1. Absorption

2. Distribution

3. Elimination

How the drug gets out of the body

A. Metabolism

B. Excretion

1. Metabolism

2. Excretion

Why study pharmacokinetics?

(3 Reasons)

* Assists in calculation of the proper dose and/or dosing intervals for a drug

* Determination of the most advantageous route of administration of a drug for an individual patient

* Adjustments in dosage due to a patients reduced capacity to eliminate a drug from the body

1. Lipid soluble

2. Small enough to go through the pores of the cells (less then 200 molecule weights)

3. Mimic and endogenous substance that is normally transported across the cell membrane by a transport protein

A. Length

B. Large absorbtive surface

C. Long transit time

1. Rate of dissolution (Breaking down)

2. Surface area of contact between the drug molecules and the membrane to be crossed

3. Lipid solubility of the drug

4. Likelihood that the drug will be ionized after absorption

Intravenous (IV)

Absorption is not necessary when giving medications IV because the drug enters _________________________,

Intravenous (IV)

______ onset of drug.

Intravenous (IV)

True or False

Large volumes of fluids can be adminstered through IV.

Intravenous (IV)

The drug is rapidly _________ by the blood, so irritating drugs can be safely given.

Intravenous (IV)

Drugs are usually only given IV in clinical setings because they are ______ and _____.

Intravenous (IV)

The catheter or the drug may cause _________.

Intravenous (IV)

The IV provides a route of entry for _______________.

Intravenous (IV)

True or False

All drugs can be administered IV.

False

Some drugs cannot be administered IV.

Intravenous (IV)

Extravasation of the IV catheter may result in _______________.

Extravasation of the IV catheter may result in drug infustion into the tissue.

Also called "infiltration of the IV"

Intramuscular (IM)

Drugs administered intramuscularly enter the blood through ________________.

Intramuscular (IM)

True or False

Drugs that are not in solution can be administered intramusuclarly.

True

Mix the powdered drug with liquid solution.

Intramuscular (IM)

Giving a medication IM is _____________ and ___________.

Intramuscular (IM)

_________ rate of absorption.

Intramuscular (IM)

Irritating substances or drugs may cause ____________.

Irritating substances or drugs may cause muscle necrosis.

Muscle Necrosis = Death of Muscle Tissue

Muscle Necrosis = Death of Muscle Tissue

Intramuscular (IM)

Irritating substances or improperly placed injections may cause __________.

Subcutaneous (SQ)

SubQ's are used for _______, _______ and ________.

Subcutaneous (SQ)

The subcutatneous space is ___________, so absorption is usually slower for SubQ then IM.

Subcutaneous (SQ)

Highly irritating or corrosive substances should not be given SubQ because of the likelihood of ___________________.

Subcutaneous (SQ)

SubQ injections are similar to ______ injections.

Oral (PO or Enteral)

Why do gastrointestinal epithelial cells form a tight barrier?

Oral (PO or Enteral)

What are 7 factors that influence Oral medication administration?

1. Solubility

2. pH

3. Gastric emptying time

4. Food

5. Co-administration of other drugs

6. Enteric coatings

7. Transit times

Some drugs are destroyed by stomach acid; some drugs damage the stomach.

Enteric Coating prevents the drug from being exposed to the stomach. The Enteric coating will NOT dissolve in teh stomach acid; it dissovles in a more basic environment like the small intestines.

NEVER CRUSH an enteric coated pill because it woudl negate the effect of the coating.

Topical

The drug is administered at ___________.

Topical

True or False

Absorption occurs very slowly.

False

No absorption is necessary since the drug is where it needs to go.

Topical

Topical medications are not absorbed, therefore, there will be no ______ effect.

Topical

Where is the drug at its highest concentration when administered topically?

Transdermal

What are transdermal medications?

Transdermal

Its site of action is the

A. Skin

B. Systemic site

B. Systemic site

Because the drug is placed on the skin, absorbed through the skin and enters the bloodstream

Transdermal

What are some examples of transdermal medications?

Hormones (Estrogen, testosterone, progesterone)

Nitroglycerine

Nicotine

Transdermal

The drug must be _________ to be able to cross the skin.

Inhalation

Although asthma medications are inhaled, their site of action is the __________ and this use is considered _________.

Inhalation

Inhaled drugs with ____________ sites of action include anesthetic gases and some drugs of abuse that are smoked, such as cocaine, nicotine, heroine and marijuana. 

Inhalation

Inhaled drugs reach the systemic circulation by .....

Inhaled drugs reach systemic circulation by:

Crossing over the pulmonary epithelium

To the pulmonary capillaries

To the systemic circulation

Inhalation

The main site of action for inhaled medications, other then asthma medication, is the _______.

