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1.Introduction to Pharmacology

1.Introduction to Pharmacology

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Pharmacology

Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

Why Do We Study Pharmacology?
• A. It’s good for you • B. You will be able to use fancy terms like ’bioavailabilty’ • C. My instructor likes to torture people • D. A competent nurse must understand why his/her patient is getting a medication, and HOW IT WORKS

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Purpose of Drug Therapy
• “… to prevent, control or cure various disease states.” • To achieve this, the right drug dose must be delivered to the tissues • Every nurse must know…
– speed of onset of drug action – intensity of drug effect – duration of drug action
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A Graphical Example:
Drug Concentration
Lethal Dose
Peak Onset

Duration

Therapeutic Range
SubTherapeutic

Time in Hours
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How Do We Study Pharmacology?

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General Concepts
Drug Dose Administration

Pharmaceutical Pharmacokinetics Pharmacodynamics Pharmacotherapeutics

Disintegration of Drug Absorption/distributio n metabolism/excretion Drug/Receptor Interaction Drug Effect or Response

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How are Drugs Administered?

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Routes of Drug Delivery
Parenteral (IV) Oral Transdermal Topical Parenteral (SC, IM) Rectal Inhaled

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What Happens After Drug Administration?
Drug at site of administration

1. Absorption
Drug in plasma

2. Distribution 3. Metabolism
in tissues Drug/metabolites

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Drug/metabolites in urine, feces, bile

4. Elimination
Modified from Mycek et al. (1997)

We are now talking about …

Pharmacokinetics

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Factors Affecting Drug Absorption
• Transport – active vs. passive • pH • Physical factors – blood flow – surface area – contact time
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ATP

ADP + Pi

ABH+

What Factors Affect Distribution?
• Blood flow – brain vs. fat • Capillary permeability – differences in capillary structure • Binding to proteins – role of albumin Endothelial cells in brain capillary
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Endothelial cells in liver capillary

Glial cell

An Important Concept: BIOAVAILABIITY
• Def’n:

• Affected by:
– 1st pass metabolism Lidocaine, propranolol) – Solubility – Instability Penicillin G, insulin) (eg: (eg:

Serum Concentration

– Fraction of a drug that reaches systemic circulation after a particular route of admin’n

Injected Dose

Oral Dose

Time
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Volume of Drug Distribution
• Drugs may distribute into any or all of the following compartments:
– Plasma – Interstitial Fluid – Intracellular Fluid

Plasma (4 litres) Interstitial Fluid (10 litres) Intracellular Fluid (28 litres)

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So What?
• Most drugs distribute into several compartments; however … • Some drugs distribute into only one or two compartments • Eg: Aminoglycoside antibiotics
– Streptomycin – Gentamycin

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Arggh! I can’t fit through these darn fenestrations!

More “So What?”
• It takes time for a drug to distribute in the body • Drug distribution is affected by elimination

Serum Concentration

1.5 Drug is not eliminated 1.0 0.5 Distribution Phase 0 0 Drug is eliminated Elimination Phase

Time

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Albumin Affects Distribution
• Drugs bind differentially to Albumin albumin • 2 drug classifications:
– Class I: dose less than available binding sites (eg: most drugs) – Class II: dose greater than binding sites (eg: sulfonamide)

Drug X

• The problem:
– one drug may out-compete the other
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Sulfonamide

Drug Metabolism (we’re still talking about Pharmacokinetics)

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Drug Metabolism
• First pass
– metabolism of drugs may occur as they cross the intestine or transit the liver
• eg: nitroglycerin

• Other drugs may be destroyed before absorption
• eg: penicillin

• Such reactions decrease delivery to the target tissues
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Drug Metabolism (cont’d)
• Two Phases: I and II – Phase I: conversion to lipophilic cpds – Phase II: conjugation • Phase I involves the cytochrome P-450 system • Ultimate effect is to facilitate elimination
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Drug Phase I
Oxidation Reduction Hydrolysis

Activation/Inactivation Phase II
Glucuronidation

Conjugation Products

An Example of Phase I and II Biotransformation:
CH3CONH PHASE I CH3CONH PHASE II -OC2H5 Phenacetin

-OH

Paracetamol

Glucuronic Acid -O- HO -OH CH3CONConjugate H O COOH Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

OH

An Example of Drug Metabolism

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First Pass Metabolism Occurs Primarily in the Liver and Gut

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Drug Elimination
• Most important route is the kidney • May also involve bile, intestine, lung, breast milk • What clinical scenarios may affect drug elimination?
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Elimination of a drug is usually linked to renal filtration, secretion and reabsorption.

