Exam 1: slide deck 6

Define pharmacokinetics

What the body does to a drug 

• Absorption 

• Distribution 

• Metabolism

• Elimination

Internal routes

through GI tract

• Oral, sublingual, buccal, rectal

Parenteral routes

through non-GI tract 

• Inhalation, injection, IV, IA, IM, SC, Intrathecal, Topical, Transdermal

oral advantages and disadvantages

• Advantages: 

1. Easiest, most convenient, self-administered 

2. Drug is absorbed in gradual, controlled manner 

• Disadvantages: “First Pass Metabolism” 

1. Relatively slow (30-60min) 

2. Acidity of stomach can break down drug

3. Rate and extent of absorption is unpredictable 

4. May irritate stomach or lining of intestines 

5. Necessitates patient compliance

oral preparations for enteric-coated

chemical envelope that resists acidic fluids/ enzymes of stomach, but dissolves in basic fluids/ enzymes of small intestines

oral preparations for extended- release

specials coatings controlling release of drug from pill into body

extends duration of action of drug → continuous release of drug as capsule dissolve

First-pass metabolism → drugs absorbed from stomach and small intestines go into

portal veins then into liver

bioavailability

percentage of drug administered that reaches the systemic circulation unchanged

sublingual and buccal advantages/ disadvantages

BYPASSES FPM

• Advantages: 

1. rapid absorption into systemic circulation 

2. Useful for emergencies 

• Disadvantages:

1. Only small amounts of drugs can be administered 

2. May irritate oral mucosa

rectal advantages and disadvantages

“suppositories”

Advantages: 

1. used is patient is unconscious, vomiting, or can’t swallow 

2. Treats local conditions well 

3. Largely bypass GI environment and FPM 

• Disadvantages:

1. erratic or incomplete absorption

2. may cause irritation of rectum

3. subjected to some FPE (about 50%)

4. noncompliance

Inhalation advantages and disadvantages

Advantages: 

1. good for local treatment of respiratory tract 

2. Large SA for absorption 

3. Rapid entry into bloodstream via pulmonary circulation

Disadvantages:

1. Inhale correctly 

2. May irritate respiratory structures 

3. Some drugs may get trapped by cilia and mucus and nerve reaches circulation

Injection

Disadvantages for all

• sterility must be maintained

• more difficult to administer

• potentially uncomfortable for patient

IV advantages and disadvantages

advantages:

• 100% bioavailability

Disadvantages

• adverse reactions are more common with bolus delivery

  • steady infusion/drips are often preferable

IA (intra-arterial) advantages and disadvantages

advantages

• large dose can reach arterial site rapidly

• drug can be administered directly to arterial target site

Disadvantages

• difficult and dangerous

IM (intramuscular) advantages and disadvantages

generally in delts or glutes

advantages:

• easily accessible

• treat local problem in muscle

• relatively rapid effect, while avoiding sudden bolus increase seen with IV

Disadvantages

• local pain and discomfort'; prolonged soreness

• absorption affected by blood flow and muscle mass

• risk of nerve or vessel injury

SC (Subcutaneous)

advantages

• slower, more prolonged absorption and effects compared to IM

• can also be used when highly localized response is desired

• relatively easy route of self-admin

Disadvantages

• only small volumes of drug can be injected

• may irritate subcutaneous tissue

• risk of lipodystrophy over time

• need to rotate ejection site

Intrathecal advantages and disadvantages

Injected within a sheath (typically subarachnoid space)

advantages:

• treat local conditions

• drug can be applied directly to an area

• In SA space, allows drugs reach CNS directly

disadvantages

• pain and discomfort, risk of infection

• high risk of error/damage to spinal cord

Transdermal characteristics

applying to skin, with expectations that drug WILL be absorbed (patches )

must have 2 properties

1. be able to penetrate skin (lipid-soluble)

2. must avoid degradation by metabolizing enzymes in dermis

Transdermal advantages and disadvantages

advantages: long-term prolonged release

• easy, non-invasive

• slow, sustained release that maintains plasma levels for prolonged period

disadvantages

• slow onset (hours at least)

• allergies and irritation

Topical characteristics

“local condition”

applied to surface of skin or mucous membranes, with expectation that drug will NOT BE ABSORBED

Topical advantages and disadvantages

advantages:

• most often used to treat local conditions on skin or membranes

• fast and effective

• easy to administer

Disadvantages

• potential for adverse effects if large amounts absorbed into circulation through mucous membranes

Iontophoresis is

aid drug through skin by using electrical current to assist movement of charged drugs across the skin

about 15-30min sessions

Phonophoresis is

has no systematic effects and uses therapeutic ultrasound waves to enhance drug absorption across skin

about 5-10min sessions

Define drug absorption.

