Cholinergic antagonists:



Actions, Interactions and Indications for Selected Pharmacologic Agents

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Zora DeGrandpre, MS, ND

©2008

ISBN # 978-0-9818002-2-6

Note: In an effort to replace the Trees needed for the publication of this book, a portion of the proceeds will be donated to maintain the forests. I thank the Trees for their service

Table of Contents:

Principles of Pharmacology 9

Routes of Administration 9

Oral: 9

Sublingual: 9

Inhalation 9

Topical 9

Transdermal 9

Parenteral 10

Other 10

Pharmacokinetics 10

Absorption 10

Effect of pH 11

Physical Variables 11

Bio-availability 11

Distribution is dependent on: 11

Drug Metabolism 12

United States FDA Pharmaceutical Pregnancy Categories 13

Autonomic Nervous System Drugs 15

Cholinergic agonists 16

Donepezil (Aricept®) 16

Anti-cholinergics:Muscarinic Antagonists 17

Oxybutynin (Oxytrol®, Ditropan®) 17

Tolterodine (Detrol®) 19

Nicotinic agonists 20

Nicotine (Nicorette®, Nicotrol®, Nicoderm®) 20

Sympathomimetics 23

α and β-adrenergic (mixed) agonist 23

Epinephrine (Adrenalin®, EpiDri™, Epifrin®, SilTrax®, PrimateneMist®, EpiPen®) 23

α-adrenergic agonists 24

Oxymetazoline (Afrin®, Allerest®, Zicam ®, Mucinex®, Neo-synephrine®, Visine®) 24

Pseudoephedrine (Allermed®, Affrinol®, Ridafed®,Sudofed ®, Dimetapp®, Triaminic® and many other combinations ) 26

α2 Agonists 27

Clonidine (Catapress ®, Duraclon®) 27

Sympathomimetic amines 28

Amphetamine / Dextroamphetamine (Adderall ®, Dexadrine ®, Dextrostat®) 28

Methylphenidate (Concerta®, Daytrana®, Metadate®, Ritalin®) 30

Adrenergic antagonists 31

Tamsulosin (Flomax®) 31

β1Antagonists: 32

Atenolol (Tenormin®) 32

Metoprolol (Toprol®, Lopressor®) 34

Mixed α/ β Antagonist: 36

Carvedilol (Coreg®) 36

Central Nervous System (CNS) Drugs 38

Benzodiazepines 38

Alprazolam (Xanax®Niravam®) 38

Lorazepam (Ativan®) 39

Temazepam (Restoril®) 41

Clonazepam (Cebercon™, Klonopin®) 42

Imidazopyridines 44

Zolpidem (Ambien®) 44

Tricyclic Anti-depressants (Monoamine Reuptake Inhibitors) 45

Amitriptyline HCl (Elavil®, Tryptano™, Vanatrip®) 45

Atypical Antidepressants: Aromatic aminoketones 47

Bupropion (Wellbutrin®, Zyban®) 47

Selective Serotonin Reuptake Inhibitors 48

Citalopram (Celexa®) 49

Fluoxetine (Prozac®, Sarafem®) 51

Paroxetine (Paxil®, Pexeva®) 52

Sertraline (Zoloft®) 54

Serotonin Agonists 55

Sumatriptan (Imitrex®) 55

Dopamine Agonists 57

Carbidopa-Levodopa (Sinemet®) 57

Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNERI) 59

Trazodone (Desyrel®) 59

Miscellaneous CNS-active agents 61

Lithium carbonate (Eskalith ®, Lithobid®, Lithonate®) 61

Anti-convulsants- mixed pharmacologic classes 63

Phenytoin (Dilantin®) 63

Carbamazapine (Atretol®, Tegretol®, Epitol®, Carbatrol®, Epitol®) 65

Divalproex (Depakote®) 67

Valproic acid (Depakene®) 67

Valproate Na (Depacon®) 67

Gabapentin (Neurontin®, Gabarone™) 69

Anti-psychotics- Typical and Atypical 71

Olanzapine (Zyprexa®, Zydis®) 71

Quetiapine (Seroquel®) 73

Risperidone (Risperdal®) 75

Muscle-Relaxants 77

Cyclobenzaprine (Flexeril®, Fexmid™, Amrix®) 77

Carbamic ester derivatives 79

Carisoprodol (Soma®, Vanadom®, Soprodal 350™) 79

Opiates and opiate analogs 81

Hydrocodone bitartrate (Hydromet®, Hydropane®, Mycodone®, Tussigon®) 81

Hydrocodone bitartrate +Acetaminophen (Vicodin®, Anexia®, CETA-Plus®, Dolacet®, Duocet®, Lorcet®, Lortab®, Hydrocet®) 81

Hydrocodone bitartrate +Aspirin (Azdone®) 81

Hydrocodone bitartrate +Ibuprofen (Vicoprofen®) 81

Fentanyl citrate (Fentora®, Sublimaze®) 83

Fentanyl Transdermal (Duragesic®) 83

Fentenyl Transmucosal (Actiq®, Fentenyl Oralet®) 83

Oxycodone HCl (Oxycontin®, OxyFast®, Percolone®, OxyDose™, Endocodone ®, Roxicodone®) 84

