INTRODUCTION TO PHARMACOLOGY AND PHARMACOKINETICS

Pharmacology By: ANNE R DELA CRUZ

Course Description

Pharmacodynamics Pharmacokinetics Clinical/therapeutic uses and toxicology NURSING RESPONSIBILITIES

Administering

drugs Assessing drug effects Intervening to make drug more tolerable Health teaching

Course Objectives
At the end of the course and given relevant actual or simulated situations/conditions, the student will be able to: Apply concept and principles of pharmacology to ensure safe and proper use of drugs Explain the action, therapeutic use, dosage, preparation, mode of administration State precautionary measures to be observed in the administration of drugs Discuss the role and responsibility of the nurse

INTRODUCTION TO NURSING PHARMACOLOGY

Pharmacology study of the biological effects of chemicals Sources of drugs 1. Plants - used as medicines since prehistoric times e.g. digitalis products - may also be processed using a synthetic version of the active chemical found in a plant. e.g. dronabinol (Marinol) contains the active ingredient delta-9-tetrahydrocannabinol found in marijuana. - sometimes drug effect occurs from ingestion of a plant derived food. e.g. natural licorice - alternative therapy

2. Animal products - are used to replace human chemicals that are not produced because of disease or genetic problems e.g insulin obtained from pancreas of cows and pigs. Genetic engineering (the process of altering DNA) - permits scientists to produce human insulin by altering E.Coli bacteria - thyroid drugs and growth hormone preparations also may be obtained from animal thyroid and hypothalamus tissues 3. Synthetic sources

4. Inorganic Compounds - salts of various elements can have therapeutic effects in the human body.
Element Aluminum Therapeutic Use Antacid to decrease gastric acidity Management of hyperphosphatemia Prevention of the formation of phosphate urinary stones Prevention of dental cavities Prevention of osteoporosis Treatment of rheumatoid arthritis Treatment of IDA

Flouride Gold Iron

Phases of drug development

Phases of drug development Preclinical trials

1. 2.

1.

2. 3.

4.

Chemicals that may have therapeutic value are tested on laboratory animals for 2 main purposes: To determine whether they have the presumed effects in living tissue To evaluate any adverse effects At the end of the preclinical trials, some chemicals are discarded for the ff reasons. The chemicals lacks therapeutic activity when used in living animals Is highly teratogenic Safety margins are so small that the chemical would not be useful in the clinical setting Too toxic to living animals to be worth the risk of developing into drugs

Phase I studies Use human volunteers to test the drugs. More tightly controlled than preclinical trials Performed by specially trained clinical investigators. Usually young healthy male are the volunteers At the end of Phase I studies, many chemicals are dropped from the process for the ff reasons: 1. They lack therapeutic effect in humans 2. They cause unacceptable adverse effect 3. They are highly teratogenic

Phase II studies Allow clinical investigators to try the drug in patients who have the disease that the drug is meant to treat. Patients are told about the possible benefits and are invited to participate in the study. Those who consent are fully informed about possible risks and are monitored very closely Drug may be removed from further investigation for the ff reasons: 1. Less effective than anticipated 2. Too toxic when used by the patient 3. Produces unacceptable adverse effect 4. Has low benefit-to-risk ratio 5. No more effective than other drugs already in the market

Phase III studies Involve use of the drug in vast clinical market. Prescribers are informed of all the known reactions to the drug and precautions required for its safe use Prescribers observe patients very closely, monitoring them for any adverse effects. Prescribers then evaluate the reported effects to determine whether they are caused by the disease or by drug. The information is collected by the drug company and is shared with the FDA A drug that produces unacceptable adverse effects is usually removed from the market

Food and Drug Administration Approval

Drugs that finish phase III studies are evaluated by the FDA FDA regulates the distribution and sale of drugs Only those drugs that receive FDA committee approval may be marketed The entire drug development and approval process can take 5 to 6 years The FDA carefully regulates the testing and approval of all drugs in the country To be approved for marketing, a drug must pass through animal testing, testing on healthy human, select testing on people with the disease being treated and then broad testing on people with the disease being treated.