Movement of drug from the site of administration into bloodstream

Define bioavailability

Percentage of drug administered that reaches the systemic circulation unchanged 

Predict how exercise and physical rehabilitation may affect the absorption of drugs, based on its route of administration.

Increases distribution into muscle, skin, fat 

Describe the chemical structure of a drug that can easily pass through a biological cell membrane.

small, uncharged, relatively lipid soluble

Describe the most common method of membrane transport for drugs to move through a biological membrane.

Simple diffusion

What are the factors that affect rate of diffusion?

Magnitude of concentration gradient

SA of membrane

lipid solubility of substances

molecular size/weight of diffusing sub.

temperature

How does magnitude of concentration gradient affect rate of diffusion

higher doses diffuses more rapidly

How does SA of membrane affect rate of diffusion

allow for most absorption

how dose lipid solubility of substance affect rate of diffusion

drugs that are uncharged and more lipid soluble will diffuse into tissues more rapidly

How does molecular size/weight of diffusing sub. affect rate of diffusion

larger drugs diffuse more slowly

How does temperature affect rate of diffusion

increase temperature increases rate of diffusion

what are factors influences absorption

route of administration

chemical properties

pH of environment

blood flow of site absorption

contact time at absorption surface

how does pH at the site of absorption affect the rate and extent of drug absorption

depends on initial charge

• acidic drugs uncharged in acidic environment better

• basic drugs in uncharged basic environment better

how does Blood flow site of administration affect the rate and extent of drug

more blood flow to a tissue, more absorption

how does contact time at site of absorption affect rate and extent of drug

presence of food in stomach dilutes drug and slow gastric emptying → drug taken with a meal is absorbed more slowly and more fully but may have a delayed onset of action

diarrhea… less contact time, less drug absorbed

Define drug distribution.

Movement of drug around the body, into and out of circulation, into and out of tissues and fluid compartments

How does blood flow to organs of a drug will affect distribution

organs that receive the most blood flow will typically receive the most drug

high: brain, heart/lungs, liver, kidneys (get most at rest)

low: muscle, skin, fat → with exercise increases in these areas

How does interactions with plasma proteins of a drug will affect distribution

only free/unbound drug can distribute into tissues

• plasma proteins → albumin acts as reservoir in blood and traps drugs in circulation

• tissue proteins/lipids/nucleic acids → some drugs get trapped in tissue leading to accumulation and slower elimination

how does lipid solubility of a drug affect its distribution

unionized, lipid-soluble drugs will diffuse out of plasma into most tissues

• water-soluble drugs tend to remain in plasma or accumulate in ISF

Identify the major site of drug storage/sequestration in the body, especially for lipid soluble drugs

adipose tissue → low blood flow/metabolic rate

• ex: benzodiazepines, inhalation anesthetics (CNS)

What are other sites of drug storage/sequestration in the body

bone: toxic agents such as heavy metals

muscle: drugs or metabolites may from reversible bonds to structures within muscle fibers, leading to accumulation/damage

• statins → low cholesterol, might cause muscle soreness

liver and kidneys: damage

Describe why drug storage can have adverse consequences. 

Drug storage may also lead to drug redistribution → prolong drug effects 

• High accumulation can lead to local damage 

  • Acetaminophen → toxic metabolite can damage hepatocytes 

Define the elements and goals of drug elimination. 

elements: metabolism + excretion

goal: terminate drug effect, detoxify the body, and get the “poison” out of the body

Define metabolism of a drug

chemical changes that take place to drug following administration

• much faster than exertion

• is enzyme-dependent

• results in metabolite = staying in the body for a long time

Define the term prodrug. 

Drug that is administered inactive, then activated by metabolism 

Identify the major organs responsible for drug metabolism. 

LIVER!!! , GI, Lungs, Kidneys, Skin 

largely carried out by Cytochrome P450 family → enzyme that metabolizes drugs

Describe the pathway for drug metabolism, including Phase I and Phase II reactions. 

Pathway:

Parent drug Phase I (catabolic) Oxidation/Hydrolysis

→ Polar metabolite

Phase II (Anabolic)Glucuronidation/Conjugation

→ conjug

What are the steps of drug metabolism

Step 1: hepatic localization → drug bio-transforms in the liver 

Step 2: Phase I reaction → introduces or uncovers polar functional group –OH or –NH2 

Uses oxidation carried out by CYP450 

Converts parent drug into polar metabolite 

Step 3: Phase II reaction → covalently attached endogenous molecule to drug or phase I   metabolite 

Uses glucuronidation as the conjugation reaction 

Yields a significantly larger, inactive, highly ionized and extremely water-soluble conjugate 

Step 4: Erection → kidneys (urine) or bile (feces) 

What is the Phase I reaction in drug metabolism

introduces or uncovers polar functional group –OH or –NH2 

• Uses oxidation carried out by CYP450 

• Converts parent drug into polar metabolite

• catabolic reaction

What is the Phase II reaction in drug metabolism

covalently attached endogenous molecule to drug or phase I metabolite 

• Uses glucuronidation as the conjugation reaction 

• Yields a significantly larger, inactive, highly ionized and extremely water-soluble conjugate

• anabolic reaction

Identify the most common type of Phase I chemical reaction. 

oxidative reaction

Identify the enzyme family that carries out the majority of Phase I metabolic reactions. 

