Advanced Pharmacology Chap.2

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Once a drug is administered, it goes through two phases,

Back 1

•The pharmacokinetic phase

•The pharmacodynamic phase

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The pharmacokinetic phase is

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what the body does to the drug, describes the movement of the drug through the body.

It is composed of four processes:

(1) absorption

(2) distribution

(3) metabolism (biotransformation)

(4) excretion (elimination)

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The pharmacodynamic phase is

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what the drug does to the body and it involves

Receptor binding

Post-receptor effects

Chemical reactions

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Drug absorption is the movement of

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the drug into the bloodstream after administration

Front 5

For the body to utilize drugs taken by mouth, a drug in solid form (such as tablet or capsule) must disintegrate into small particles and combine with a liquid to form a solution, a process known as

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dissolution [drugs in liquid form are already in solution], in order to be absorbed from the gastrointestinal (G.I) tract into the bloodstream

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Tablets are not 100% drug, a tablet has

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fillers and inert substances [such as simple syrup, vegetable gums, aromatic powder, honey, and various elixirs which are called excipients] are used in drug preparation to allow the drug to take on a particular size and shape and to enhance drug dissolution

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Disintegration is the breakdown of

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an oral drug into smaller particles

Front 8

Enteric-coated (EC) drugs resist disintegration in

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the gastric acid of the stomach, so disintegration does not occur until the drug reaches the alkaline environment of the small intestine

Front 9

Absorption across the mucosal lining of the small intestine [G.I tract] occurs through

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passive transport

active transport

pinocytosis

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The mucous membrane that lines the G.I tract is composed of lipids (fat) and protein such that

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lipid-soluble drugs are able to pass rapidly [easily] through the mucous membrane

Front 11

Water-soluble drugs need a carrier, either an enzyme or a protein, to pass through

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the mucous membrane of the G.I tract

Front 12

Large particles are able to pass through the mucous membrane of the G.I tract if they are

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nonionized (have no positive or negative charge)

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Drugs that are lipid soluble and nonionized [no charge] are absorbed

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FASTER than water soluble and ionized [charged] drugs

Front 14

Following absorption of oral drugs from the G.I tract, they pass from the intestinal lumen to the liver via the portal vein. In the liver, some drugs are metabolized to

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an inactive form and are excreted, thus REDUCING the amount of active drug available to exert a pharmacologic effect

This is referred to as the first-pass effect or first-pass metabolism

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Bioavailability refers to the percentage of

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administered drug available for activity [amount that will have a pharmacological effect on the body]

Front 16

Factors that alter bioavailability include

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(1) Drug form [such as tablet, capsule, sustained-release]

(2) Route of administration (such as enteral, topical, or parenteral)

(3) Gastric mucosal healthy and motility

(4) Administration with food and other drugs

(5) Changes in liver metabolism caused by liver dysfunction or inadequate hepatic blood flow

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Distribution is the movement of the drug from

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the circulation to body tissues

Front 18

Drug distribution is influenced by

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The rate of blood flow to the tissue

The drug’s affinity to the tissue

Protein binding

Front 19

As drugs are distributed in the plasma, many bind with

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plasma proteins

These plasma proteins are

Albumin

Lipoproteins

Alpha-1-acid-glycoprotein [AGP]

Front 20

Drugs that are more than 90% bound to protein are known as

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highly protein-bound drugs

Examples are: warfarin, glyburide, sertraline, furosemide, and diazepam

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Drugs that are less than 10% bound to protein are

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weakly protein-bound drugs

Examples are: gentamycin, metformin, metoprolol, and lisinopril

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The portion of the drug bound to protein is

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inactive because it is not available to interact with tissue receptors and therefore is unable to exert a pharmacologic effect

The portion that remains unbound to the protein is free and is the active portion of the drug that can exert it pharmacological effects on the body

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When two highly protein-bound drugs are administered together, they compete for

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protein-binding sites, leading to an increase in free drug being released into the circulation

For example, if warfarin (99% protein bound) and furosemide (95% protein bound) were administered together, warfarin [the more highly bound drug] could displace furosemide from its binding site.

In this situation, it is possible for drug accumulation to occur and for toxicity to result.

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Metabolism, or biotransformation, is the process by which the body

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chemically changes drugs into a form that can be excreted

Front 25

Liver enzymes are collectively referred to as the

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cytochrome P450 system, or the P450 system, of drug metabolizing enzymes convert drugs to metabolites

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The drug half-life (t½) is the time it takes for the amount of drug in the body to be

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reduced by half [50%]

Front 27

A steady state occurs when the amount of drug being administered is

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the same as the amount of drug being eliminated

Front 28

By giving a large initial dose, known as a

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loading dose, that is significantly higher than maintenance dosing, therapeutic effects can be obtained while a steady state is reached.

