Pharmacology Overview

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Pharmacology Overview

• Westminster College
• Nursing 220
• Julie Balk NP, MS
• Spring 2005

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Value of Pharmaceuticals
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Understanding theValue of Pharmaceuticals

• Saving lives, enhancing quality of life,
  relieving pain and curing and preventing disease
• Reducing disability, surgery, hospitalization,
  physician visits and nursing home care
• Increasing productivity and causing fewer days
  lost from work
• Helping reduce overall health care costs

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Medicines and vaccines have played a central role
in the progress in treating disease

• Leading causes of death have been eliminated and
  people are living longer, healthier and more
  productive lives
• Doctors now have thousands of tools medicines
  and the understanding of disease that comes with
  them to heal the sick and prevent illness
• With the great potential for continued
  breakthroughs, prescription medicines will
  continue to play an important role in treating
  patients and containing health care costs

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In 1920, life expectancy at birth was 54 years.
The average American born today can expect to
live more than 76 years
DROP IN DEATH RATES FOR DISEASES WITH
PHARMACEUTICALS, 1965-1996
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New Product Development
Compound Success Rates by Stage
5,00010,000Screened
250Enter Preclinical Testing
5Enter Clinical Testing
1Approved by the FDA
Net Cost 802 million invested over 15 years
Source Tufts Center for the Study of Drug
Development
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Questions?
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Pharmacology Basics
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Drug Nomenclature

• Chemical Name
• Generic Name
• Trade/Brand Name
• N-Acetyl-para-aminophenol
• Acetaminophen
• Tylenol, Tempra, Acephen, Aceta, Anacin-3,
  Arthritis Pain Formula Aspriin Free, Bromo
  Seltzer etc

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Drug Classification

• Drugs categorized by expected action on the body
  and then more specifically by the mechanism of
  action
• Antihypertensiveslowering of BP
• ACE Inhibitorslower BP by blocking the
  Rennin/Angiotensin system

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Drug Body
Relationships

• Pharmacokinetics
• Absorption
• Distribution
• Metabolism
• Excretion
• Linear/Nonlinear

• Pharmacodynamics
• Mechanism of Action
• MOA (drug-receptor)
• Duration of action

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Pharmacokinetics

• Effect of the Body on Drug (ADME)
• Absorption
• Distribution
• Metabolism
• Excretion

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Absorption

• Bioavailability (up to 100)
• Peak plasma concentrations (Cmax)
• Time to peak plasma conc (Tmax)
• Product dosage forms may change these variables
  (eg, tablet, capsule, oral liq, injectable)

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Distribution

• Volume of distribution (Vd)
• relates amount of drug in body to concentration
  of drug in blood or plasma
• Protein binding
• relates to amount of free drug and interactions

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Metabolism

• First-Pass elimination
• drug metabolized prior to entry into the
  systemic circulation (eg, propranolol)
• Metabolism is primarily the liver but can occur
  in the gut and other sites.
• Metabolism (generally) inactivates and prepares
  drug for elimination
• Responsible for many drug/drug interactions

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Elimination

• Half-life of drug (T ½)
• biological or therapeutic
• Steady state - relates to 3-5 half-lifes
• Many drugs rely on renal elimination and are
  sensitive to renal function
• Estimated Creatinine Clearance (CrCl)
• (140-Age(yrs)) x Weight (kg)
• 72 x Serum Cr (SCr)
• Note multiplied by 0.85 for females

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Pharmacodynamics

• Effect of the Drug on the Body
• Receptors
• Agonists
• Antagonists
• Mixed agonists
• Therapeutic Index (TD50/ED50)
• Idiosyncratic response (metabolism/allergy)

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Special Populations

• Hepatic disease
• Renal disease
• Age
• Gender
• Race
• Pregnancy/Breast Feeding

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Questions?
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Drug-Drug Interactions
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Definition

• The modification of the effects of one drug (the
  object drug) by the prior, concomitant, (or
  future?) administration of another drug (i.e.,
  the precipitant drug).

Tatro DS. Drug Interactions. In Textbook of
Therapeutics Drug and Disease Management. 6th
ed 199633-44.
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Epidemiology

• Potential risks and prevention, part 3
• Drug-induced threats to Life
• ADEs published in Clin-Alert (1977-1997)
• 846 drug-induced life threats
• Mean age 45.1 yrs (s.d. 22.3 yrs)
• 11 of ADEs due to drug interactions

Am J Health-Syst Pharm. 2001 581399-405
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Epidemiology

• Potential risks and prevention, part 3
• Drug-induced threats to Life
• 11 of ADEs due to drug interactions
• Usual doses used for both drugs (78)
• Drugs administered orally (59)
• Exposure lasted 1-7 days (44)
• Interacting drugs used for less than 24 hours
  (35)

Am J Health-Syst Pharm. 2001 581399-405
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Epidemiology