Phase IV Continual evaluation After a drug is approved for marketing, prescribers are obligated to report to the FDA any untoward or unexpected adverse effect. An approved drug is given a brand name (trade name) by the pharmaceutical company that developed it. Generic name of the drug is the original designation that the drug was given when the drug company applied for the approval process. Chemical names are names that reflect the chemical structure of a drug.

FDA Pregnancy Categories

Category A Adequate studies in pregnant women have not demonstrated a risk to the fetus in the 1st trimester, and there is no evidence of risk in later trimester Category B Animal studies have not demonstrated a risk to the fetus but there are no adequate studies on pregnant women, or animal studies in pregnant women have not demonstrated a risk to the fetus Animal studies have shown an adverse effect on the fetus but there are no adequate studies in humans There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks Studies in animals or humans demonstrate fetal abnormalities or adverse reaction

Category C Category D

Category X

CONTROLLED SUBSTANCES

The Controlled Substances Act of 1970 regulates the manufacturing, distribution and dispensing of drugs that are known to have abuse potential The DEA is responsible for the enforcement of these regulations

DEA Schedules of Controlled Substances

Schedule I (C-I) Schedule II (C-II) High abuse potential and no accepted medical use (heroin, marijuana) High abuse potential with severe dependence liability (narcotics, amphetamines and barbiturates)

Schedule III (C-III) Less abuse potential than schedule II drugs and moderate dependence liability (nonbarbiturates sedatives, nonamphetamine stimulant, limited amount of certain narcotics) Schedule IV (C-IV) Less abuse potential than schedule III and limited dependence liability (some sedatives, antianxiety agents, and non-narcotics agent) Schedule V (C-V) Limited abuse potential. The purchaser must be atleast 18 years of age (antitussive, antidiarheals, small amounts of narcotic)

GENERIC DRUGS Are chemicals that are produced by companies that just manufacture drugs. They do not have the research, advertising More cheaper ORPHAN DRUGS Drugs that have been discovered but that are not financially viable These drugs have been adopted for development by a drug company in exchange or tax incentives

OVER-the-COUNTER (OTC) DRUGS Are deemed safe when used as directed and are available without a prescription Disadvantages 1. Could mask the s/sx of underlying disease, making diagnosis difficult 2. Taking these drugs with prescription medication could result in drug interaction and interfere with drug therapy 3. Not taking as directed could result in serious overdoses

CHAPTER II

DRUGS & the BODY

Pharmaceutic, Pharmacokinetic & Pharmacodynamic Phases

DRUG ACTIONS

To replace or act as substitute for missing chemicals To increase or stimulate certain cellular activities To depress or slow cellular activities To interfere with the functioning of foreign cells, such as invading microorganisms or neoplasms. (drugs that act in this way are called chemotherapeutic agents

I. Pharmaceutic Phase
Is the 1st phase of drug action In the GIT, drugs need to be in a solution so they can be absorbed A drug in solid form must disintegrate into small particles to dissolve into a liquid. Disintegration Is the breakdown of a tablet into smaller particles Dissolution Is the dissolving of the smaller particles in the GI fluid before absorption Rate Limiting Is the time it takes the drug to disintegrate and dissolve to become available for the body to absorb it.

II. Pharmacokinetics
Is the process of drug movement to achieve drug action The four processes are: II. A. Absorption II. B. Distribution II. C. Metabolism (Biotransformation) II. D. Excretion (Elimination)

II. A. Absorption
Is the movement of drug particles from the GI tract to the body fluids by passive absorption, active absorption or pinocytosis. Passive Absorption Occurs mostly by diffusion (movement from higher concentration to lower concentration) The drug does not require energy to move across the membrane Active absorption Requires a carrier such as an enzyme or protein to move the drug against a concentration gradient Energy is required for active absorption Pinocytosis Is the process by which cells carry a drug across their membrane by engulfing the drug particles.

Drugs that are lipid soluble and nonionized are absorbed faster than water-soluble and ionized drugs Pain, stress and foods that are solid, hot and fatty can slow gastric emptying time. First-pass effect The process in which the drug passes to the liver first e.g warfarin and morphine Bioavailability It is the percentage of the administered drug dose that reaches the systemic circulation The percentage of bioavailability for the oral route is always less than 100%, but for IV routes is usually 100%.

