxicity is associated with the use of doxorubicin and daunorubicin (the anthracyclines). Bleomycin can cause pulmonary fibrosis, which can be fatal). Vincristine is known for its nervous system toxicity. Cytotoxic Drugs Alkylating Agents o Alkylating agents all work by adding an alkyl group to DNA. PAGE 51 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Antimetabolites o Methotrexate competitively inhibits dihydrofolate reductase o Leucovorin provides reduced folate to rescue normal cells from the action of methotrexate. o Methotrexate is used to treat psoriasis and sever rheumatoid arthritis in addition to a whole variety of cancers. It can be administered intrathecally. o The purine and pyrimidine analogues all have to activated (phosphorylated) before they are effective. Antibiotics and Other Natural Products o The antibiotics all disrupt DNA function. o The anthracyclines have cardiac toxicity. o Bleomycin can cause fatal pulmonary fibrosis. It does not have significant myelosuppressive effects. o Plicamycin (mithramycin) can be used to treat lifethreatening hypercalcemia associated with malignancy. o The vinca alkaloids (vincristine, vinblastine, and vinorelbine) bind to tubulin and disrupt the spindle apparatus during cell division. o For vincristine, the neurological toxicity is doselimiting. For vinblastine and vinorelbine, the bone marrow toxicity is dose-limiting. o Paclitaxel works by preventing depolymerization of microtubules. o Etoposide, teniposide, and irinotecan are plant products that inhibit topoisomerase. Antibodies Other Cytotoxic Drugs Hormonal Agents Aromatase inhibitors block estrogen formation and are used to treat estrogen-dependent tumors (breast cancer) resistant to tamoxifen. Tamoxifen and toremifene are competitive antagonists of the estrogen receptor, used in the treatment of breast cancer. The "lutamides" are competitive testosterone antagonists that are used to treat prostate cancer. PAGE 52 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Both GnRH analogues and antagonists will decrease serum levels of estrogen and testosterone and used to treat androgen-dependent prostate cancer. Kinase Inhibitors Miscellaneous Agents Implications For Dentistry: Anticancer Drugs Currently available antitumor drugs cannot distinguish between malignant cells and dividing normal cells and are potentially damaging to both. The mouth, by virtue of the rapid cellular turnover of the oral mucosa, the daily exposure of oral tissues to minor trauma, and the presence of an extensive and potentially infective microflora, is at special risk of developing drug-induced toxicity. Adverse reactions include stomatitis, hemorrhage, acute and chronic infection, and rapid progression of caries and periodontal bone loss. In addition, the pain associated with these conditions can impair nutrition. Drugs that Affect the Endocrine System o Adrenocortical Hormones Organization of the Class hydrocortisone (cortisol) is the main glucocorticoid produced by the adrenal glands. Aldosterone is the main mineralocorticoid produced by the adrenal glands. The pharmacologic actions of steroids are an extension of their physiological effects. All of the steroids (including the sex steroids) bind to intracellular receptors in target tissues. Glucocorticoids Glucocorticoids promote catabolism of proteins and gluconeogenesis. Glucocorticoids inhibit inflammatory and immunological responses. This is the basis of their therapeutic use and the reason why patients on glucocorticoids have increased susceptibility to infections. The complications of glucocorticoid therapy appear in all organ systems. A potentially serious complication of long-term use is osteoporosis. Mineralocorticoids PAGE 53 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Mineralocorticoids are involved in salt and water balance. Inhibitors of Adrenocortical Synthesis Therapeutic Uses of Corticosteroids in Dentistry Oral Ulcerations o Topical corticosteroids are useful for a variety of ulcerative lesions of the oral mucosa Temporomandibular Joint Disorders o intra-articular injection of glucocorticoids such as prednisolone or dexamethasone may be beneficial Postoperative Sequelae o glucocorticoids are often used to reduce edema and trismus after dental surgical procedures Anaphylaxis and Other Allergic Reactions o glucocorticoids may enhance the effects of effects of epinephrine anaphylaxis Implications for Dentistry: Patients Taking Glucocorticoids patients on long-term glucocorticoids have decreased resistance to infection and poor wound healing patients on long-term therapy may need to increase dose in order to support the stress of some procedures o Sex Steroids Organization of Class Estrogens The major estrogens produced by the body are