Codeine (Phosphate or Sulfate salts) 86

Methadone (Diskets®, Dolophine®, Methadose®) 88

Respiratory System Agents 89

Anti-asthmatics 89

Sympathomimetics 89

Albuterol (Proventil®, Ventolin®, AccuNeb®, Volmax®, ProAir®, VoSpire®) 89

Beclomethasone (Beconase®, QVAR ®, Beclovent®, Vancenase®) 91

Salmeterol (Serevent Diskus®) 92

Anti-Cholinergics 94

Ipratropium (Atrovent®) 94

Corticosteroids 95

Budesonide (Entocort®, Pulmicort®, Rhinocort®) 97

Fluticasone (Flonase®, Flovent ®, Cutivate ®,Veramyst™) 98

Triamcinolone (Aristocort®, Kenacort®, Azmacort®, Flutex™, Oralone ®, Nasacort ®) 100

Respiratory Drugs: Miscellaneous 102

Cromolyn sodium (Crolom®, Gastrocrom ®, Intal ®, Nasalcrom®) 102

Montelukast (Singulair ®) 104

Anti-histamines 105

Cetirizine (Zyrtec ®) 105

Diphenhydramine (Allermax®, Benedryl®, Compoz®, Diphen®, Hyrexin®, Genahist®, Nytol®, Sleepinal®, Midol®, Sominex®, Unisom®) 107

Loratadine (Alavert®, Claritin®, Equate®) 108

Hematopoietic System Drugs 109

Anemia 109

Vitamin B12, Cyanocobalamin (BigShot B12®, Cyanoject®, Rubramin®, Hydro-Crysti-12®, LA-12®, CaloMist™) 109

Folic acid (Folvite ®, FA-8®, Folacin®, Folicet™) 110

Iron Dextran (DexFerrum ®, InFed®) 111

Iron sucrose (Venofer®) 111

Coagulation disorders 112

Acetylsalicylic acid (Aspirin®, Acuprin®, Bayer®, Ecotrin®, EMPIRIN®, Norwich®, Sureprin®, Zorprin®) 112

Clopidogrel (Plavix®) 114

Heparin (Hep-Lock®, Hep-Pak®, Uniparin®, Homochron™, Monoject®) 116

Warfarin (Coumadin®, Jantoven™) 118

Vitamin K (AquaMEPHYTON®, Mephyton®) 120

Anti-hyperlipidemic agents 121

Niacin/ Vitamin B3/ Nicotinic acid/ Niacinamide (Slo-Niacin®, Niacor®, Nicolar®) 121

Statin drugs 122

Atorvastatin (Lipitor®) 122

Lovastatin (Altocor®, Mevacor®, Altoprev®) 124

Anti-Inflammatory Agents 126

Anti-Arthritic Agents 126

Hydroxychloroquine (Plaquenil®, Quineprox®) 126

Methotrexate (Amethopterin®, MTX®, Rheumatrex®, Trexall®) 127

Analgesics 130

Prostaglandin synthesis inhibitors 130

Acetylsalicylic acid (Aspirin®, Acuprin®, Bayer®, Ecotrin®, EMPIRIN®, Norwich®, Sureprin®, Zorprin®) 130

Acetaminophen (Acephen®, Aceta®, Aminofen® Anacin®, Tylenol ®, Datril®, Feverall®, Liquiprin®Genapap®, Maranox®, Tempra®) 132

NSAIDs 134

Ibuprofen (Advil®, Motrin®, Genpril®, Medipren®, Menadol®, Midol®, Nuprin ®) 134

Naproxen (Aflaxen™, Anaprox®, Aleve®, Mediproxen®, Naprosyn ®, Naprelan®) 136

Celecoxib (Celebrex ®) 138

Miscellaneous: 140

Sulfasalazine (Azulfidine ®, Salazopyrn ®, Sulfazine®) 140

Cardiovascular System Drugs 142

β1 Antagonists: 143

Atenolol (Tenormin®) 143

Metoprolol (Toprol®, Lopressor®) 144

Mixed α/ β Antagonist: 146

Carvedilol (Coreg®) 146

α2 Agonists 148

Clonidine (Catapress ®, Duraclon®) 148

ACE Inhibitors 149

Benazapril (Lotensin®) 150

Lisinopril (Prinvil®, Zestril®) 151

Ca2+ Channel Blockers 153

Verapamil (Calan®, Covera®, Isoptin ®, Verelan®) 153

Diltiazem (Cardizem®, Cartia ®, Diltia®, Dilacor® Tiazac®, Taztia™) 155

Nitrates 156

Isosorbide dinitrate (Dilatrate®, Isordil ®) 157

Isosorbide mononitrate (Imdur®, Imso®, Monoket ®) 157

Nitroglycerin (Diponit®, Minitran®, Nitro-Dur ®, Nitolingual®, Nitrostat®, Nitrotab™, Nitrol®) 158

