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Pharmacology of Enteral Agents

Pharmacology of Enteral Agents. Advantages Acceptance Administration Low cost Decreased incidence of adverse reactions Decreased severity of adverse reactions No needles Various dosage forms Decreased severity of allergic reactions. Disadvantages Patient compliance Delayed onset

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Pharmacology of Enteral Agents

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  1. Pharmacology of Enteral Agents

  2. Advantages Acceptance Administration Low cost Decreased incidence of adverse reactions Decreased severity of adverse reactions No needles Various dosage forms Decreased severity of allergic reactions Disadvantages Patient compliance Delayed onset Erratic absorption Inability to titrate Inability to readily alter level of sedation Prolonged duration Not for severe anxiety levels Adverse drug-drug interactions Special training and permit Oral Sedation…

  3. Terminology… • Absorption—the process by which a drug enters the circulation • Factors affecting absorption • Drug form (tablet, capsule, elixir) • Gastric emptying • Acidity • Presence of food and types of food • GI motility • Most drugs are absorbed in the small intestine

  4. Alterations in Drug Absorption • P-glycoprotein carrier system • Found in the plasma membranes in the intestine, proximal tubules of the kidney, brain, liver, testes • Acts as a pump for drugs and toxins being transported away from tissues, out of the tissues • Part of the “first pass effect” • “Gate-keeper” for cytochrome P450 system

  5. P-glycoprotein (P-gp) Extracellular Membrane CYP3A4 Intracellular

  6. Terminology… • First Pass Effect--initial extensive metabolism in the liver as the drug travels from the small intestine via the hepatic portal system through the liver • Results in reduction of plasma concentration • Important for benzodiazepines with low bioavailability • Triazloam • Midazolam

  7. FIRST PASS METABOLISM

  8. Terminology… • Distribution—process by which the drug in the plasma enters target tissues, depot tissues, metabolic and excretory sites • Factors affecting distribution • Lean-body mass vs. fat content • Concentration of plasma proteins • Malnutrition • Age • Pregnancy • Competition for protein binding sites from other drugs

  9. ROUTE IV IM SUBCUTANEOUS ORAL RECTAL INHALATION TRANSDERMAL BIOAVAILABILITY 100 75 to </=100 75 to </=100 5 to <100 30 to <100 5 to < 100 80 to </=100 Bioavailability (%)…

  10. Terminology… • Biotransformation—metabolic pathways in the body, primarily the liver, convert absorbed drugs into different chemical configurations, usually with the end result of making the drug less active and more readily excretable (polar and water soluble) • Phase I—utilizing Cytochrome P450 • Phase II—conjugation

  11. Phases of Metabolism • Phase I • Oxidation, hydrolysis, or reduction increasing the drugs water solubility • Phase II • Attachment of an additional molecule creating an inactive and more water soluble compound • Glutathione, conjugation, glucuronidation, sulfation, acetylation, methylation

  12. Metabolism R Phase I Hepatocyte R Billiary capillary OH R Phase II O - Glucuronide

  13. Cytochrome P450… • Genetically determined super family of enzymes found in the liver and gut to detoxify endogenous and exogenous substances • Blood flow the liver • Activity and concentration of enzymes • Liver disease • Basis for the pharmacokinetic drug interactions most frequently encountered in dentistry. (CYP 3A4 isoenzyme inhibition)

  14. Terminology… • Excretion– process by which a drug in the circulation is removed from the body (urine, bile, feces) • Renal function and disease • Water solubility and chemistry of a drug or metabolite

  15. *Peripheral compartment

  16. Enhanced Bioavailability of Triazolam following Sublingual Versus Oral Administration. Scavone JM et al, J. Clinical Pharm 1986;26:208-210 • AUC greater for sublingual than orally • 28.9 vs 22.6 ng-hr/ml • Sublingual peak plasma concentration greater • 4.7 vs 3.9 ng/ml • No difference in elimination half-life and the time of peak concentration

  17. Enhanced Bioavailability of Triazolam following Sublingual Versus Oral Administration. Scavone JM et al, J. Clinical Pharm 1986;26:208-210 • The bioavailability of sublingual triazolam increased by an average of 28% vs oral administration • First-pass extraction bypassed • Clinical effects may likewise be enhanced by sublingual administration. 4 3 0.5 mg oral 0.5 mg sublingual 2 1 PLASMA TRIAZOLAM CONCENTRATION (ng/ml) .7 .4 .2 14 16 4 10 0 2 6 8 12 18 HOURS AFTER DOSE