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Food for Thought
• What conditions might affect renal function (and therefore drug elimination)? • What other organ systems are involved in drug clearance?

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Important Point
• The pharmacokinetic profile of a drug also depends on its mode of administration …

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Example: Intravenous Infusions
• Plasma concentration rises until elimination = input • Faster infusions get more drugs on board, but does not change the time to achieve a steady state

Plasma Concentration

Fast Infusion

Slow Infusion

Time
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Time at which steady state is achieved

Example: Intravenous Injection
• Peak plasma concentration of the drug is achieved at time = 0 • There is no steady state concentration. Why? 100 mg injected

Plasma Concentration

50 mg injected

Time
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Example: Oral Dose
• A single oral dose will give you a single peak plasma concentration • The drug concentration then continuously declines • Repeated doses result in oscillations in plasma concentration

Plasma Concentration

Time

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Are We Having Fun Yet?

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What is Pharmacology?
From the Greek pharmakon (drug), legein (to speak)

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• Broadly defined as the study of how chemical agents affect living processes. • Hormones • Neurotransmitters • Growth factors • local Autocrine factors • Drugs (Pharmaceuticals) • Toxic agents in the environment
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• the medicinal/ organic chemist may create the candidate compound (sometimes referred to as a new chemical entity, NCE), it is the pharmacologist who is responsible for testing it for pharmacological activity.

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• ultimately will lead to the discovery of novel drug targets for therapeutic intervention in diseases where distal steps in signal transduction have gone awry

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Pharmacology
• The study of how drugs exert their effects on living systems. Pharmacologists work to identify drug targets in order to learn how drugs work. Pharmacologists also study the ways in which drugs are modified within organisms.
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In most of the pharmacologic specialties, drugs are also used today as tools to gain insight into both normal and abnormal function. science of drugs

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Drug

• Any chemical that affects the processes of a living organism

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Medical pharmacology • is the study of drugs used for the diagnosis, prevention, and treatment of disease.

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Some Pharmacology Definitions and Areas of Study

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Pharmacotherapeutics • use of drugs to treat disorders; the emphasis is on clinical management

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Pharmacoepidemiology

• study of the effect of drugs on populations; questions dealing with the influence of genetics are particularly important

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Pharmacoeconomics

• study of the cost-effectiveness of drug treatments; the cost of medications is of worldwide concern, particularly among certain groups such as the elderly and AIDS patients
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Pharmacodynamic properties

• of a drug describe the action of the drug on the body, including receptor interactions, doseresponse phenomena, and mechanisms of therapeutic and toxic action.
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Pharmacokinetic properties

• describe the action of the body on the drug, including absorption, distribution, metabolism, and excretion. Elimination of a drug may be achieved by metabolism or by excretion.
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THE NATURE OF DRUGS

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Size • The great majority of drugs lie in the range from molecular weight 100 to 1,000. Drugs in this range are large enough to allow selectivity of action and small enough to allow adequate movement within the various compartments in the body.
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Chemistry and reactivity

• Drugs may be small, simple molecules (amino acids, simple amines, organic acids, alcohols, esters, ions, etc.), carbohydrates, lipids, or even proteins. Binding of drugs to their receptors,
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• the specific molecules in a biologic system that mediate drug effects, is usually by noncovalent bonds (hydrogen bonds, van de Waals attractions, and ionic bonds), and less commonly by covalent bonds. • Weaker, noncovalent bonds require a better fit of the drug to the receptor binding site and, usually, a reversible type of action. Very strong bonding, eg, covalent bonds, usually involves less selectivity and an irreversible interaction.