Cardiac glycosides 160

Digoxin (Digitek®, Lanoxicaps®, Lanoxin ®) 160

Anti-arrhythmics 161

Amiodorone (Cordorone®, Pacerone ®) 162

Propafenone (Rythmol ®) 164

Diuretics 165

Furosemide (Lasix®) 165

Hydrochlorothiazide (HCTZ) (Esidrix®, Ezide ™, HydroDiuril®, Hydro-Par®, Microzide®, Oretic®) 167

Spironolactone (Aldactone®, Spirono™) 169

Gastrointestinal System Agents 171

Antacids 171

Calcium carbonate (Alka-Mints®, Alkets®, Calci-Chew®, Caltrate®, Os-Cal®, Oyst-Cal®, Rolaids®, Tums® 171

H+Pump Inhibitors 173

Esomeprazole (Nexium®) 173

Histamine2 receptor antagonists 174

Ranitidine (Zantac®) 174

Cathartics and Laxatives 175

Irritants 175

Stimulants 175

Stool softeners 176

Bisacodyl (Bisac-Evac ®, Carter’s Little Pills®, Correctol®, Dacodyl®, Deficol®, Dulcolax®, Feen-a-Mint®, Fleet®, Theralax® 176

Docusate Calcium (DC Softgels®, Pro-Cal Sof®, Sulfolax®) 177

Docusate sodium (Colace®, Correctol®, DOS Softgels®, Modane Soft®, Regulax SS®, Silace®, Regulax®) 177

Osmotic Agents 178

Polyethylene glycol (GlycoLax™, MiraLax®) 178

Magnesium Hydroxide (Milk of Magnesia®, Freelax™) 179

Magnesium Sulfate (Epsom Salts) 179

Bulking Agents 180

Psyllium (Alramucil®, Fiberall®, Genfiber®, Hydrocil®, Konsyl®, Maalox®, Metamucil®, Modane Bulk®, Reguloid®, Restore®, Serutan®, Sylact®, V-Lax®) 180

Anti-diarrheal 181

Loperamide (Imodium®, Kaopectate®, Diarrhea Control®) 181

Anti-emetic 183

Prochlorperazine maleate (Compazine®, Compro™) 183

Genitourinary System Drugs 185

Male GU System 185

Tamsulosin (Flomax®) 185

Sildenafil (Viagra®, Revatio™) 186

Endocrine System Drugs 189

Thyroid agents 189

Dessicated Thyroid (Armour Thyroid®, Bio-Throid®, Etwon™, Thyrotab®, Westhroid®) 189

Levothyroxine (Estre™, Synthroid®, Levolet®, Levo-T®, Levothroid®, Levoxyl®, Thyro-Tabs®, Unithroid®) 190

Tri-iodothyronine, 192

(Cytomel®, Triostat®) 192

Corticosteroids 194

Beclomethasone (Beconase®, Beclovent ®,Vancenase®, Vanceril®,QVAR ®) 196

Hydrocortisone (Cortef®, Cortenema®, Hydrocortone ®, Anusol®, Cortizone®, Dermarest®) 197

Prednisone (Deltosone®, Predone™, Sterapred®) 201

Triamcinolone (Aristocort®, Kenacort, Azmacort®, Cinalog™, Cinolar™, Flutex™, Nasacort ®, Kenalog®, Oralone®) 203

Female Reproductive Hormones 207

SERMs 207

Clomiphene citrate (Clomid®, Milophene®, Serophene®) 207

Raloxifene (Evista®) 209

Estrogens and estrogen derivatives 210

Conjugated Estrogens (Premarin®, Cenestin™, Enjuvia™) 215

Estrone (Estra AQ®, Estragyn 5®, Estro-A®, Primestrin®) 215

Estriol: 217

Estradiol: Estrace®, Estring®, EstroGel®, Gynodiol®, Innofem® 220

Estradiol acetate: Femring™ 220

Estradiol cyprionate: Depo-Estradiol® 220

Transdermal: Alora®, Climara®, Delestrogen®, Esclim®, Estraderm®, Menostar™, Vivelle®, Vivelle-Dot® 220

Estradiol hemihydrate: Estrasorb™ 220

Estradiol valerate: Clinagen LA40®, Delestrogen® 220

Progesterone and progesterone derivatives 223

Medroxyprogesterone (Amen®, Depo-Provera®, Provera®, Prodroxy™, Provera®) 223

Progesterone (Crinone®, Progesterone MC 10 ®, First™- ®, First™-Progesterone VGS 100 ® Progesterone VGS 25, 50, 200, 400 ®, Gesterone™, Gestrin™, Prochieve®, Prometrium®) 225

Contraceptives 228

Norgestimate/Ethinyl Estradiol (MonoNessa®, Ortho Tri-Cyclen® Lo Ortho-Cyclen®, Ortho-Tri-Cyclen®, Previfem®, Sprintec-28®, Tri-Previfem®, Tri-Sprintec®, TriNessa®) 228