  18. 16 14 12 Triazolam Route Of Administration 6 4 TRIAZOLAM (ng/ml) 2 0 6 0 8 10 12 2 4 TIME (hr) Triazolam Pharmacokinetics After Intravenous, Oral and Sublingual AdministrationKroboth, PD et al J Clin Psychopharm 15: Aug 95 259-262 • Fraction absorbed relative to IV was 20% greater SL vs Oral • Bioavailability 44% (oral) 53% (sublingual) • SL avoid first-pass metabolism producing earlier and higher peak concentrations

  19. Terminology… • Half-life—time required to reduce the amount of drug in the circulation by one-half • Age • Disease • Blood flow to liver • Idiosyncrasy—unusual/unpredictable response to a drug • Hyperalgesia • dysphoria

  20. Terminology… • Toxicity—Adverse effect that is a direct extension of a drug’s therapeutic actions (loss of consciousness) • Therapeutic Index—ratio of the toxic dose of a drug to its therapeutic dose: the higher the ratio, the greater the relative safety of the drug

  21. Patient Considerations… • Factors determining variability in patient response: • Age (very young and old) • Genetics (CYP) • Disease states • ETOH consumption • Normal biological variations • Pharmacokinetic factors

  22. Special Considerations… • Pediatric patients • Weight and dosage calculations • Enhanced vagal responses • Ability to swallow solid dose forms • Taste variations • Increased likelihood of aspiration

  23. Special Considerations… • Geriatric patients • Phiz changes: decreased functional reserve cerebral, renal and hepatic blood flow • Chronic diseases • Multiple medications • Decreased intestinal absorption • Decreased receptor populations • Decreased lean body mass • Decreased plasma protein binding • Decreased initial doses of sedatives

  24. Medically Compromised Patients • Drug interactions • Altered response to drugs • Need for adjunctive medications • Stress-reduction protocol

  25. Factors in Drug Selection and Dosage… • Age • Weight • Medical status • Level of anxiety

  26. Pharmacologic Principles for Oral Sedative Drugs… • All produce CNS depression • Drowsiness, dizziness • Drug interactions—CNS depressants • Warnings • Drowsiness—don’t drive, legal decision, etc • May be habit forming • Accompanied by a responsible adult • Food interactions • Presence of food delays gastric emptying and delays onset/reduces effectiveness of agents

  27. Principles Continued • Re-administration of Oral Agents • NOT recommended secondary to accumulation • When more than one agent is used the dosage of both agents must be reduced • Variable effects of oral sedation • Dosage of sedatives should be reduced in children, elderly, and the medically compromised patients

  28. FDA Pregnancy Categories… • A—studies fail to demonstrate a risk to the fetus in the first trimester, no evidence of risk in later trimesters. The possibility of fetal harm appears remote • B—either animal studies have not shown a risk, but there are no controlled studies in pregnant women, or animal studies have shown a fetal risk that was not confirmed in controlled studies in women

  29. FDA Pregnancy Categories… • C—animal studies have shown a risk but no controlled studies in women, or there are no studies in women or animals. Drugs should be given only if the potential benefits justify the potential risks to the fetus • D—there is positive evidence of fetal risk. If the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective • X—the drug is contraindicated in women who are or may become pregnant

  30. Standard Dose • The standard dose of a drug is based on trials in healthy volunteers and patients with average ability to absorb, distribute, metabolize and eliminate the drug • The standard dose will not be suitable for every patient

  31. Benzodiazepines… • Mechanism of action • GABA receptor agonist (facilitator) • Metabolism/excretion; Liver/urine • Advantages • Sedation • Wide therapeutic index • Antianxiety effects • Useful for producing sleep the night before • Reversal agent (flumazenil)

  32. Diazepam (Valium) • Usual dosage; 1o prior to appt • Adults; 2-10 mg • Children; 0.15-0.3 mg/kg • Onset; 1 hr, peak concentration in 2 hrs • Duration; 1-3 hours • Contraindications • Allergy, narrow angle glaucoma • Precautions • Drug interactions at CYP3A4 and CYP2C19 • Availability • 2,5,and 10 mg tablets; syrup 10mg/5cc • Active metabolites—yes • Pregnancy category D

  33. Lorazepam (Ativan) • Usual dosage 1 hour prior to appt • Adult 2-4 mg • Child; 0.05 mg/kg not to exceed adult dose • Onset; 1 hour • Duration; 2-4 hours • Containdications • Allergy, narrow angle glaucoma • Precautions • Excessive sedation • Not to be used in patients with primary depressive disorder or psychosis • Active metabolites—No • Pregnancy category--D

  34. Oxazepam (SERAX) • Usual dosage one hour prior to appt • Adult;10-30 mg • No child dose • Onset; 1 hour • Duration; 2-4 hours, peak at 3 hours • Contraindications—allergy • Precautions—same as other sedative agents • Availability • 10,15,30 mg capsules and 15 mg tablets • Active metabolites—No • Pregnancy category—D