CYP450

Identify the isoform of CYP450 which metabolizes the most drugs. 

CYP3A4

CYP450 inducers

 increase expression and availability of specific CYP450 isoenzymes in the body 

• Effect → accelerate rate of biotransformation/metabolism of target drugs 

• Decrease the plasma half-life of co-administered drugs

CYP450 inhibitors

directly block the functional activity of CYP450 enzymes 

• Effect → impair, slow down, prevent the metabolic breakdown of target drugs 

• Increase the plasma half-life of co-administered drugs 

drug-drug interaction of co-administration with/CYP450 inducer

• Effect → inducer causes liver to metabolize the co-administered dug much faster the normal 

• Clinical outcome → decreased plasma concentration of co-administered drug, leading to reduced therapeutic efficacy or complete treatment failure 

• Secondary risk → can increase the presence of reactive or toxic metabolites 

drug-drug interaction of co-administration with/CYP450 inhibitor

• Effect → inhibition prevents the liver from clearing the co-administered drug 

  • Clinical outcome → increased plasma concentration of the co-administered drug and as it accumulates leads to exaggerated drug effect causing high risk of adverse reaction or drug toxicity

Tolerance

need for increased drug dosage to produce same therapeutic effect

Pharmacokinetic tolerance

prolonged use of drug “induces” expression of CYP enzyme/induces faster drug metabolism

phase II metabolites are larger, even less active, more likely to ionized, more water-soluble =

more likely to be excreted

Identify the most common type of Phase II reaction. 

Glucuronide formation

Define drug excretion. 

removal of either an active drug or drug metabolite from body

Identify the organs most commonly involved in drug excretion. 

kidneys!

Describe how glomerular filtration rate (and kidney excretion) changes with age or disease.

Age: declines b/c function decreases or immature kidney function in peds

Disease: DM, HTN, CKD directly cause GFR decline or structural/functional organ damage/reduced renal blood flow

Half-life of a drug

amount of time required to reduce drug concentration by Half

• 4-5 half-lives are necessary to reduce drug concentration by 95-97% (effectively eliminated from the body)

How can increase in distribution of drug affect drugs half-life, duration of action, rate of dosing

increase half-life

increase action

decrease in rate dosing

How can decrease in distribution of drug affect drugs half-life, duration of action, rate of dosing

decrease in half-life

decrease in action

increase in rate dosing

how can increase clearance of drug affect drugs half-life, duration of action, rate of dosing

decrease in half-life

decrease in action

increase in rate dosing

how can decrease clearance of drug affect drugs half-life, duration of action, rate of dosing

increases half-life

increase action

decrease rate dosing

what clinical situation would a half-life increase

decrease hepatic or renal blood flow

decreased organ function

decreased metabolism of drug

what clinical situation would a half-life decrease

increased hepatic or renal blood flow

increased metabolism of drug

What are the primary factors that cause variation in drug response an PK

genetics

disease

drug interactions

age

diet

sex

Genetics

mutations resulting in abnormal/absent proteins

genetic polymorphisms ( subtly affect protein function)

PD/PK affected

Pharmacogenomics!

Disease

structural or functional damage to liver

Drug-drug interaction variations

majority of DDI are significant

however act

• synergistically to produce beneficial effect

• additively in producing adverse effects

• cancel each other out

• alter metabolism of another drug

• alter absorption or distribution of another drug

drug interaction and age cause

older patient more sensitive

• higher plasma levels = not metabolized or excreted as readily

• increased body fat, decreased cv function

children also very sensitive

• immature liver and kidney function

• differences in membrane function, plasma proteins, regional blood flow, body comp.

variation of drugs with diet

can affect absorption, metabolism, response
most drugs are FDI insignificant

• grapefruit juice and CYP450

• Tyramine and catecholamines

variation of drugs with sex

distinct difference in absorption, distribution, biotransformation

sex-related differences in body comp., GI function, enzyme activity

hormonal difference influence PD, PK

Given a drug’s half-life, calculate how long that drug will remain in the body before it is effectively cleared. 

Ex: drug half-life is 2hrs 

4 to 5 x T1/2 

4x 2= 8

5x2=10 

8 to 10 hours

Describe how changes in blood flow would affect the half-life of a drug.