Norgestimate/Estradiol (Ortho-Prefest™, Prefest®) 230

Norelgestromin/ethinyl estradiol (OrthoEvra®) 233

Male Hormones 235

Testosterone (Androderm®, AndroGel®, Striant®, Testim®, Testoderm®, Testopel®Depo-Testosterone®, TestaSpan™, Testopel®, Tostrelle™, Virilon®Injection) 235

Testosterone cypionate (Depo-Testoserone®) 235

Testosterone enanthate (Delatestryl®) 235

Miscellaneous Hormones 237

Androstenedione 237

Calcitonin (Fortical®, Miacalcin®, Salmonine®) 239

Dehydroepiandrosterone: (Prestara™, Vitamist®, DHEA-M for Men, DHEA-W for Women) 240

Pregnenolone 242

Insulin, Glucagon and Anti-Hypoglycemic agents 243

Glucagon (GlucaGen®, Glucagon®) 243

Insulin 246

Oral Hypoglycemics 249

Glyburide (DiaBeta®, Glynase PresTab®, Micronase ®, Glycron™) 249

Metformin (Fortamet ™, Glucophage®, Riomet®) 251

Rosiglitazone (Avandia®) 253

Anti-neoplastics 255

Tamoxifen citrate (Sotamox®, Nolvadex®) 255

Anastrozole (Arimidex®) 257

Cyclophosphamide (Cytoxan®, Neosar®) 258

Doxorubicin (Adriamycin ®, Rubex®) 260

Etoposide (VP16-213) (Toposar®, VePesid®, Etopophos®) 263

5-Flurouracil (Adrucil®, Carac™, Efudex ®, Fluroplex®) 265

Cyclosporine (Gengraf®, Neoral®, Sandimmune®, Restasis™, Pulminiq™, SangCya™) 267

Methotrexate, MTX (Amethopterin®,Rheumatrex®, Trexall®) 270

Vinblastne (Velban ®) 273

Paclitaxel (Onxol ™, Taxol®) 275

Dermatological agents 277

Isotretinoin (Accutane®, Amnesteem ™, Claravis®, Sotret®) 277

Benzoyl peroxide (Benzac ®, Benzagel®, Clearplex™, Clearskin™, Desquam®, Fostex®, Lavoclen ™, Loroxide®, Panoxyl®, Zodem®) 279

Topical Analgesics 280

Benzocaine (Americaine®, Anacaine®, Anbesol®, Boil-Ease®, Cepacol®, Comfort Caine™, DentiCare™, Dermoplast®, Detane®, Dry Socket™, Freez Eez™, Gingicaine™, Hurricaine®, Isodettes®, Lanacane®, Numzident®, Orabase ®, Orajel®, Otocain®, Outgro®, Pro-caine™, Retre Gel™, Rid-A-Pain®, Solarcaine®, Sting-Kill®, Topex™, Topicale™, Zilactin®) 280

Capsaicin (Analgesic Balm with Capsaicin, ArthriCare®, Arthritis Formula®, Arthritis Pain Relief Rub®®, Axsain™, Capzasin® HP Arthritis Formula, Dr. S®, Eucalyptamint® 2000, Icy Hot®, Menthac®, Pain-X™, Rid-a-Pain®, RT Capsin®, Salonpas®, Trixaicin®, Zostrix®) 281

Methyl salicylate (Oil of Wintergreen, Sweet Birch Oil, Exocaine®, Gordogesic®, Bengay® (with menthol)) 282

Musculoskeletal Agents 283

Bisphosphonates 283

Alendronate (Fosamax®) 283

Calcitonin (Fortical®, Miacalcin®, Salmonine®) 285

Anti-microbials 286

β-lactams: Cell wall synthesis inhibitors 286

Amoxicillin (Amoxil ®, DisperMox™, MOXATAG™, Moxilin™, Sumox ™, Trimox®) 288

Amoxicillin/ Clavulanate (Augmentin®Amoclan) 290

Cephalosporins 291

Cephalexin (Keftab®, Bio-Cef™, Keflex®, Keftab®, Panixine DisperDose™) 291

Protein synthesis inhibitors: Macrolides, Tetracyclines 293

Macrolides:: Azithromycin, Erythromycin 295

Azithromycin (Azasite™, Zithromax®, Zmax™) 295

Erythromycin (A/T/S®, Akne Mycin®, Akne-Mycin®, E-Mycin®, E.E.S.®, Emcin Clear, Emgel®, Ery Pads™, Ery-Tab®, ERYC®, Erycette®, EryDerm®, Erygel®, Erymax®, EryPed®, Erythra-Derm®, Erythrocin®, Ilosone®, Ilotycin®, My-E®, Staticin®, T-Stat®) 296

Tetracyclines: Tetracycline, Doxycycline 298

Tetracycline (Emtet™, Panmycin™, Sumycin®, Tetra 250™ 298

Doxycycline (Adoxa®, Alodox™, Atridox™, Bio-Tab™, Doryx®, Doxal™, Doxy™, Monodox®, Oracea™, Oraxyl™, Periostat®, Vibra-Tabs®, Vibramycin®) 301