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Shape
• The overall shape of a drug molecule is important for the fit of the drug to its receptor. Between a quarter and a half of all drugs in use exist as stereoisomers. • In most cases the stereoisomers are chiral enantiomers. Enantiomers are mirrored image twin molecules that result from the presence of an asymmetric carbon, or in a few cases, other asymmetric atoms in their structures. • Chiral enantiomers often differ in their ability to bind to and alter the function of receptors. They also can differ in their rates of elimination and in their toxicity.

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• Most chiral drugs are still provided as racemic mixtures (mixtures of isomers) because it is expensive to separate the stereoisomers. In the past, little was known about the relative activity of stereoisomers. However, the Food and Drug Administration (FDA) now requires information about the structure and activity of each isomer present in a racemic mixture of a new medication.
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Drug Names
• Chemical name • Generic name • Trade name • Official name

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Chemical Name
• Gives the exact chemical makeup of the drug • Not capitalized • The drug’s chemical composition and molecular structure

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Generic Name(nonproprietary name)
• Name given before the drug becomes official • May be used in all countries and all manufacturers • Not capitalized

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Trade Name(proprietary name)
• Name can only be used by the manufacturer • Name that is registered by the manufacturer and followed by the trademark symbol • A drug may have several trade names, depending on the number of manufacturers • Is capitalized

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Official name
• The name under which the drug is listed by the US Food and Drug Administration (FDA). • The FDA is empowered by federal law to name the drugs for human use in the United States.

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Drug Names: Examples
Chemical name • (+/-)-2-(p-isobutylphenyl) propionic acid Generic name • ibuprofen Trade name • Motrin
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Examples
• Chemical name:4-Thia10azabicyclol{3.2.0}heptane-2-carboxyclic acid,6-[2S-[2a,-5a,6B(S*)]] • Generic name:ampicillin • Official name:ampicillin,USP • Brand name:Principen,Polycillin

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Pharmacologic Principles
• Pharmaceutics • Pharmacokinetics • Pharmacodynamics • Pharmacotherapeutics • Pharmacognosy

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Pharmacologic Principles

Pharmaceutics • The study of how various drug forms influence pharmacokinetic and pharmacodynamic activities
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Pharmacokinetics
Is what the body does to the drug. The magnitude of the pharmacological effect of a drug depends on its concentration at the site of action. • Absorption • Distribution • Metabolism • Elimination
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Pharmacodynamics
• The study of what the drug does to the body: – The mechanism of drug actions in living tissues

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Is what the drug does to the body. Interaction of drugs with cellular proteins, such as receptors or enzymes, to control changes in physiological function of particular organs. • Drug-Receptor Interactions
– Binding

• Dose-Response
– Effect

• Signal Transduction
– Mechanism of action, Pathways
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Pharmacogenetics
Area of pharmacology concerned with unusual responses to drugs caused by genetic differences between individuals. Responses that are not found in the general population, such as general toxic effects, allergies, or side effects, but due to an inherited trait that produces a diminished or enhanced response to a drug.
• Differences in Enzyme Activity
– Acetylation polymorphism – Butylcholinesterase alterations – Cytochrome P450 aberration

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Pharmacotherapeutics
• The use of drugs and the clinical indications for drugs to prevent and treat diseases • Study of which drug would be most or least appropriate to use for a specific disease, what dose would be required,etc.