estradiol, estrone, and estriol. The most common use of estrogens is in oral contraceptives. The most common side effects of estrogens are nausea and vomiting. Diethylstilbestrol (a nonsteroidal molecule) has been associated with cervical and vaginal carcinoma in daughters of women who take the drug during pregnancy. Anti-estrogens The selective estrogen receptor modulators (SERM) are not pure antagonists, but mixed agonists/antagonists. Clomiphene stimulates ovarian function and is used in the treatment of infertility Progestins Progesterone is the main natural progestin. PAGE 54 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 The major use of progestins is in oral contraceptives. The most common side effects of progestin use are weight gain, edema, and depression. Antiprogestins Mifepristone is an antiprogestin that works to terminate pregnancy by breaking down the uterine lining. Oral Contraceptives The most common pharmacological means of preventing pregnancy is the use of estrogens and progestins to interfere with ovulation. Progestin alone in pill form (mini-pill) or implants also provides contraception. The side effects of the oral contraceptives are related to the estrogens and progestins that are part of the pills. Androgens Testosterone is the major androgen produced in the body. The primary therapeutic use of androgens is for replacement therapy in patients with testicular deficiency. The side effects of the androgens are related to their physiological actions. Antiandrogens Finasteride is a 5alpha-reducatase inhibitor that is used to treat cases of benign prostatic hypertrophy (and to stimulate hair growth). GnRH agonists and antagonists The hypothalamic-pituitary-gonadal axis can be suppressed by administration of either a GnRH agonist or an antagonist. PDE5 inhibitors are not sex steroids but are used to treat erectile dysfunction. Sildenafil, tadalafil, and vardenafil inhibit a phosphodiesterase found in vascular smooth muscle. o Thyroid and Parathyroid Drugs Organization of the Class The thyroid stores thyroid hormone as thyroglobulin Thyroid Replacement Therapy There are two major thyroid hormones called T3 and T4, T3 is the most active form Levothyroxine (a sodium salt of T4) is the most commonly used drug for thyroid replacement therapy. PAGE 55 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Levothyroxine is the drug of choice for treatment of hypothyroidism. Drugs that are thyroid downers Surgery or radioactive iodine can be used to destroy the thyroid gland. Propylthiouracil and methimazole inhibit thyroid synthesis. Implications for Dentistry: Thyroid Hypothyroid patients show exaggerated response to CNS depressants such as sedatives and opioids Hyperthyroidism contributes to osteoporosis of the alveolar bone; dental caries and periodontal disease are more common, changes in gingiva may lead to ill-fitting dentures Parathyroid Drugs High serum calcium suppresses PTH secretion and low serum calcium stimulates PTH release. Teriparatide is a recombinant parathyroid hormone used in treatment of osteoporosis. Cinacalcet increases sensitivity of calcium-sensing receptors in the parathyroid gland resulting in a decrease in PTH and serum calcium levels. o Insulin, Glucagon, and Oral Hypoglycemic Drugs Organization of Class Type I diabetes is related to loss of insulin-secreting cells in the pancreas. Type II diabetes is related to target cell resistance to the action of insulin. Insulins Insulin must be administered by injection. The most common side effect of insulin is hypoglycemia. Insulin preparations vary in their time to onset and duration of action. Oral Hypoglycemic Agents The sulfonylureas act by stimulating the release of insulin from the beta cells in the pancreas by an interaction with the ATP-sensitive potassium channels. The most common adverse effect of the sulfonylureas is hypoglycemia. The "glitazones" increase insulin sensitivity. PAGE 56 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Metformin also increases insulin sensitivity. A rare, but potentially fatal, side effect is lactic acidosis, particularly in patients with renal impairment. Exenatide, liraglutide, and pramlintide are peptides that lower serum glucose levels, slow gastric emptying, and increase satiety. Implications for Dentistry diabetics have delayed wound healing and impaired ability to deal with infection xerostomia, increased incidence and severity of caries, candidiasis, gingivitis, periodontal disease, and periapical abscesses may occur patients taking anti-hyperglycemic agents are at risk for hypoglycemia. Patients taking beta blockers may have their symptoms of hypoglycemia masked, resulting in a more severe reaction Miscellaneous Drugs o Histamine and Antihistamines Organization of