Aminoglycosides:Tobramycin 303

Tobramycin (AK-Tob®, Nebcin®, TOBI®, Tobrex®) 303

Sulfonamides: Sulfamethoxazole-trimethoprim(SMX-TMP) 305

Sulfamethoxazole-trimethoprim (SMX-TMP) (Bacter Aid™, Bactrim™, Septra®, Sulfatrim®, Sultrex™) 306

Fluoroquinolines: Ciprofloxacin 308

Ciprofloxacin (Ciloxan®, Cipro®, Ciprofloxacin, ProQuin®) 308

Anti-fungals 310

Azoles: Clotrimazole, fluconazole 310

Clotrimazole (Anti-Fungal™, Clotrimazole, Cruex®, Desenex®, Femcare®, Gyne-Lotrimin®, Gynix™, Jock Itch Relief, Lotrimin®, Mycelex®, Trivagizole 3™) 311

Fluconazole (Diflucan®) 312

Polyenes: Nystatin 314

Nystatin (BioStatin™, Mycostatin®, Nyamyc™, Nystex®, Nystop®) 314

Allylamine: Terbinafine 315

Terbinafine (Desenex Max®, Lamisil®) 315

Anti-virals: DNA polymerase inhibitors: Acyclovir, Penciclovir, Famciclovir 316

Acyclovir (Zovirax®) 317

Famciclovir (Famvir®) 318

Valcyclovir (Valtrex®) 319

Anti-Virals- Miscellaneous : Amantadine 320

Amantadine (Symmetrel®) 320

Anti-retrovirals: NRTIs, Protease Inhibitors 322

Nucleoside reverse transcriptase inhibitors (NRTIs): Didanosine, Lamivudine, Zidovudine 322

Didanosine (ddI, Videx®) 322

Lamivudine, 3TC (Epivir®) 324

Zidovudine, ZDV (Retrovir®) 325

Protease inhibitors: Indinavir 326

Indinavir, ZDV (Crixivan®) 326

Vaccination 328

Heavy Metal toxicity Drugs 331

: 331

Penicillamine (Cuprimine®, Depen ®) 331

DMPS: 2,3-Dimercapto-1-propanesulfonic acid (Unithiol®, Dimaval®) 333

DMSA ™, Succimer (Chemet®) 334

Edetate Calcium Disodium, Calcium EDTA 335

Deferoxamine 336

Emergency Situations: 337

Ringers lactate (VisIV™) 337

Saline (Sodium Chloride) 338

D5W, D10W (5% and 10% Dextrose in water) 339

D50 (50 g Dextrose/Glucose) 339

Glucose (B-D® Glucose, Dex4® Glutol™, Glutose 15™, Glutose™, Insta-Glucose®) 340

Principles of Pharmacology

Routes of Administration

Oral:

Drug must be stable to enzyme degradation (e.g. salivary) and acid hydrolysis/denaturation in the stomach. Drug must be absorbed by the GI and must also be stable for First-Pass metabolism. Easy self-administration.

← First Pass Metabolism: Any drug that is absorbed through the GI tract must first pass through the portal system. Drugs are metabolized by the liver to inactive or less active derivatives to varying degrees. Many drugs therefore cannot be given by mouth.

Sublingual:

Avoids the problems of oral administration and First Pass metabolism. Absorption is through the mucosa directly to capillaries and is dependent on the properties of the drug. Easy self-administration.

Inhalation

Generally is a rapid absorption and easy self-administration. Not suitable for some patients or conditions.

Topical

Useful for local action and or with agents that can cause systemic problems such as hypersensitivity or toxicity. Used primarily for dermatologic, otic, ophthalmologic, vaginal, rectal, and nasal applications. Easy self-administration

Transdermal

Useful for “patch” applications and when sustained drug release is desirable. Drug must be lipophilic. Easy self-administration.

Parenteral

❑ Intravenous (IV)

❑ Intramuscular (IM)

❑ Subcutaneous (SC, SubQ)

Other

Intranasal

Intrathecal /Intraventricular: The drug is delivered directly into the CSF

Pharmacokinetics

❑ Half-life: (t1/2) amount of time required for the concentration of the drug to decrease by ½

❑ Therapeutic Index = Toxic Dose/ Effective Dose

Absorption

❑ Passive diffusion: driven by concentration gradients (from higher to lower drug concentration). No energy is required. No carrier is necessary (therefore no saturation effects).

← Lipid-soluble drugs: cross the cell membrane

← Water-soluble drugs: pass through aqueous channels/pores in the membrane

❑ Active transport: Requires energy and a specific transport system. Saturation kinetics are present. May be transported against a concentration gradient.

Effect of pH

❑ Most drugs are weak acids or weak bases

❑ Weak acids:

← HA⇋H+ + A-

← A charged (anionic) drug, A- will not pass through the cell membrane. The drug must be in the protonated form to pass into the cell.