Factors that alter Bioavailability The drug form (capsule, tablet, sustained-release, liquid, transdermal patch, suppositories, inhalation) Route of administration (oral, rectal, topical, parenteral) GI mucosa and motility Food and other drugs Changes in liver metabolism caused by liver dysfunction or inadequate hepatic blood flow.

II. B. Distribution

1. 2. 3.

Is the process by which the drug becomes available to the body fluids and body tissues. Drug distribution is influenced by: Blood flow Drugs affinity to the tissue Protein-binding effect Only free drugs (drugs not bound to protein) are active and can cause a pharmacologic response.

When two highly protein-bound drugs are given concurrently, they compete for protein-binding sites, thus causing more free drug to be released into the circulation In this situation, drug accumulation and possible drug toxicity can occur A low protein level decreases the number of protein-binding sites and can cause an increase in the amount of free drug in the plasma. Drug overdose then result. Drug dose is prescribed according to the percentage in which the drug binds to protein Abscesses, exudates, body glands and tumors hinder drug distribution

II. C. Metabolism (Biotransformation)

Liver is the primary site of metabolism. Most drugs are inactivated by liver enzymes and are then converted by hepatic enzymes to inactive metabolites or water soluble substances for excretion. When drug metabolism rate is decreased, excess drug accumulation can occur and lead to toxicity. Half-life Is the time it takes for one half of the drug concentration to be eliminated. By knowing the half-life, the time it takes for a drug to reach steady state of serum concentration can be computed.

II. D. Excretion (Elimination)

1. 2. 3. 4. 5. 6. 7.

Kidney the main route of drug elimination (urine) Other routes include: Hepatic metabolism Bile Feces Lungs Saliva Sweat Breast milk

Protein-bound drugs cannot be filtered through kidneys. Once the drug is released from the protein, it is a free drug and eventually excreted in the urine. Urine pH influences drug excretion. Acid urine promotes excretion of weak base drugs With a kidney disease that results in decreased in GFR or decreased renal tubular secretion, drug excretion is impaired.

Creatinine clearance The most accurate test to determine renal function Varies with age and gender NV : 85-135 ml/min Creatinine is a metabolic byproduct of

III. PHARMACODYNAMICS

Is the study of drug concentration and its effect on the body. Drug response can cause a primary or secondary effect. Is the science dealing with interactions between the chemical components of living systems and the foreign chemicals, including drugs, that enters those systems.

Dose Response Is the relationship between the minimal versus the maximal amount of drug dose needed to produce the desired drug response. Onset of action Is the time it takes to reach the minimum effective concentration after a drug is administered. Peak action Occurs when the drug reaches its highest blood plasma concentration Duration of action Is the length of time the drug has a pharmacologic effect

Receptor sites (key works in a lock) Reacts with certain chemicals to cause an effect within the cell. In many situations, nearby enzymes break down the reacting chemicals and open the receptor site for further stimulation The specific chemical (the key) approaches the cell membrane and find a perfect fit (the lock) at a receptor site.

There are four Receptor Families 1. kinase-linked receptors the ligand-binding domain for drug binding is on the cell surface. 2. Ligand-gated ion channels the drugs spans the cell membrane, the channel opens allowing for the flow of ions into and out of the cells. The ions are primarily sodium and calcium. 3. G protein-coupled receptor systems there are 3 components to this receptor response: a. The receptor b. G protein that binds with guanosine triphosphate (GTP) c. The effector that is either an enzyme or an ion channel. 4. Nuclear receptor cell nucleus and not on the surface of the cell membrane.

Agonists Drugs that produce a response Antagonists Drugs that blocks response Categories of Drug Action 1. Stimulation 2. Replacement 3. Inhibition or killing 4. Irritation Drug action might last hours, days, weeks or months depending on the half-life of the drugs.

Peak drug level Is the highest plasma concentration of drug at a specific time. Indicate the rate of absorption Trough drug level Is the lowest plasma concentration of a drug and it measures the rate at which the drug is eliminated. Indicates the rate of elimination.

Side effects Are physiologic effect not related to desired drug effects All drugs have side effects, desirable or undesirable Adverse reactions More severe than side effects Always undesirable Toxic effects Can be identified by monitoring the plasma therapeutic range.