Sublingual or Buccal

Very _______ drugs have a _______ onset comparable to IV administrations when given sublingual.

Buccal/Sublingual

Lipid soluble drugs have a _____ onset comparable to IV administrations.

Sublingual or Buccal

Examples of Sublingual or Buccal drugs are .....

Nitroglycerine

Nicotine (Chewing tobacco or gums)

Rectal or Vaginal

Rectally or vaginally administered drugs are ______.

Rectal or Vaginal

Their site of action is the ____ or _____.

Rectal or Vaginal

A few drugs can be given rectally for _________ effects.

The movement of drugs throughout the body

Note: All drugs taht gain entry into the bloodstream go everywhere the bloodstream goes. The site of action mighbt be in one part of the body (the head for pain relief of a headache) but the drug goes everywhere the blood goes.

True or False

Drugs that enter the bloodstream only have 1 site of action.

False

Drugs that enter the bloodstream effect a certain site of action; however, the drug goes every in the body that blood goes.

1. Absorption

2. First Pass Metabolism

True or False

The entire dose of a drug will be absorbed into systemic circulation.

False

All of the dose may not be absorbed by some drugs due to the first pass metabolism in the liver.

Chemical changes in a drug molecule made in the body (in the liver or elsewhere)

Also called Metabolism

Yes - Hepatic metabolism of drugs administered by routes other than PO are involved

However, when administered by routes other than PO, only a portion of the drug is metabolized by the liver because only a portion of cardiac output (and drug) goes to the liver.

The hepatic metabolism of drugs administered by routes other than oral is slower for this reason.

True or False

Orally administered medications have a slower hepatic metabolism rate then drugs administered other routes.

False

Orally administered medications have a faster hepatic metabolism then drugs administered other routes.

True or False

All drugs go through hepatic metabolism.

True

All drugs go through hepatic metabolism; only oral drugs go through the first pass effect.

Drugs administered other routes than PO experience a slower hepatic metabolism rate because only a potion of the cardiac output, and therefore the drug in the blood, goes to the liver.

1. Drugs are absorbed in the veins

2. Reach the Vena Cava

3. Right Heart

4. Pulmonary Circulation

5. Left heart

6. Exit through the Aorta

7. Enter systemic circulation and are distributed to the arteries, arterioles and capillaries

* Same is true for orally administered drugs that reach the hepatic vein.

Lipid soluble drugs can exit circulation in the capillaries through:

A. Fenestrations

B. Diffusion

C. Fenestrations and Diffusion

Ionized or polar drugs can exit circulation in the capillaries through:

A. Fenestrations

B. Diffusion

C. Fenestrations and Diffusion

Portion of every drug will be delivered to the liver and kidney because ....

(2 reasons)

A portion of every drug will be delivered to the liver and kidney because

A. The organs could be a site of drug action (may contain receptors)

B. The organs may eliminate a portion of the drug by metabolism (liver) or excretion (kidneys)

1. Excretes the drug (excretion)

2. Kidneys may have drug receptors for certain drugs

1. Metabolism

2. May contain receptors for certain drugs

Some drugs will bind a high percentage of their molecules in the blood to plasma ______.

Which plasma ______ are they more likely to bind to more often then others?

Protein bound drugs cannot leave circulation to reach their receptors, therefore, the drug levels of protein bound drugs do not mean anything.

We want to obtain a measurement of the free drug only OR measure the drug effect rather then the drug level.

The same qualifications drugs must have to cross the GI tract

1. Lipid soluble

2. Transported by a transporter protein

3. Low molecular weight (less then 200)

The blood brain barrier is harder for a drug to cross than the GI epithelium.

Because:

1. Capillaries are not fenestrated

2. Baseement membranes are continuous

3. Astrocytic foot processes cover the exterior of the capillaries.

1. Capillaries are not fenestrated

2. Baseement membranes are continuous

3. Astrocytic foot processes cover the exterior of the capillaries.

* Star-shaped glial (neural) cells in the brain and spinal cord

Functions include:

-Biochemical support of endothelial cells that form the blood brain barrier

-Provide nutrients to the nervous tissue

Maintain extracellular ion balance

-Repair and scar brain and spinal cord following traumatic injuries.

-Lipid soluble drugs

-Ionized/polar drugs only with a transport molecule

Ionized or Polar drugs cannot fit in the tight fenestrations of the blood barrier, nor are they lipid soluble enough to diffuse across the capillary wall.

None - the placenta presents no barrier to drugs.