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Pharmacognosy
• The study of natural (plant and animal) drug sources • By studying the compositions of natural substances and how the body reacts to them, one gains better knowledge for developing synthetic versions

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Toxicology
• Study of poisons and poisonings • As almost all drugs are capable of being toxic effects of substances on the living organism

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Drug Category
• Prescription • Nonprescription • Controlled substance

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Prescription Drugs
• Designated by the federal government as being harmful, unless their use is supervised by a licensed health care provider • Nurse practitioner, physician, or dentist • Nurse monitors for harmful effects • Largest drug category

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Rx
• Name of the drug • Dosage • Route • Times of administration • Signature

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Nonprescription Drugs
• OTC colds, headaches, constipation, diarrhea, upset stomach • Safe when used as directed • Potentially harmful • Read the label

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Controlled Substance
• High potential for abuse • Physical dependency • Psychological dependency

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Pregnancy
• Both prescription and OTC can have teratogen effects • In general most drugs should be avoided in pregnancy unless benefits outweight risks • The Motherisk Program

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INTRODUCTION TO PHARMACOKINETICS

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• Pharmacokinetics concerns the effects of the body on the administered drug. It can be pictured as the processes of absorption, distribution, and elimination. Elimination includes both metabolism and excretion.
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Drug Absorption of Various
Oral Preparations
Liquids, elixirs, syrups Suspension solutions Powders Capsules Tablets Coated tablets Enteric-coated tablets
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Fastest      Slowest

Absorption of Drugs.
• Drugs usually enter the body at sites remote from the target tissue and are carried by the circulation to the intended site of action. Before a drug can enter the bloodstream, it must be absorbed from its site of administration. The rate and efficiency of absorption differs depending on the route of administration. Common routes of administration of drugs and some of their features include:
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Pharmacokinetics: Absorption
• The rate at which a drug leaves its site of administration, and the extent to which absorption occurs.
– Bioavailability – Bioequivalent

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Pharmacokinetics: Absorption
Factors That Affect Absorption
• Administration route of the drug • Food or fluids administered with the drug • Dosage formulation • Status of the absorptive surface • Rate of blood flow to the small intestine • Acidity of the stomach • Status of GI motility
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Pharmacokinetics: Absorption
Routes
• A drug’s route of administration affects the rate and extent of absorption of that drug. – Enteral – Parenteral – Topical

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Pharmacokinetics: Absorption
Enteral Route
• Drug is absorbed into the systemic circulation through the oral or gastric mucosa, the small intestine, or rectum. – Oral – Sublingual – Buccal – Rectal
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Enteral Drug Absorption

Generally a passive process, fueled by a concentration gradient transporting drugs from the gut into the portal circulation Significant types of pre-systemic clearance:
• Intestinal and hepatic metabolism i.e., via cytochrome P450 (CYP) enzymes • Active transport via P-glycoprotein • Resulting “first-pass effect”

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GI drug absorption and pre-systemic metabolism

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First-Pass Effect
The metabolism of a drug and its passage from the liver into the circulation. • A drug given via the oral route may be extensively metabolized by the liver before reaching the systemic circulation (high first-pass effect). • The same drug—given IV—bypasses the liver, preventing the first-pass effect from taking place, and more drug reaches the circulation.
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Oral/Enteral Drug Administration

Advantages:
• Avoids hazards of IV lines, infections, phlebitis • Facilitates earlier ICU discharge (example enteral methadone instead of fentanyl infusion) • Lowers drug acquisition costs by an average of 8-fold

• Caution! Drug bioavailability in critical illness may be deranged.
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Oral/Enteral Drug Administration Should Be Avoided in Those With…
• Ileus, no active bowel sounds • Ischemic bowel • Gastric residuals • Nausea and vomiting • Malabsorption syndrome • Questionable gut perfusion and poor hemodynamics • Interacting substances in gut
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Interacting GI Substances May Interfere with Absorption

• Examples: Phenytoin, quinolones, tetracyclines
• Enteral nutrition with enteral phenytoin often lowers serum levels by as much as 80%.
- Many patients require intravenous phenytoin to maintain adequate serum levels.