• Incidence of potential DDIX
• Surgical patients 17
• Medical ward patients 22
• Nursing home patients 19
• Outpatient clinic patients 23

Tatro DS. Drug Interactions. In Textbook of
Therapeutics Drug and Disease Management. 6th
ed 199633-44. Durrence CW, et al. Am J Hosp
Pharm 1985421553-6. Borda IT, et al. JAMA
1968205645-7. Blaschke TF, et al. Clinical
Pharmacology in the Aged Patient
19811611-26. Stanaszek WF, et al. Hosp Pharm
197813255-63.
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Epidemiology

• Hospitalized patients with elevated digoxin
  levels
• 1,433 patients with assay over 6-month period
• 82 patients (6) had level gt2.4 ng/mL
• DDIX was contributory in 10 of 82 (12)
• Implicated drugs included quinidine,
  clarithromycin, erythromycin, and amiodarone

Marik PE, Fromm L. Am J Med 1998105110-5.
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General Mechanisms of DDIX

• Pharmacokinetic
• Alterations in Hepatic Metabolism
• Alterations in Renal Excretion
• Alterations in Absorption
• Alterations in Distribution/Protein Binding
• Pharmacodynamic

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Hepatic Metabolism of DrugsCytochrome P-450 (CYP
450)

• Heme-containing enzymes
• Lipid bi-layer of endoplasmic reticulum in
  hepatocytes
• Small intestine, kidney, lung, brain
• Oxidative metabolism
• Genetic polymorphism
• Poor/slow metabolizers
• Extensive/fast metabolizers

Michalets EL. Pharmacotherapy 19981884-112.
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Pharmacodynamic DDIX

• Changes in clinical response to a drug without a
  change in the pharmacokinetics or serum
  concentration of the object drug.
• Synergism or antagonism of the pharmacologic
  effects of two or more drugs

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Pharmacodynamic DDIX

• EXAMPLES
• Verapamil-Propranolol
• Negative inotropic and chronotropic effects are
  additive
• Fluoxetine/SSRI-cyproheptadine
• Serotonergic effects of fluoxetine may be blocked
  by the serotonin antagonist.
• Naloxone-Opiate analgesics
• Opiate effects are reversed by an opiate
  antagonist, such as naloxone.

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Pharmacodynamic DDIX

• Herbal preparations
• Ginkgo biloba warfarin
• Ginkgo inhibits platelet aggregation may see
  increased risk of bleeding
• St. Johns Wort serotonergic drugs
• St. Johns Wort inhibits serotonin may see
  increased serotonergic effects
• Kava CNS depressants
• Kava is an herbal sedative may see additive
  effects with benzodiazepines, barbiturates,
  antipsychotics, and alcohol

Cupp MJ. Amer Fam Physician 1999591239-1244.
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Herbal Product DDIX

• Top 7 herbal preparations
• Echinacea supportive therapy for colds/flu
• Garlic elevated lipid levels and vascular chgs
• Ginko organic brain syndrome and peripheral
  arterial occlusive dz
• Ginseng improve well being and boost energy
• Kava kava used for anxiety and/or stress
• Saw Palmetto urinary problems in BPH
• St. Johns Wort used for depression and anxiety

Drugs 200161(15)2163-2175
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Herbal Product DDIX
Drugs 200161(15)2163-2175 Am J Health-Syst
Pharm. 200259(4)339-47
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High Risk Drugs

• Narrow therapeutic index
• Steep dose-response curve
• CYP-450 substrates, inhibitors, or inducers

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High Risk Patients

• Multiple drug regimens
• Elderly
• Critically ill
• Transplant patients on immunosuppression
• Patients with diminished metabolic or elimination
  potential
• Hepatic failure
• Acute/chronic renal failure

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More High Risk Patients

• Specific disease states
• CV disease digoxin, warfarin, antiarrhythmics
• Diabetes cisapride
• Epilepsy phenytoin, phenobarbital, carbamazepine
• Transplant cyclosporine
• Infection erythromycin
• Respiratory theophylline, antihistamines

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Tools for Identifying DDIX

• Pocket References
• PDR Drug Interaction Handbook
• CYP450 Pocket card (www.drug-interaction.com)
• Others
• PC-based programs
• Handheld programs (www.epocrates.com)

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ePocrates qRx
www.epocrates.com
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Minimizing Drug Interactions

• Use caution when prescribing new drugs
• Consider hepatic and/or renal dysfunction
• Ask about herbal use
• Adjustments in the elderly
• polypharmacy
• errors in administration
• reduced doses may be necessary
• Utilize references and/or software whenever
  possible

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AVOID Medication Errors

• Obtain a list of current medications and their
  doses then check for the following
• Allergies
• Vitamins and herbal products
• Old medications DCs within the last month
• Interactions (pocket reference/computer)
• Dependence on current or DCd medications
• Mendelian patterns family sensitivity/preference
  s

Arch Intern Med. 2002162405-412
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Questions?