Pharmacokinetics

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Pharmacokinetics

• Andrew Healey, Instructor
• Matthew Miller, Lab Assistant

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Review

• Pharmacokinetics
• The life of a drug in the body
• ?Route of Administration
• Absorption taken into the body
• Distribution moved into tissues
• Metabolized changed so can be excreted
• Excreted removed from the body

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What We Will Cover (Quickly)

• Routes of Administration
• Absorption
• Distribution
• Metabolism
• Excretion
• Onset, Peak, and Duration
• Pages 6 12 in CPMIE

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Routes of Administration

• Enteral
• Uses the gastrointestinal tract for ingestion
• Parenteral
• Avoids or circumvents GI tract
• All forms of injections IM, SQ, IV, etc.
• Inhalation,
• Topical (also parenteral)
• Applied to skin or mucous membranes

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Local vs. Systemic Effects

• Local
• Drug exerts effect at site of administration
• Systemic
• Drug absorbed, distributed throughout the body
  systems
• They are not mutually exclusive
• Think about side effects!!!

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Enteral Routes

• Absorbed from stomach / intestine
• To the liver FIRST PASS EFFECT
• IMPORTANT FACT
• Drugs administered as rectal suppositories
  undergo relatively little first pass effect.
• Then distributed to the rest of the body
• Most drugs are fat-soluble WHY?

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FIRST-PASS EFFECT

• EXTREMELY IMPORTANT!!!
• PRINCIPLE
• Most blood supplying the GI tract travels to the
  liver before it goes to the rest of the body
• THIS IS CALLED A PORTAL SYSTEM.
• Liver metabolic (change) machine
• Often inactivates drugs

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First Pass Effect V/imp!
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Enteral Route A/D

• ADVANTAGES
• Convenient
• Relatively safe
• Economical
• Most common

• DISADVANTAGES
• Absorption can be variable
• Food-drug interactions!!!!
• Absorption variable
• Irritation NV
• First pass effect
• Some drugs inactivated by gut (eg insulin)
• Effect too slow for emerg
• Some have unpleasant taste

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Enteral Route Special Points

• Sublingual (under the tongue)
• Spray or pill
• Rapid absorption of certain drugs
• AVOIDS first-pass drug metabolism in liver
• Unpleasant taste

• Rectal (in anus)
• suppository
• Local (eg. Hemorrhoids)
• Systemic (eg. Abs)
• Useful when NV
• RELATIVELY LITTLE first-pass metabolism
• Irritating, inconvenient

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Parenteral Routes

• Intravenous injection
• Intramuscular injection
• Subcutaneous injection
• Intrathecal injection (eg. epidural)
• Intra-articular injection (eg. for arthritis)
• Inhalation
• Topical

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Parenteral Injections A/D

• ADVANTAGES
• Prompt response
• No first-pass effect
• More accurate dose
• Useful if NV and/or change in LOC

• DISADVANTAGES
• Rapid onset therefore no recall gt adverse effects
  quick too!
• Sterile preparations
• Painful
• Expensive
• Cannot usually self-administer

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Intravenous Route A/D

• ADVANTAGES
• Rapid onset - emerg
• Continuous titration
• Accurate dose
• Larger vol over longer period of time
• Ability to administer irritating substances
  because of dilution in a large volume of fluid

• DISADVANTAGES
• Dangerous rapid onset of pharmacological action
• Overdose no recall / stopping absorption
• Safe doses given too rapidly may be toxic
• Embolism oil!
• Sterile preparations and aseptic techniques
  required

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Special Points IM, SQ

• INTRAMUSCULAR
• Rapid absorption (solutions)
• Slow absorption (suspensions/oil)
• Painful
• Bleeding if on anticoag
• Absorption dependent on blood flow

• SUBCUTANEOUS
• Absorption slower than IM, dependent on flow
• Cant be used with irritants or lg vols
• Less painful

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Topical Administration

• BRIEF
• the patch
• Dose is proportional to the area of the patch
• Distribution depends on blood flow
• Nasal Mucosa (nose)
• Potent drugs for systemic effects
• Absorption irregular
• very useful for local effects vasoconstrictors

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Inhalation A/D

• ADVANTAGES
• Extensive absorbing surface
• Extensive blood supply
• Particles lt 2 um penetrate deep into lungs
• Rapid, local effects

• DISADVANTAGES
• Administration requires GOOD TECHNIQUE and
  special equipment
• Amount reaching alveoli is variable
• Many physiologic variables affect absorption
  cilia, mucus, size of particle
• Possible systemic side effects
• Thrush

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Case Ms. Georgia Govans

• Georgia Govans, 79 years old, is admitted with
  osteomyelitis of the hip, a severe infection,
  after a recent repair of a hip fracture. Temp
  102.4F and hx of severe peripheral vascular
  disease.
• Ms. Govans is admitted under your supervision.
  Your resident comments that he is worried about
  her because she is so severely ill.

