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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