• Bi- and trivalent cations bind to quinolone and tetracycline antibiotics, potentially leading to treatment failures.
- Avoid concurrent administration of substances such as iron, aluminum (sucralfate), magnesium, etc.
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First-Pass Effect
• Routes that bypass the liver:
– Sublingual – Buccal – Rectal* – Intravenous – Intranasal Transdermal Vaginal Intramuscular Subcutaneous Inhalation

*Rectal route undergoes a higher degree of firstpass effects than the other routes listed.
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Pharmacokinetics: Absorption
Parenteral Route
• Intravenous* • Intramuscular • Subcutaneous • Intradermal • Intrathecal • Intraarticular *Fastest delivery into the blood circulation
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Pharmacokinetics: Absorption
Topical Route
• Skin (including transdermal patches) • Eyes • Ears • Nose • Lungs (inhalation) • Vagina

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Oral (swallowed)
• Maximum convenience but may be slower and less complete than parenteral (non-oral) routes. Dissolution of solid formulations (eg, tablets) must occur first. The drug must survive exposure to stomach acid. This route of administration is subject to the first pass effect (metabolism of a significant amount of drug in the gut wall and the liver, before it reaches the systemic circulation).

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Sublingual (under the tongue)
• Permits direct absorption into the systemic venous circulation thus avoiding the first pass effect. May be fast or slow depending on the physical formulation of the product. Nitroglycerin is administered by this route in the treatment of angina.

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Rectal (suppository).
• Same advantage as sublingual route; larger amounts are feasible. Useful for patients who cannot take oral medications (eg, because of nausea and vomiting).

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Intramuscular
• Absorption is sometimes faster and more complete than after oral administration. Large volumes (eg, 5 - 10 mL) may be given. Requires an injection. Generally more painful than subcutaneous injection. Vaccines are usually administered by this route.

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Subcutaneous
• Slower absorption than intramuscular. Large volumes are not feasible. Requires an injection. Insulin is administered by this route.

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Inhalation
» For respiratory diseases, this route deposits drug close to the target organ; when used for systemic administration (e.g., nicotine Susan Masters, PhD 63

• in cigarettes, inhaled general anesthetics) it provides rapid absorption because of the large surface area available in the lungs.

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Topical
• Application to the skin or mucous membrane of the nose, throat, airway, or vagina for a local effect. It is important to note that topical drug administration can result in significant absorption of drug into the systemic circulation. Drugs used to treat asthma are usually administered this way.

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Transdermal
• application to the skin for systemic effect. Transdermal preparations generally are patches that stick to the skin and are worn for a number of hours or even days. To be effective by the transdermal route, drugs need to be quite lipophilic. Nicotine is available as a transdermal patch for those who are trying to stop cigarette smoking.

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Intravenous
• Instantaneous and complete absorption (by definition, 100%); potentially more dangerous because the systemic circulation is transiently exposed to high drug concentrations.

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Distribution of Drugs
• The distribution of drugs from the site of absorption, through the bloodstream and to the target tissue depends upon:

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• The blood flow to the tissue is important in the rate of uptake of a drug. Tissues that receive a high degree of blood flow (eg, brain, kidney) have a fast rate of uptake whereas tissues with a low degree of blood flow (eg, adipose tissue) accumulate drug more slowly.

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• Solubility of the drug in the tissue. Some tissues, eg, brain, have a high lipid content and dissolve a higher concentration of lipophilic agents. • Binding of the drug to macromolecules in the blood or tissue limits their distribution.

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• The ability to cross special barriers. Many drugs are poorly distributed to the brain and the testis because these tissues contain specialized capillaries (the smallest type of blood vessel). The endothelial cells that line these capillaries form a blood-brain barrier and a blood-testis barrier by preventing the movement of hydrophilic molecules out of the blood and into the tissue, and by actively pumping lipophilic molecules out of the endothelial cell and into the blood.

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Pharmacokinetics: Distribution
The transport of a drug in the body by the bloodstream to its site of action.
• Protein-binding • Water soluble vs. fat soluble • Blood-brain barrier • Areas of rapid distribution: heart, liver, kidneys, brain • Areas of slow distribution: muscle, skin, fat

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Pharmacokinetics: Metabolism
(also known as Biotransformation) The biologic transformation of a drug into an inactive metabolite, a more soluble compound, or a more potent metabolite.
• Liver (main organ) • Kidneys • Lungs • Plasma • Intestinal mucosa
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Pharmacokinetics: Metabolism
Factors that decrease metabolism:
• Cardiovascular dysfunction • Renal insufficiency • Starvation • Obstructive jaundice • Slow acetylator • Erythromycin or ketoconazole drug therapy
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Pharmacokinetics: Metabolism
Factors that increase metabolism:
• Fast acetylator • Barbiturates • Rifampin therapy