Almost all active drugs that can cross the GI barrier and/or blood-brain barrier, can also cross the placenta barrier.

1. Charged drugs

2. Protein drugs (insulin, cytokines, etc)

We can treat the fetus by treating the mother. What 3 treatments are given to the mother to treat the fetus?

1. Supplemental Oxygen

2. Antibiotics

3. Steroids for fetal lung maturation

Teratogens (drugs that cause birth defects)

Opiods or other respiratory depressants

Ask if it is the right thing to do; be sure it does not harm the fetus.

This is difficult for a healthcare provider and pregnant women to do.

Nursing Implications

What should a nurse always ask a women patient before administering medications?

Ask the women if they are pregnant before giving them a drug OR an Xray

* Sometimes the woman does not realize she is pregnant

Less evidence to support its safety or harmful effects to the fetus.

* Use judgment *

Elimination: Removal of drugs from the body

2 Parts: Metabolism & Excretion

Enzymes in the liver perform chemical reactions on drug molecules

Each enzyme performs a different chemical reaction on the drug.

Cytochrome P450 Enzymes

or

Microsomal Enzymes

1. Hydroxyl Group (OH)

2. Acetate (C2H3O2)

3. Glucuronide (attached to many drug molecules)

The effects of metabolism cause .....

(4 causes of metabolism on a drug)

1. Inactivation

2. Increased effectiveness

3. Activation of a prodrug

4. Increased drug toxicity

1. Infants

2. People with liver disease

*Drugs with primarily hepatic (liver) metabolism must be administered to these individuals with caution and their dose may need to be decreased

* Draw blood to examine liver enzymes (inreased liver enzymes in the blood indicate dying liver cells, but do not reflect the number of live functioning liver cells) - not a good test

* Decreases in plasma proteins in the blood means decreased liver functioning (because plasma proteins are synsthesized in teh liver)

* Albumin and Coagulation factors (not good indicators)

AST

ALT

GGT

Decrease of plasma proteins in the blood is a good indicator of decreased liver function.

Why?

Because most plasma proteins are synthesized in the liver. If the liver is not functioning properly, plasma proteins will not be synthesized (made), therefore, there will be less of them in the blood.

Some drugs inhibit certain Cytochrome P450 enzymes. This may cause interference with other drug metabolism.

For example: Drug Y inhibits Cytochrome P450 enzymes. Drug Z needs Cytochrome P450 enzymes for metabolism. If Drug Y & Z are taken together, Drug Z will not metabolize correctly due to the inhibition of Cytochrome P450 enzymes caused by Drug Y. This will increase the blood levels of Drug Z and cause possible toxicity or severe effects to the patient.

If hepatic metabolism is les than optimal, for whatever reasons, the amount of hepatically metabolized drug in the blood stream will be increased, leading to toxicity.

**Dosages should be decreased if there is a problem with hepatic metabolism.

A drug that causes the enzymes in the liver to become more numerous, so that they can metabolize drugs more quickly.

Common inducers are:

Phenobarbital & Carbamazepine (Anti-seizure drugs)

Rifampin (Tuberculosis drug)

Tobacco

Some "herbal supplements" = St. John's Wort

Common inducers are:

Phenobarbital & Carbamazepine (Anti-seizure drugs)

Rifampin (Tuberculosis drug)

Tobacco

Some "herbal supplements" = St. John's Wort

If a cytochrome P450 enzyme that metabolizes a drug is increased because the patient is also taking an inducer, the patient will metabolize the drug more quickly and less of the drug will remain in the blood stream.

Inducer of Cytochrome P450 = Causes quicker metabolism and less of the drug in the bloodstream for drugs taken concurrently with the inducer

1. Protein bound drugs are not filtered

2. Charged drugs are not reabsorbed

3. Only non-ionized forms of weak acids and bases will be reabsorbed

4. Few drugs are actively transported in or out of the tubule

Renal Excretion

Protein bound drugs (are/are not) filtered.

Renal Excretion

Charged drugs (are/are not) reabsorbed.

Renal Excretion

Only the ___________ form of weak acids and bases will be reabsorbed

Renal Excretion

A few drugs are actively transported in or out of the __________.

1. Blood urea nitrogen (BUN) - not a good indicator

2. Elevated Creatinine levels - may indicate impaired renal function

3. Creatinine clearance - good indicator of renal function (GFR) but its inconvenient to measure.

Creatine Clearance (mL/mIN) =

(140-age) X (body weight (kg)) /

72 X serum Cr (mg/dL)

(* .85 in women ONLY)

Men: 85-125 mL/min

Women: 75-115 mL/min

1. Biliary Excretion

2. Breast Milk

Step 1: Bile ducts empty into the duodenum

Step 2: Drug is excreted back into the intestine

Step 3: Reabsorbed

Step 4: Re-enters the blood stream (enterohepatic circulation) - prolongs drug activity

There are therapeutic and toxic ranges for plasma levels for most drugs.