← Weak acids (higher pKa) will be absorbed more easily in weakly acidic environments

← pH = pKa+ log [A-]/[HA]

❑ Weak bases

Drug Metabolism

Kinetics: Most drugs follow first-order Michaelis-Menten kinetics. The rate of metabolism is directly related to the concentration of the drug and a constant fraction of the total drug is metabolized per unit of time. Some drugs follow zero-order (non-linear) kinetics and the rate of metabolism remains constant over time.

❑ Hydrophobic drugs cannot generally be eliminated by the kidneys and are handled by the liver using two sets of reactions to make the drugs more water-soluble. The drug activity may be increased, decreased or unchanged by Phase I reactions. In general, Phase II reactions decrease pharmacologic activity.

← Phase I:

❑ Phase II

❑ Some drugs undergo Phase II and then Phase I reactions

United States FDA Pharmaceutical Pregnancy Categories

← Pregnancy Category A

o No risk to fetus in the all trimesters of pregnancy. (Animal and human studies)

← Pregnancy Category B

o Animal studies have failed to demonstrate a risk to the fetus. Either there are no adequate and well-controlled studies in pregnant women or there are no negative animal studies, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

← Pregnancy Category C

o Animal studies have shown an adverse effect on the fetus. There are no adequate and well-controlled studies in humans. Potential benefits may necessitate use of the drug in pregnant women despite potential risks.

Autonomic Nervous System Drugs

Adrenergic antagonists

← MOA:

▪ α1 antagonists: Act primarily on the CV system. Vasoconstriction is inhibited, bringing about a net decrease in bp. Decreases smooth muscle contraction and increases ease of urine flow.

□ Overall clinical effect depends on status and specificity of blockage. If α2-receptors are also blocked, there will be an increased sympathetic response and potentially a smaller drop in bp due to increased NE release and baroreceptor reflex.

▪ α2 antagonists: Centrally, these antagonists block either post-synaptic α2- adrenergic receptors (↑ sympathetic response) or pre-synaptic α2- adrenergic receptors, ↑NE release. The net result is an increase in bp, decreased resistance to urine outflow, increased insulin release and increase smooth muscle tone.

▪ β1 antagonists: Act primarily on the CV system, decreased heart rate (↓ SA node rate), decreased contractility and decreased peripheral arteriolar resistance. Renin secretion is decreased, but it is not known if this is important in the hypotensive effects.

▪ β2 antagonists: Act to increase bronchiolar constriction. Generally little effect in normal individuals, but may induce bronchospasm in patients with asthma or COPD. Increased CA release may increase serum glucose in diabetics.

▪ Mixed adrenergic antagonists: The overall effect will be dependent on degree of selectivity and clinical status. Often difficult to predict.

α1 Antagonists

Tamsulosin (Flomax®)

▪ Canadian Brand Names

• Flomax

▪ Uses:

• BPH

▪ Pharmacologic class: α1-adrenergic blocker

▪ Therapeutic class: Anti-adrenergic

▪ Pregnancy Risk Category B

▪ CI:

• Hypersensitivity

▪ Adverse Reactions

• Dizziness, restlessness, vertigo, headache, insomnia,

• Orthostatic hypotension

• Decreased libido and ejaculation

• Cough

▪ Precautions:

• Hypertension, orthostatic hypotension

• Concurrent use of other adrenergic antagonists

• Females

• Elderly

• Pregnancy, lactation

• Renal, hepatic disease

▪ Drug-Lab interactions

• None known

▪ Lab monitoring:

• None necessary

▪ Selected interactions

• Protease inhibitors, anti-hypertensives, concurrent use of adrenergic blockers, alcohol

• Food

□ Grapefruit juice

• Herbal

□ α, β agonists: Ephedra, Yohimbe, Hypericum

□ Herbs with hypertensive effects:

➢ Zingiber, Glycyrrhiza

□ Anti-hypertensive herbs:

➢ Allium cepa, Allium sativa, Borago, Capsicum, Centella, Rauwolfia.

Selective Serotonin Reuptake Inhibitors

← MOA: Block the re-uptake of 5HT thereby increasing local concentrations of the neurotransmitter. Reflex decrease of receptors may be the basis of long-term action.

Citalopram (Celexa®)

▪ Uses:

• Depression

▪ Pharmacologic class: Selective Serotonin Re-uptake Inhibitor (SSRI)

▪ Therapeutic class: Anti-depressant

▪ Pregnancy Risk Category C

▪ CI:

• Hypersensitivity

• MAOI use

• Abrupt withdrawal

▪ Adverse Reactions

• Major: Suicide, akathisia, choreoathetosis, coagulopathy, hemolytic anemia, hepatic necrosis, GI bleed, neuroleptic malignant syndrome, renal failure, serotonin syndrome, SIADH, toxic epidermal necrolysis, torsade de pointes, ventricular fibrillation, anaphylaxis

• Apathy, psychosis, mania, migraine, dizziness, drowsiness, agitation, headache, insomnia, nervousness, poor concentration, worsening depression

• Tachycardia, orthostatic hypotension

• Blurry vision, nausea, vomiting, diarrhea

• Rash, polyuria, amenorrhea, dysmenorrhea, ED, priapism

• Arthralgia, myalgia, dyspnea

• Erythema multiforme, rash, pruritis, yawning.