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Pharmacokinetics: Metabolism
Delayed drug metabolism results in:
• Accumulation of drugs • Prolonged action of the effects of the drugs

Stimulating drug metabolism causes:
• Diminished pharmacologic effects

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Pharmacokinetics: Excretion
The elimination of drugs from the body
• Kidneys (main organ) • Liver • Bowel – Biliary excretion – Enterohepatic circulation

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Pharmacokinetics
Half-Life
• The time it takes for one half of the original amount of a drug in the body to be removed. • A measure of the rate at which drugs are removed from the body.

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Pharmacodynamics
Drug actions:
• The cellular processes involved in the drug and cell interaction

Drug effect:
• The physiologic reaction of the body to the drug

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Pharmacodynamics
Onset
• The time it takes for the drug to elicit a therapeutic response

Peak
• The time it takes for a drug to reach its maximum therapeutic response

Duration
• The time a drug concentration is sufficient to elicit a therapeutic response
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Pharmacodynamics: Mechanisms of Action
The ways by which drugs can produce therapeutic effects:
• Once the drug is at the site of action, it can modify the rate (increase or decrease) at which the cells or tissues function. • A drug cannot make a cell or tissue perform a function it was not designed to perform.

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Pharmacodynamics: Mechanisms of Action
• Receptor interaction • Enzyme interaction • Nonspecific interactions

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Pharmacotherapeutics: Types of Therapies
• Acute therapy • Maintenance therapy • Supplemental therapy • Palliative therapy • Supportive therapy • Prophylactic therapy
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Pharmacotherapeutics: Monitoring
• The effectiveness of the drug therapy must be evaluated. • One must be familiar with the drug’s • intended therapeutic action (beneficial) • and the drug’s unintended but potential side effects (predictable, adverse drug reactions).

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Pharmacotherapeutics: Monitoring
• Therapeutic index • Drug concentration • Patient’s condition • Tolerance and dependence • Interactions • Side effects/adverse drug effects
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Pharmacotherapeutics: Monitoring
Therapeutic Index
• The ratio between a drug’s therapeutic benefits and its toxic effects

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Pharmacotherapeutics: Monitoring
Tolerance
• A decreasing response to repetitive drug doses

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Pharmacotherapeutics: Monitoring
Dependence
• A physiologic or psychological need for a drug

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Pharmacotherapeutics: Monitoring
Interactions may occur with other drugs or food
• Drug interactions: the alteration of action of a drug by: – Other prescribed drugs – Over-the-counter medications – Herbal therapies

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Pharmacotherapeutics: Monitoring
Interactions
• Additive effect • Synergistic effect • Antagonistic effect • Incompatibility

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Pharmacotherapeutics: Monitoring
Medication Misadventures
Adverse drug events • ALL are preventable • Medication errors that result in patient harm Adverse drug reactions • Inherent, not preventable event occurring in the normal therapeutic use of a drug • Any reaction that is unexpected, undesirable, and occurs at doses normally used
Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

Pharmacotherapeutics: Monitoring
Some adverse drug reactions are classified as side effects.
• Expected, well-known reactions that result in little or no change in patient management • Predictable frequency • The effect’s intensity and occurrence is related to the size of the dose

Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

Pharmacotherapeutics: Monitoring
Adverse Drug Reaction An undesirable response to drug therapy
• Idiosyncratic • Hypersensitivity reactions • Drug interactions

Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

Pharmacotherapeutics: Monitoring
Iatrogenic Responses Unintentional adverse effects that are treatment-induced
• Dermatologic • Renal damage • Blood dyscrasias • Hepatic toxicity
Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

Pharmacotherapeutics: Monitoring
Other Drug-Related Effects
• Teratogenic • Mutagenic • Carcinogenic

Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

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