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The main route of drug excretion, elimination of drugs from the body is through

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the kidneys

Front 30

Normal urine pH varies from

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4.6 to 8.0

Acidic urine [less than 4.6] promotes elimination of weak base drugs

Alkaline urine [greater than 8.0] promotes elimination of weak acid drugs

Front 31

The dose-response relationship is the body’s

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physiologic response to changes in drug concentration at the site of action

Front 32

Potency refers to the amount of drug needed to

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elicit a specific physiologic response to a drug

Front 33

The point at which increasing a drug’s dosage no longer increases the desired therapeutic response is referred to as

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maximal efficacy

Front 34

The therapeutic index (TI) describes the relationship between

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the therapeutic dose of a drug (ED50) and the toxic dose of a drug (TD50)

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If the ED50 and TD50 are close, the drug is said to have

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a narrow therapeutic index

Front 36

Onset is the time it takes for

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a drug to reach the minimum effective concentration (MEC) after administration

Front 37

A drug’s peak occurs when

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it reaches its highest concentration in the blood

Front 38

Duration of action is

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the length of time the drug exerts a therapeutic effect

Front 39

The peak drug level is

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the highest plasma concentration of drug at a specific time, and it indicates the rate of drug absorption

Front 40

If the drug is given orally, the peak time is usually

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2 to 3 hours after drug administration [check peak level at this specific relapsed time]

Front 41

If the drug is given intravenously, the peak time is usually

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30 to 60 minutes after the infusion is complete

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If the drug is given intramuscularly, the peak time is usually

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2 to 4 hours after injection

Front 43

The trough drug level is

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the lowest plasma concentration of a drug, and it measures the rate at which the drug is eliminated

Front 44

The four receptor families include

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(1) cell membrane–embedded enzymes

(2) ligand-gated ion channels

(3) G protein–coupled receptor systems

(4) transcription factors

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Cell membrane–embedded enzymes:

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The ligand-binding domain for drug binding is on the cell surface

The drug activates the enzyme inside the cell, and a response is initiated

Front 46

Ligand-gated ion channels

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The channel crosses the cell membrane

When the channel opens, ions flow into and out of the cells

This primarily affects sodium and calcium ions

Front 47

G protein–coupled receptor systems

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The three components to this receptor response are

(1) the receptor

(2) the G protein that binds with guanosine triphosphate (GTP)

(3) the effector, which is either an enzyme or an ion channel

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Transcription factors

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Found in the cell nucleus on DNA, not on the surface.

Activation of receptors through transcription factors regulates protein synthesis and is prolonged

With the first three receptor groups, activation of the receptors is rapid

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Drugs that activate receptors and produce a desired response are called

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agonists

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Drugs that prevent receptor activation and block a response are called

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antagonists

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Drugs that affect multiple receptor sites are considered

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nonspecific

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Adverse drug reactions (ADRs) are

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unintentional, unexpected reactions to drug therapy that occur at normal drug dosages

Front 53

Drug toxicity occurs when drug levels

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exceed the therapeutic range; toxicity may occur secondary to overdose (intentional or unintentional) or drug accumulation

Front 54

Factors that influence drug toxicity include

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disease, genetics, and age

Front 55

Pharmacogenetics refers to the study of

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genetic factors that influence an individual’s response to a specific drug.

Genetic factors can alter drug metabolism, resulting in either enhanced or diminished drug response

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Pharmacogenomics refers to the study of how genetics play a role in a person’s

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response to drugs (absorption, distribution, metabolism, and excretion).

Through the use of pharmacogenomics, the goal is to develop precision medicine, which uses the person’s genetic makeup to determine appropriate drug therapy, thereby improving patient outcomes and safety

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Tolerance refers to

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a decreased responsiveness to a drug over the course of therapy; an individual with drug tolerance requires a higher dosage of drug to achieve the same therapeutic response

Front 58

Tachyphylaxis refers to

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an acute, rapid decrease in response to a drug; it may occur after the first dose or after several doses

Front 59

Placebo effect is a drug response not attributed to

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the chemical properties of the drug

Front 60

Drugs that promote induction of enzymes are called

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enzyme inducers

Enzyme inducers increase the metabolism of a drug and promote drug elimination/decreased plasma concentration of the drug; this results is a decrease in therapeutic drug action

Examples of enzyme inducers are: phenobarbital, carbamazepine, and rifampin

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Enzyme inhibitor decrease

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the metabolism of certain drugs (such as theophylline, warfarin, phenytoin) and cause an increase in the plasma concentration of these drugs; which leads to toxicity/dosage should be reduced

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When two drugs are administered in combination, and the response is increased beyond what either could produce alone, the drug interaction is called

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an additive effect

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When two or more drugs are given together, one drug can have

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a synergistic effect on another

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When two or more drugs are given together, one drug can have

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a synergistic effect on another

Front 65

When drugs with antagonistic effects are administered together, one drug

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reduces or blocks the effect of the other

Front 66

A classic drug-food interaction occurs when a monoamine oxidase inhibitor (MAOI) antidepressant (such as phenelzine) is taken with tyramine-rich foods

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Tyramine is a potent vasoconstrictor, and when taken in conjunction with an MAOI, the result could be a hypertensive crisis.

Tyramine containing foods are cheese, wine, organ meats, beer, yogurt, sour cream, or bananas.

Front 67

Grapefruit alters the metabolism of many drugs through

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inhibition of the CYP450-3A4 drug-metabolizing enzyme

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Nutritional deficiencies such as protein-energy malnutrition (PEM) may alter

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pharmacokinetic processes and drug responses, resulting in toxicity

Examples of PEM [kwashiorkor and marasmus]

Front 69

A drug-induced photosensitivity reaction is

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a skin reaction caused by exposure to sunlight

Front 70

The two types of photosensitivity reactions are

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photoallergic and phototoxic

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The two types of photosensitivity reactions are

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photoallergic and phototoxic

Front 72

Photoallergic reaction occurs when a drug (such as sulfonamide) undergoes

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activation in the skin by ultraviolet light to a compound that is more allergenic than the parent compound.

Due to the fact that it takes time to develop antibodies, photoallergic reactions are a type of delayed hypersensitivity reaction

Front 73

With a phototoxic reaction, a photosensitive drug undergoes

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photochemical reactions within the skin to cause damage