1. Increased hepatic or renal blood flow accelerated clearance → decreases half-life 

2. Decreased blood flow reduced clearance → increased half-life

Describe how changes in organ function would affect the half-life of a drug.

Structural or function organ impairment decrease clearance → increases half-life 

Describe how changes in the presence of CYP450 inhibitors would affect the half-life of a drug.

Increase CYP450 accelerating biotransformation/clearance → decreases half-life 

Describe how changes in the presence of CYP450 inhibitors would affect the half-life of a drug.

Block CYP450 slowing metabolic breakdown and clearance → increases half-life 

Pharmacogenetics/Pharmacogenomics

Examining how individual genetic mutation and polymorphism affect protein function to alter PK and PD 

Predict how disease and/or age will affect pharmacokinetic principles of absorption

1. Disease: can decrease contact time at the mucosal surface, resulting in reduced drug absorption  

2. Age: 

   1. older → alterations in GI motility, mucosal blood flow, digestive environment changes/rates 

   2. Younger → membrane permeability, regional blood flow, body comp.

Predict how disease and/or age will affect pharmacokinetic principles of distribution

1. Disease:

   1. Cirrhosis:  impairs plasma protein (albumin) synthesis, reduces drug binding in blood and raises fraction of free active drug. 

   2. Heart failure: reduces cardiac output and perfusion, slow distribution to tissues 

2. Age 

   1. Older: increased % body fat, deceased TBW, lower CV perfusion

   2. Infants: higher TBW % and distinct plasma protein binding levels

Predict how disease and/or age will affect pharmacokinetic principles of metabolism

1. Disease 

   1. Liver damage: reduces SER/CYP450 capacity in drug metabolizing system, impairing biotransformation and raising plasma drug levels 

2. Age 

   1. older/younger: display reduced or immature liver enzyme function and decreased hepatic blood flow, slowing metabolism and elevating drug concentrations

Predict how disease and/or age will affect pharmacokinetic principles of excretion.

Disease

• Kidney disease: reduce GFR and renal blood flow, slowing drug elimination and prolonging half-life 

Age: both pop. show reduced renal clearance, prolonged drug half-lives, increased drug sensitivity  

1. Older: undergo a natural age-related decline 

2. Infants: immature renal filtration mechanisms

Drug drug Interaction (DDI)

Occurs when one drug alters the absorption, distribution, or metabolism of another drug, or when multiple drugs interact additively, synergistically, or antagonistically to alter therapeutic efficacy or adverse outcomes

food drug interaction (FDI)

Occurs when food, beverages, or dietary components alter the rate or extent of drug absorption, metabolism, or pharmacological response (such as food slowing gastric emptying or grapefruit juice inhibiting CYP450 enzymes)

Pharmacokinetics is best defined as:
A. The study of how drugs alter physiological functions
B. The study of the movement of drugs through the body
C. The study of drug-receptor interactions
D. The study of genetic variability in drug response

B. The study of the movement of drugs through the body

Which of the following best describes the major processes of pharmacokinetics?
A. Administration, absorption, distribution, metabolism, excretion
B. Diffusion, transport, binding, elimination
C. Receptor activation, protein binding, clearance, degradation
D. Synthesis, secretion, signal transduction, elimination

A. Administration, absorption, distribution, metabolism, excretion

A patient with difficulty swallowing tablets may be prescribed a buccal medication. An advantage of this route is:

A. Rapid onset and bypass of first-pass metabolism
B. Slow absorption and prolonged effect
C. Large volume of drug can be administered
D. Drug delivery directly into systemic circulation via portal vein

A. Rapid onset and bypass of first-pass metabolism

A PT is treating a patient on transdermal nitroglycerin patches. Which is the main disadvantage of this route?

A. Bypasses first-pass metabolism
B. Provides slow and steady drug delivery
C. Can cause local skin irritation and limited absorption for some drugs
D. Allows rapid titration of drug effect

C. Can cause local skin irritation and limited absorption for some drugs

Which parenteral route of administration offers 100% bioavailability immediately after administration?
A. Subcutaneous (SC)
B. Intravenous (IV)
C. Intramuscular (IM)
D. Inhalation

B. Intravenous (IV)

Inhalation as a route of drug administration has the advantage of:
A. Slow onset of action
B. Avoiding systemic absorption
C. Large surface area for absorption and rapid entry into circulation
D. Protection from first-pass metabolism in the lungs

C. Large surface area for absorption and rapid entry into circulation

Drug absorption is best defined as:

A. The removal of drug from the body by kidneys
B. The process by which a drug enters systemic circulation from its site of administration
C. The binding of drug to plasma proteins
D. The conversion of drug to an inactive metabolite

B. The process by which a drug enters systemic circulation from its site of administration