Class The action of histamine is mediated through at least two receptors, H1 and H2. Intestinal and bronchial smooth muscles contain mostly H1 receptors. Gastric secretion is mediated by H2 receptors. H1 Receptor Antagonists These drugs are competitive antagonists of the H1 receptor. The H1 antagonists (antihistamines) are used to treat cases of allergic rhinitis and motion sickness, and sometimes induce sleep. The nonsedating antihistamines, that is, the ones belonging to second generation (astemizole, cetirizine, fexofenadine, desloratadine, and loratadine) do not cross the blood-brain-barrier, so are less sedating. o Respiratory Drugs Organization of Class Drugs used in the treatment of bronchoconstriction include inhaled corticosteroids, beta-agonists, cholinergic antagonists, and methylxanthines. Beta2-agonists cause bronchodilation. Inhaled corticosteroids are also used in the treatment of asthma. PAGE 57 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Beta Agonists Leukotriene Modifiers Leukotriene modifiers are approved for oral prophylaxis and chronic treatment of asthma. Methylxanthines Cholinergic Antagonists Ipratropium (short-acting) and tiotropium (long-acting) are anticholinergic agents used for the treatment of COPD in adults. Cromolyn and Omalizumab Cromolyn sodium is used prophylactically in the treatment of asthma. Omalizumab is a monoclonal antibody specific for IgE and is used for the treatment of allergic asthma. Pulmonary Hypertension Endothelin-receptor antagonists (ambrisentan and bosentan) and prostacyclin analogs (epoprostenol, iloprost and treprostinil) are available for use in pulmonary hypertension. Implications for Dentistry: Respiratory Drugs patients should have all medications with them in case of an attack continued use of oral steroids can contribute to slower healing in the oral cavity stress can precipitate attacks, as well as some dental materials and latex gloves aspirin should be avoided in patients with asthma; acetominophen is the analgesic of choice in patients with asthma opioids can increase histamine release in patients who have increased airway resistance dry mouth can be a problem due to mouth breathing and/or medications o Drugs that affect the GI tract Organization of Class Drugs that Act in the Upper GI Tract The proton pump inhibitors (the "…prazoles") inhibit the H+-K+-ATPase enzyme of the parietal cell. This reduced acid secretion. o Omeprazole o Esomeprazole PAGE 58 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 H2 receptor antagonists prevent histamine-induced acid release. H2 antagonists include Cimetidine and Ranitidine. The aluminum salts and calcium carbonate antacids cause constipation. The magnesium salts cause diarrhea. Therefore, they are often mixed. Sucralfate forms a protective coating on the mucosa, particularly ulcerated areas. Metoclopramide and cisapride increase the rate of gastric emptying. Misoprostol is a prostaglandin analogue that increases bicarbonate and mucin release and reduces acid secretion. It is used to treat NSAID-induced ulceration. Drugs that Act in the Lower GI Tract Drugs that Act in the Lower GI Tract The bulk forming agents used to treat constipation contain plant matter that absorbs water and softens the stool. These include: calcium polycarbophil, methylcellulose, psyllium The stimulants used to treat constipation increase water and electrolytes in the feces and increase motility. These include bisacodyl, danthron, phenolphthalein, senna 5-aminsalicylate (5-ASA) is the active metabolite of Sulfasalazine, which is used to treat inflammatory bowel disease. Orlistat is a lipase inhibitor being used to treat obesity. Implications for Dentistry: The GI Drugs patients with GERD may have trouble with reclining in the dental chair aspirin and NSAIDs are contraindicated in patients with gastric or duodenal ulcers; acetominophen is preferred; celecoxib may be used Proton pump inhibitors may reduce the absorption of drugs in which gastric pH influences bioavailability (ketoconazole, ampicillin) There is a potential for interaction of GI drugs (cimetidine, omeprazole, aluminum or magnesium salts) with diazepam o Nonnarcotic Analgesics and Anti-Inflammatory Drugs Organization of Class Nonsteroidal Anti-inflammatory Drugs (NSAIDs) PAGE 59 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY PAGE 60 OF 63 FALL 2012 All of the NSAIDs (including aspirin) are thought to exert their clinical effects by inhibiting prostaglandin synthesis All the NSAIDs (including aspirin) have analgesic, antipyretic, and anti-inflammatory effects. The older (nonspecific) NSAIDs also have antithrombotic effects. The most common adverse effects of the NSAIDs (including aspirin) are GI injury and renal injury. Ketorolac is an NSAID that