Minimum effective concentration: Minimum plasma concentration taht will produce an effect (comparable to threshold in dose-curve response)

Toxic Concentration: Maximum concentration where adverse effects are due to too much drug

The half life of a drug is the time needed to eliminate 50% of the total amount of drug in the body.

* Measured by plasma levels

* In 1 half-life, the plasma level will decrease by half

Rule of Thumb for Drug Half-Lifes

A given drug will be completely eliminated from the body in ____ half lives.

Alcohol

No matter how much is present, it will eliminate itself from the body at a constant rate. High levels can take a long time to eliminate from the body.

1. Heredity

2. Renal Disease

3. Hepatic Disease

4. Concurrent therapy with a drug that inhibits an enzyme involved in metabolism

5. Concurrent therapy with a drug that induces an enzyme

Factors Influencing Drug Elimination in Patients

How does Heredity influence drug elimination in patients?

Factors Influencing Drug Elimination in Patients

How does Renal Disease influence drug elimination in patients?

Factors Influencing Drug Elimination in Patients

How does Hepatic Disease influence drug elimination in patients?

Factors Influencing Drug Elimination in Patients

How does Concurrent therapy with a drug that inhibits a particular enzyme influence drug elimination in patients?

1. Renal Disease

2. Hepatic Disease

3. Concurrent therapy with a drug that inhibits enzymes needed to metabolize the drug

4. Sometimes heredity

Factors Influencing Drug Elimination in Patients

How does Concurrent therapy with a drug that induces a particular enzyme influence drug elimination in patients?

For patients whom a given drug's half-life may be prolonged, we would adjust the dose downward to avoid giving a toxic amount of the drug.

**We would have to monitor the effects of therapy and drug levels**

For patients whom a given drug's half-life may be shortened, we would adjust the dose upward to make sure the therapeutic level was achieved.

**We would have to monitor the effects of therapy and drug levels**

Acetaminophen, a drug metabolized by the liver, is administered to a patient with liver failure. Which of the following is true?

A. The half-life may be shortened in this patient.

B. Drug levels will be decreased in this patient.

C. The patient will metabolize the drug more quickly

D. The patient is more likely to experience a toxic effect of acetaminophen.

Repeated Dosing

With repeated dosing, every time a dose is given, the blood level _________.

Repeated Dosing

During dosing intervals, the drug is eliminated acccording to its ___________.

Repeated Dosing

At the beginning of dosing, drug levels are _____ and the drug is eliminated ______.

Repeated Dosing

As more doses are taken, the peak drug levels (increase/decrease), and the drug is eliminated more (slowly/quickly) because the rate of elimination depends on the amount of drug present.

Repeated Dosing

At some point, the amount eliminated in the dosing interval will equal ________. 

Repeated Dosing

At some point, the amount eliminated in the dosing interval will equal the dose. At that point, there will be ______ and _____ before and after each dose, but the mean drug concentration will remain ______ as long as dosing continues. This is called steady state or plateau.

Repeated Dosing

Steady State or Plateau

Repeated Dosing

The average (mean) drug concentration at a steady state depends on the ________ and the _______. However, it will take _____ half-lives to reach steady state no matter the dose or dosing interval.

If peaks and troughs are too high or too low, the dose and dosing interval can be ______________.

Why?

If peaks and troughs are too high or too low, the dose and dosing interval can be proportionally reduced.

Why?

This produces more freaquent peaks and troughs because the dosing interval is smaller, but the peaks and troughs will be smaller because the dose is smaller.

Example on Slide 88

4-5 Half Lives

If we want to reach the therapeutic range more quickly, we can give a loading dose, a large dose given at the start of therapy.

* Loading is followed by intermittent dosing as usual

* It still takes 4-5 half-lives to reach steady state, but the drug will be in the therapeuti range for all that time.

Large dose given at the start of therapy to reach therapeutic range more quickly

* The loading dose is followed by intermittent dosing as usual

* Still takes 4-5 half-lives to reach steady state, but the drug will be in therapeutic range for all that time.

The inactive molecule, drug A, is given IV and immediately metabolized to an active molecule, Drug B. Which of the following is true?

A. The half-life of drug A is long

B. The half-life of drug B is short

C. The duration of effect depends on the half-life of Drug B

D. The half-lives of Drugs A and B are the same in everyone.