▪ Precautions:

• Hepatic, renal, cardiac dysfunction

• History of mania, seizure disorder, suicidal tendencies

• History of addictive behaviors

• Driving, operating machinery

• Electroconvulsive therapy

• Elderly

• Pregnancy, lactation

• Hyponatremia

• Children < 18 yo

▪ Drug Lab interactions

• ↓ Na+

▪ Lab Monitoring

• Liver function tests

• Thyroid function tests

• Serum Na+

▪ Selected interactions

• Adrenergics, protease inhibitors, anti-depressants, anti-histamines, barbiturates, CNS depressants, H+ pump inhibitors, statins, MOAI’s, other SSRIs, NSAIDs, sympathomimetics, opiates/opioids, TCAs

• Herbal

□ Nervines

➢ Avena, Humulus, Hypericum, Leonurus, Matricaria, Passiflora, Piper methysticum, Piscidia, Pulsatilla, Roseminarius, Scutelleria, Verbena, Viburnum, Viscum.

□ Mentha X piperita: activates endogenous opioids

□ MAO inhibition in vitro

➢ Ginkgo, Hypericum, Panax, Eschoscholazia, Piper methysticum

□ Cardiac glycosides:

➢ Hypericum, Crataegus, Digitalis, Convallaria, Selenicereus

□ GABA containing herbs: Astragalus

□ Herbs that may interfere with serotonin:

➢ Aspidosperma, Hypericum, Iris versicolor, Mentha X piperita, Pausinystalia, Tanacetum, Urtica.

□ α and β agonist: Ephedra, Hypericum, Pausinystalia

□ Herbs containing PA

➢ Borago, Petasites, Eupatorium purpurea and Eupatorium spp, Senecio spp, Pulmonaria.

□ Thyroid active herbs:

➢ Capsella, Lycopus, Lithospermum, Melissa, Leonurus, Thymus serpyllum, Viscum album, Withania

□ Herbs with histaminic interactions

➢ Aloe vera, Hyoscyamus, Phytolacca, Scutelleria, Urtica

□ Herbs with anti-protease activity

➢ Curcuma, Ligusticum

□ Herbs with opiate interactions:

➢ Hypericum, Piscidia, Silybum

□ Herbs which induce endorphins

➢ Viscum album

Corticosteroids

|Metabolic effects | | |

|Carbohydrate metabolism |↑ gluconeogenesis |↓ glucose utilization in periphery⇒ |

| |↑ glycogen synthesis |↑ [glucose]plasma |

|Protein metabolism |↑ proteolysis |↑ use of aa for gluconeogenesis |

|Lipid metabolism |↑ lipolysis |↑ fat redistribution |

|Electrolyte /water metabolism |↑ Na+, H2O reabsorption |↑ K+, H+, Ca2+ excretion |

| | |↓ Ca2+ intestinal uptake |

← MOA: Corticosteroids are primarily used clinically as anti-inflammatory agents and immunosuppressants. Corticosteroids may have glucocorticoid and mineralocorticoid effects, depending on the particular agent. The effect of corticosteroids is generally delayed, as the mechanism involves interaction with target receptors followed by import into the nucleus and eventual alteration of gene expression and protein synthesis.

|Adverse effects | |

|Steroid withdrawal |Exacerbation of underlying disease process |

| |Acute adrenal insufficiency |

| |HPA suppression recovery varies from weeks to > 1 year |

|Prolonged high dose |HPA suppressive effects |

| |Fluid/Electrolyte/metabolic: |

| |Hypokalemic alkalosis, edema, hypertension, hyperglycemia, glucosuria |

| |Immune: |

| |↑ susceptibility to infection |

| |Skeletal system: |

| |↑ osteoporosis, osteonecrosis |

| |GI: ↑ PUD, GI bleeds |

| |Muscles: Steroid myopathy |

| |Ophthalmic: cataracts |

| |Psychological: |

| |Mood changes, neuroses, psychoses, suicidal behavior, “steroid rage” |

|Systemic effects |

|Cardiovascular |↑ Na+/ H2O⇒ ↑ bp |↑ vascular reactivity to vasoactive substances |

| | |↑ vascular permeability |

|Skeletal muscle |↑ muscle wasting (steroid myopathy) after high |Low corticosteroid levels: fatigue, weakness |

| |concentrations for prolonged periods | |

|CNS |Direct effects: Mixed. Appear to depend on dose, |Indirect effects: depend on bp, glucose and |