Evaluation Methods

Mid Term Test Final Exam Patient Information Pamphlet Pop Quizzes (x 4)

- 25% - 35% - 20% - 10%

Test/exam will be multiple choice, true false and matching

Why Do We Study Pharmacology?

A. Its good for you B. You will be able to use fancy terms like bioavailabilty C. My instructor likes torture D. A competent nurse must understand why his/her patient is getting a medication, and HOW IT WORKS

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

A Graphical Example:
Drug Concentration
Lethal Dose
Peak Onset

Duration

Therapeutic Range
SubTherapeutic

Time in Hours

HOW DO WE STUDY PHARMACOLOGY?

General Concepts
Drug Dose Administration Disintegration of Drug Absorption/distribution metabolism/excretion Drug/Receptor Interaction Drug Effect or Response

Pharmaceutical Pharmacokinetics Pharmacodynamics Pharmacotherapeutics

HOW ARE DRUGS ADMINISTERED?

Routes of Drug Delivery

Parenteral (IV) Oral Transdermal Topical Parenteral (SC, IM) Rectal Inhaled

What Happens After Drug Administration?

Drug at site of administration

1. Absorption
Drug in plasma

2. Distribution 3. Metabolism
in tissues Drug/metabolites

Drug/metabolites in urine, feces, bile

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

We are now talking about

Pharmacokinetics

Factors Affecting Drug Absorption

Transport
active

ATP

vs. passive ADP + Pi

pH Physical factors
blood

flow surface area contact time

ABH+

What Factors Affect Distribution?

Blood flow
brain

vs. fat

Endothelial cells in liver capillary

Capillary permeability
differences

in capillary structure of albumin Endothelial cells in brain capillary Glial cell

Binding to proteins
role

An Important Concept: BIOAVAILABIITY

Defn:

Serum Concentration

Fraction of a drug that reaches systemic circulation after a particular route of adminn

Injected Dose

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

Oral Dose

Time

Volume of Drug Distribution

Drugs may distribute into any or all of the following compartments:

Plasma Interstitial

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

Fluid Intracellular Fluid

So What?

Most drugs distribute into several compartments; however Some drugs distribute into only one or two compartments Eg: Aminoglycoside Arggh! I cant fit through these antibiotics Streptomycin darn fenestrations!
Gentamycin

More So What?

Serum Concentration

It takes time for a drug to distribute in the body Drug distribution is affected by elimination 1.5
Drug is not eliminated 1.0 0.5 Distribution Phase 0 0 Drug is eliminated Elimination Phase

Time

Albumin Affects Distribution

Drugs bind differentially to albumin 2 drug classifications:

Class I: dose less than available binding sites (eg: most drugs) Class II: dose greater than binding sites (eg: sulfonamide)

Albumin

Drug X

The problem:

one drug may outcompete the other

Sulfonamide

Drug Metabolism (were still talking about Pharmacokinetics)

Drug Metabolism

First pass
metabolism
eg:

of drugs may occur as they cross the intestine or transit the liver
nitroglycerin

Other drugs may be destroyed before absorption

eg:

penicillin

Such reactions decrease delivery to the target tissues

Drug Metabolism (contd)

Drug

Two Phases: I and II

Phase

I: conversion to lipophilic cpds Phase II: conjugation

Oxidation Reduction Hydrolysis

Phase I

Phase I involves the cytochrome P-450 system Ultimate effect is to facilitate elimination

Activation/Inactivation
Glucuronidation

Phase II

Conjugation Products

An Example of Phase I and II Biotransformation:

CH3CONH PHASE I CH3CONH PHASE II CH3CONH -OC2H5 Phenacetin

-OH

Paracetamol

OH -O- HO -OH O COOH Glucuronic Acid Conjugate

An Example of Drug Metabolism

First Pass Metabolism Occurs Primarily in the Liver and Gut

Drug Elimination

Most important route is the kidney May also involve bile, intestine, lung, breast milk What clinical scenarios may affect drug elimination?

Elimination of a drug is usually linked to renal filtration, secretion and reabsorption.

Food for Thought

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

Important Point

The pharmacokinetic profile of a drug also depends on its mode of administration

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

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?

Plasma Concentration

100 mg injected

50 mg injected

Time

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

Plasma Concentration

Time

Are We Having Fun Yet?