Review of Basic Principles of Pharmacology

Chapter 2 Review of Basic Principles of Pharmacology

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Introduction

Pharmacodynamics

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Drug-receptor interaction

Drug-receptor activity

Dose-response relationship

Drug potency and efficacy

Pharmacokinetics

Absorption

Distribution

Metabolism

Elimination

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Pharmacodynamics

The effect of drugs on the body

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Pharmacokinetics

Absorption

Distribution

Metabolism

Excretion

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Drug-Receptor Interactions

Most drugs work by binding to receptors.

Receptors are located on the cell surface.

The drug molecule must “fit” into the receptor.

Like a lock and key mechanism

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Drug-Receptor Binding

Drug-receptor binding is reversible.

Drug-receptor binding is selective.

Drug-receptor binding is graded.

The more receptors filled, the greater the pharmacological response.

Drugs that bind to receptors may be agonists, partial agonists, or antagonistic.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

How Drug Dose Is Determined

Dose-response relationship

Therapeutic index

Plasma level profile

Half-life

Bioavailability

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Drug-Dose Relationship

Dose-response curve: depicts the relation between drug dose and magnitude of effect

Doses below the curve do not produce a pharmacological response.

Doses above the curve do not produce much additional pharmacological response.

May have unwanted effects → toxicity

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Plasma Level Profile

Onset of action: time between administration and first sign of drug effect

Peak of action: maximum concentration of drug

Point at which amount of drug being absorbed and distributed is equal to amount being metabolized and excreted

Duration of action: continued entry of drug into body with levels above minimum effective concentration

Termination of action

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Minimum Effective and Minimum Toxic Concentration

Minimum effective concentration (MEC): level below which therapeutic effects will not occur

Minimum toxic concentration (MTC): level above which toxic effects begin

Therapeutic index or range: MTC to MEC

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Drug Bioavailability

Percentage of drug that is absorbed and available to reach the target tissues

By definition, when a medication is administered IV, its bioavailability is 100%.

When a medication is administered via other routes (e.g., PO), its bioavailability decreases due to incomplete absorption and first-pass metabolism.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Therapeutic Blood Level

It usually takes 4 to 5 ½ lives to get to steady state blood levels.

Loading dose

It takes 4 to 5 ½ lives to totally eliminate a drug from the body.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Absorption

Definition: movement of a drug from its site of administration into the blood

Variables that influence absorption

Nature of the cell membrane

Blood flow at site of administration

Solubility of drug

Molecular weight

Drug concentration

Dosage form

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Distribution

Definition: movement of absorbed drug in bodily fluids throughout body to target tissues

Distribution requires adequate blood supply.

Drug distributed to areas of high blood flow first

Areas of low blood flow

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Protein Binding

In circulation, drugs are bound to protein.

Some of the drug is not bound and is called free drug.

Free drug + Bound drug ⬄ Drug-protein complex

Dynamic

Free drug is active drug.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Degree of Drug Binding

Drugs exist in bound and unbound states.

Travel when bound, cross membranes when unbound

“Highly” protein-bound

Ratio of bound drug usually remains stable

Low plasma proteins (low albumen) will result in more free drug in circulation.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Competition for Protein-Binding Sites

Finite number of plasma proteins

Compete and displace each other → more free drug

Higher risk for toxicity

More drug may be eliminated

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Tissue Distribution

Fat

Lipid-soluble fats have a high affinity for adipose tissue.

Adipose tissue has low blood flow.

Bone

Some drugs have affinity for bone.

For example, tetracyclines deposit in bones and teeth.

Blood-brain barrier

The blood-brain barrier is relatively impenetrable.

Usually protective

Only lipid-soluble drugs cross barrier.

Placental barrier

Many drugs pass barrier.

Low molecular weight drugs pass easier.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Metabolism

AKA: biotransformation

Definition: chemical change of drug structure to:

1. Enhance excretion

2. Inactivate the drug

3. Increase therapeutic action

4. Activate a prodrug

5. Increase or decrease toxicity

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Factors That Influence Metabolism

Age

Genetically determined differences

Pregnancy

Liver disease

Time of day

Environment

Diet

Alcohol

Drug interactions

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Factors That Influence Metabolism (cont’d)

Drugs undergo one or both of two types of chemical reactions in the liver:

Phase I: oxidation, hydrolysis, or reduction to increase water solubility of drug molecules

Phase II: conjugation or union of drug molecule with water-soluble substance

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Phase I Enzymes: Cytochrome P450 Isoenzymes

The majority of drugs are metabolized in the liver by the hepatic isoenzymes.

Cytochrome P450 isoenzymes

CYP 450

Most common

1A2, 2C9, 2C19, 2D6, 3A4 (3A3/4)

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

CYP 450 Enzymes

There are developmental differences in the isoenzymes.

There are genetic differences in isoenzymes.

Some disease states alter isoenzyme activity.

For example, cystic fibrosis has altered CYP 2D9 activity.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Phase I Enzymes: CYP 450

The enzymes may be slowed (inhibited) or increased (induced).

Concurrent therapy with an inhibitor or inducer may alter the metabolism of a medication.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Prodrug Metabolism

A prodrug is a drug which is administered in an inactive (or significantly less active) form.

Once administered, the prodrug is metabolized in the body into the active compound.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Elimination

AKA: excretion

Definition: removal of the drug from the body by organs of elimination

Most drugs are eliminated by the kidneys.

Drugs are also eliminated by

Lungs

Gastrointestinal (GI) tract

Sweat and saliva

Mammary glands (breast milk)

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Renal Elimination

Passive glomerular filtration

Active tubular secretion

Tubular reabsorption

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Glomerular Filtration

The availability of the drug for glomerular filtration

Drug must be unbound from protein

Free-, unbound, and water-soluble metabolites are filtered by the glomeruli.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Factors That Affect Renal Excretion

Kidney function

Age

Hydration

Cardiac output

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

GI Tract Excretion

Biliary excretion

After being metabolized in the liver, the metabolite is excreted into the bile.

Some drugs may then be reabsorbed in the intestine.

Enterohepatic cycle

Fecal excretion

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Lung Excretion

Gases

General anesthetics and volatile liquids

Rate of excretion is based on respiratory rate and pulmonary blood flow.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Sweat/Salivary Excretion

Not very many drugs

Excretion in sweat may be a cause of adverse effects, such as a rash (dermatitis).

Salivary excretion

May be the reason patients complain of “taste” in their mouth with certain drugs

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

Mammary Excretion

Many drugs are excreted in breast milk.

Smaller molecular weight

Lipid soluble

Breast milk is acidic.

Pharmacotherapeutics for Advanced Nurse Practitioner Prescribers, 4th Edition

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