| |duration and endogenous production of |electrolyte concentrations |

| |neurotransmitters. | |

| |Effects include mood elevation, depression, neuroses, | |

| |psychoses | |

|Hematopoietic |↑ hematopoiesis |↑ neutrophils |

| |↓ lymphoid tissue | |

| |↓ lymphocytes, eosinophils, monocytes, basophils | |

|Inflammation and |↓ Arachidonic acid AA metabolites and acute phase |Suppression of both humoral and cellular immune |

|Immunosuppression |reactants |response. |

| |↓ cytokines, lymphokines | |

| |↓ Adhesion molecules |Multiple mechanisms of both inflammatory and |

| |↓ Histamine, Leukotrienes |immunological effects. |

Female Reproductive Hormones

SERMs

MOA: Selective estrogen receptor modulators (SERMs) compete with estradiol for hypothalamic estrogen receptors, blocking the negative feedback control pathways. Treatment with SERMs therefore increases the release of gonadotropin releasing hormone (GnRH), in turn increasing the release of both FSH and LH. FSH and LH then stimulate the ovaries to develop follicles, produce estrogens that then induce the FSH/LH rise from the pituitary. SERMs are usually given in the follicular phase of the menstrual cycle.

The SERMs also have estrogen agonist effects as well as antagonistic effects in the ovary, endometrium, cervix, bone and mammary tissues. With Clomiphene, the estrogen agonist effects on the HP axis are secondary to the antagonist effects, while with raloxifene, the effects on bone and lipid metabolism are estrogen agonistic and the effects on the uterus and mammary tissue are antagonistic.

Insulin

|Route |Onset |Peak |Duration |Type |Names |

|SubQ |15 min |1 hr |3-4 hr |Rapid/Aspart |Insulin Aspart (rDNA): NovoLog® |

| | | | | |Insulin Aspart (rDNA)+ Insulin Aspart protamine: NovoLogMix 70/30® |

|SubQ |15 min. |30-90 min |3-4 hr |Rapid/Lispro |Insulin (lispro): Humalog® |

| | | | | |Insulin glulisine recombinant: Apidra® |

| | | | | |Insulin lispro protamine: Humulog Mix 50/50® |

| |15 min. |30-90 min |3-4 hr |Rapid/ |Insulin glulisine, recombinant: Apidra® |

| | | | |Glulisine | |

|Inhalation |10-20 min |2 hr |6 hr |Rapid |Insulin inhalation (rDNA): Exubera® |

| | | | | | |

|SubQ |30-60 min |2-4 hr |Unknown |Short/ Regular Insulin |Humulin R, Iletin II Regular, Novolin R, Penfill, Velosulin BR |

| | | | | |Canadian names: Insulin-Toronto, Novolin ge Toronto. |

|IV |10-30 min |15-30 min |Unknown |Short/ Regular Insulin |Mixed insulins as needed |

|SubQ |1-3 hr |6-8 hr |12-16 hr |Intermediate/ |Lente: Humulin L, Lente Iletin II |

| | | | |Lente/NPH/ |NPH/Isophane: Humulin N, Novolin N, NPH-N, NPH Iletin II |

| | | | |Isophane |Canadian names: Novolin ge Lente |

| | | | | | |

| | | | |Long/ |Humulin U, Novolin ge Ultralente, Novolin U, Ultralente U |

| | | | |Ultralente | |

|SubQ |60-60 min |6-10 hr |24 hr |Very Long//Glargine |Lantus |

-----------------------

Rate of

Metabolism

Drug Dose

1st order kinetics:

Low Dose

Zero order kinetics:

High Dose

Cholinergic Responses:

▪ “! HR, CO, bpÒ! Bradycardia, Dizziness

▪ ‘! intestinal, salivary secretions and intestinal motilityÒ! Diarrhea, nausea, vomiting

▪ ‘! Bronchiolar smooth muscle tone

▪ ‘! ciliary m. Ò! ‘! miosigh Dose

Cholinergic Responses:

↓ HR, CO, bp⇒ Bradycardia, Dizziness

↑ intestinal, salivary secretions and intestinal motility⇒ Diarrhea, nausea, vomiting

↑ Bronchiolar smooth muscle tone

↑ ciliary m. ⇒ ↑ miosis

▪ ↑ tone of detrusor m⇒ ↑ urination

▪ ↑ sweat gland activity⇒ diaphoresis

Autonomic, Parasympathetic Neuron:

Pre-synaptic Neurotransmitter: ACh (Nicotinic)

Post-synaptic Neurotransmitter: ACh (muscarinic)

Autonomic, Sympathetic Neuron:

Pre-synaptic Neurotransmitter: ACh (Nicotinic)

Post-synaptic (Adrenergic) Neurotransmitter: NE (α or β)

Motor Neuron:

Nicotinic receptor

Neurotransmitter:

ACh

Cholesterol

Pregnenolone

17-α-OH- Pregnenolone

Dehydroepiandrosterone

Androstenediol

Progesterone

Corticosterone

Aldosterone

17-α-OH- Progesterone

Cortisol

Androstenedione

Estrone

Testosterone

Estradiol

Dihydrotestosterone

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