can be administered intramuscularly or intravenously. Ibuprofen is now also available for intravenous administration. COX-2 inhibitors COX-2 Inhibitors end in "coxib". These agents should be anti-inflammatory without harming the GI tract or altering platelet function. A 2004 study showed an increase risk of cardiovascular disease in patients taking COX-2 inhibitors and rofecoxib and valdecoxib were removed from the market. Salicylates, Including Aspirin Aspirin causes irreversible inactivation of COX. It is the only NSAID to do this. Use of aspirin has been associated with Reye syndrome in children. Overdose of aspirin is called salicylism. Symptoms include ringing in the ears (tinnitus), dizziness, headache, fever, and mental state changes. The pH after ingestion of large amounts of aspirin are complex, but important to understand. o Stimulation of the medullary respiratory center causes an increase in ventilation. This leads to respiratory alkalosis (increased pH and decreased pCO2). o There is uncoupling of oxidative phosphorylation This leads to an increase in plasma CO2, which further stimulates the respiratory center. o Aspirin has zero-order kinetics. Acetaminophen Acetominophen has analgesic and antipyretic actions, but does not have anti-inflammatory or antithrombotic activity. Acetominophen can cause fatal liver damage. Other Drugs for Arthritis DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Some gold preparations are used in treatment of rheumatoid arthritis. Auranofin is an orally effective gold preparation. Adalimumab, etanercept, and infliximab, inhibitors of tumor necrosis factor activity, can be used in the treatment of rheumatoid arthritis. Antigout Agents Colchicine can be used in acute attacks of gouty arthritis. It reduces inflammation. Allopurinol and feboxostat are urate-lowering agents that inhibit xanthine oxidase, thus reducing synthesis of uric acid. Drugs Used in the treatment of headaches NSAIDS are the mainstay of treatment of headaches and migraines 5-HT1 Receptor Agonists "-Triptans" o Immunosuppressives Organization of Class Calcineurin Inhibitors Ciclosporine inhibits antibody and cell-mediated immune response and is the drug of choice for prevention of transplant rejection. Mycophenolate Mofetil and Azathioprine Monoclonal Antibodies o Drug Used in Osteoporosis Organization of Class Pharmacological therapy is targeted toward both prevention of bone loss and treatment of established osteoporosis (increasing bone mass and reducing fractures). Bisphosphonates Alendronate The bisphosphonates inhibit osteoclastic activity and decrease bone turnover and resorption. They have been shown to reduce the incidence of fractures. osteonecrosis of the jaw is a raw but serious side effect in patients taking bisphosphonates Selective Estrogen Receptor Modulators Raloxifene has been approved for the prevention of postmenopausal osteoporosis. Estrogens Parathyroid Hormone PAGE 61 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Teriparatide, recombinant parathyroid hormone, is effective in reducing the incidence of new fractures in patients with osteoporosis. Calcitonin Other Agents o Toxicology and Poisoning Toxicology is the study of the toxic or harmful effects of chemical. It is also concerned with the symptoms and treatment of poisoning and the identification of the poison. The general principles of the toxic effects of chemicals are, for the most part, the same as the principles of the therapeutic effects of drugs. The single most important treatment of poisoned patients is supportive care. To reduce absorption in an alert, relatively asymptomatic patient, use activated charcoal. o Critical Emergency Drugs for Dentists Oxygen Epinephrine Nitroglycerin Bronchodilator Glucose Aspirin Primary Support Drugs Anticonvulsant: diazepam or midazolam Corticosteroids: for acute allergic reaction or adrenal insufficiency Antihistamine: useful in treatment of minor or delayed allergic reactions Respiratory stimulant (aromatic ammonia) is used as a general arousal agent during syncopal episod References Clark, M.A., Finkel, R., Rey, J.A., and Whalen, K. (2012). Lippincott’s Illustrated Reviews: Pharmacology (Fifth Edition). Baltimore, MD: Lippincott Williams & Wilkins. Stringer, J.L. (2011). Basic Concepts in Pharmacology: What You Need to Know for Each Drug Class (Fourth Edition). New York, NY: McGraw-Hill. Top 200 Drugs of 2010, retrieved from: http://www.pharmacytimes.com/publications/issue/2011/May2011/Top-200-Drugs-of2010 PAGE 62 OF 63 DR. ROESCH 9110 APPLIED PHARMACOLOGY FALL 2012 Yagiela, J.A., Dowd, F.J., Johnson, B.S., Mariotti, A.J., and Neidle, E.A. (2011). Pharmacology and Therapeutics for Dentistry (Sixth Edition). St. Louis, MO: Mosby Elsevier. PAGE 63 OF 63 DR. ROESCH