  35. Triazolam (HALCION) • Usual dosage one hour prior to appt • Adult; 0.25 mg • Not recommended for children • Onset; 1 hour, peak plasma level 2 hours • Duration; 1-3 hours • Contraindications—pregnancy • Precautions—can produce anterograde amnesia. Excessive sedation in elderly • Availability • O.125 and 0.25 mg tablets • Active metabolites—No • Pregnancy category—X

  36. Alprazolam (XANAX) • Usual dosage one hour prior to appt • Adult; 0.25-1 mg • Not recommended for children • Onset; 1 hour, peak in 1-2 hours • Duration; 1-3 hours • Contraindications—allergy and narrow angle glaucoma • Precautions • Drug interactions at CYP 3A4 • Availability • 0.25, 0.5 and 1 mg tablets • Active metabolites—No • Pregnancy category--D

  37. Midazolam (VERSED) • Usual dosage 15-30 min prior to appt • Not recommended for adult • Child; 0.25-0.5 mg/kg not to exceed 20 mg • Onset; 15-30 minutes • Duration; 30 min to 1 hour • Contraindications • Allergy • Narrow angle glaucoma • Precautions • Drug interactions at CYP3A4 • Availability; syrup 2 mg/cc • Active metabolites—No • Pregnancy category—D

  38. Zolpidem (AMBIEN) • Usual dosage 1 hour prior to appt • Adult; 10 mg • Not recommended for children • Onset; 1 hour peak effect in 1.6 hours • Duration; 2-3 hours • Contraindications; allergy • Precautions; same as other oral sedatives • Availability; 5 and 10 mg tablets • Active metabolites—No • Pregnancy category—B

  39. Antihistamines… • Sedation is a common action of some H-1 receptor antagonists • Additional beneficial effects; anticholinergic actions and some reduction in salivation • Hyproxyzine • Diphenhydramine

  40. Hydroxyzine (ATARAX, VISTARIL) • Usual dosage 1 hour prior to appt • Adult; 50-100 mg • Child; 1.1-2.2 mg/kg • Onset; 30min, peak effect 2 hours • Duration; 3-4 hours • Contraindications; allergy • Precautions; same as other oral sedatives • Availability • Atarax; 10, 25, 50, 100 mg tabs; syrup 10mg/5cc • Vistaril; 25,50,100 mg capsules;oral susp 25mg/5cc • Active metabolites—No • Pregnancy category—D

  41. Diphenhydramine (BENADRYL) • Usual dosage 1 hour prior to appt • Adult; 50-100 mg • Child; 1.5 mg/kg not to exceed adult dose • Onset; 1 hour • Duration; 4-6 hours • Contraindications; allergy • Precautions; anticholinergic actions; • Worsen asthma, glaucoma GI/urinary obstruction • Availability; 25, 50 mg tabs; elixir 12.5/5cc • Active metabolites—No • Pregnancy category—B

  42. Phenothiazines… • Traditionally used in the treatment of some major psychiatric diseases • Some members of this group possess significant sedative activity • Other therapeutic actions • Anticholinergic • Antidopaminergic • Anti-adrenergic • antiemetic

  43. Promethazine (PHENERGAN) • Usual dosage 1 hour prior to appt • Adult; 25-50 mg • Child; 2.2 mg/kg as a sole agent • 1.1 mg/kg in combination with other drugs • Onset; 1 hour peak effect 2 hours • Duration; 3-4 hours (may persist 12 hrs) • Precautions • Use with caution in pts with Sz disorders • Tardive dyskinesias • Availability; 12.5, 25, 50 mg tabs; • Syrup 6.25 and 25 mg/5cc • Suppositories 12.5, 25, 50 mg • Active metabolites—No • Pregnancy category—C • New FDA warning: (2006) this drug is no longer indicated in children under 2 years of age…and should be used with great caution in any child (all preps of the drug)

  44. Drug Interaction InvolvingSedative Agents • Pharmacokinetic interactions • One drug inhibits or stimulates the absorption, distribution, metabolism or excretion of another drug • Increased activity of some Benzos by erythromycin which inhibits CYP3A4 isoenzyme • Pharmacodynamic interactions • Interaction of 2 drugs as a result of a common physiologic effect • Increased CNS depression with co-administration of opioid and Benzodiazepine

  45. Drug Interaction InvolvingSedative Agents • Summation; interaction between 2 drugs in which the effect of both drugs is approximated by the simple additive effect of each drug given separately • 1 + 1 = 2 • Potentiation; interaction in which total effect of both drugs given together is greater than predicted by the sum of each drug given separately • 1 + 1 > 2

  46. Drug Interaction InvolvingSedative Agents • Antagonism; the reduction in the effect of one drug by another • Competitive • Non-competitive • Physiologic

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