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Ms. Georgia Govans

• What key factors/points must we consider in
  choosing the route of administration?
• What drug do we give for bacterial infections?

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Ms. Georgia Govans

• State what route of administration you choose for
  this patient and justify your answer.
• If she had a temperature of 100F and it was a
  throat infection, would your route of
  administration differ? Explain.

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THE LIFE OF A DRUG Drug Absorption

• Pharmacokinetics

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Absorption

• Getting from outside the body to inside the body
• In what routes of administration is this
  skipped??
• All drugs have to cross membranes at either this
  step or at the distribution step!

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How do things get across the membrane?

• Passive Transport (LAZY!)
• Diffusion of lipid soluble substances
• Protein channels
• Facilitated transport
• Active Transport (HARD WORK!)
• Transport against gradients
• Active, co-transport, counter transport

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PASSIVE Diffusion

• Movement from an area of high concentration to
  low concentration

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PASSIVE Protein Channel T

• Protein channels in the membrane allow certain
  drugs to pass through

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PASSIVE Facilitated Transport

• conformational help from a protein
• Binding site exposed
• Rock
• Spit inside cell

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ACTIVE transport

• Molecules move uphill (towards higher
  concentration)
• Rocking the protein using energy!!! ltATP!!!gt

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CO-transport

• One molecule goes downhill
• The other (the one that needs to be transported)
  goes uphill
• Hence CO transport

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COUNTER-transport

• Similar to co-transport
• One moves downhill (in one direction)
• The other moves uphill (in the OTHER direction)

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Taking a bite pinocytosis

• A cell engulfs a drug particle
• Often occurs with Vitamins (A, D, E, K)
• Big fat-soluble molecules!

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Watch speed limit

• Ask yourself how many cells lie between the site
  of administration and the bloodstream more
  layers, slower
• Slower rates in the oral, IM, SQ routes
• Complex membrane systems GI, muscle, skin

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SAMPLE Question

• Which of the following routes of administration
  will result in the quickest absorption?
• Sublingually
• Intravenous injection
• Intramuscular injection
• Rectal suppository

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Other factors affect speed

• Most oral administered drugs absorbed in small
  intestine
• Surface area
• The bigger the basket, the more likely you are to
  score
• The bigger the surface, the more drug gets across

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Other factors affect speed

• Blood Flow
• Especially IM, SQ injections
• EXAMPLE Question
• A nurse calls you to see a patient who is feeling
  unwell and has been vomiting for the past three
  hours. You both agree this patient requires an
  injection of Gravol. The nurse draws up the
  Gravol and asks, Doctor, does it matter where I
  do the injection in the deltoid or the gluteal?
• HOW DO YOU RESPOND?

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Other factors affect speed ANSWER

• In theory, yes, it does matter.
• More blood, more absorption
• Blood flows faster through the deltoid muscle
  than through the gluteal muscle.
• However, gluteal muscle can accommodate a large
  volume of drug.
• In practice, it really doesnt matter.

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Other factors affect speed

• Pain Stress decreased absorption
• Drug-Food Interactions
• Fatty meals slow rate of moving from stomach to
  small intestine
• Delays absorption
• Dosage form
• Drug-Drug interactions

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THE LIFE OF A DRUG Drug Distribution

• Pharmacokinetics

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Drug Distribution

• How drug, once absorbed, gets to tissues and
  fluids of the body
• We must talk about
• Water Compartments in the body
• Volume of Distribution
• Depends on several factors
• Blood flow
• Solubility
• Protein Binding

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Water Compartments

• Total Body H20 Inside cells Outside cells
• Inside cells 28 L
• Outside cells 14 L
• Outside cells Between cells Water in blood
• Water in blood is plasma 4 L
• Between cells 10 L

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Volume of Distribution

• Vol of Distribution (VD) is equal to the dose (mg
  (bits)) divided by the plasma concentration
  (mg/mL (bits in vol))
• VD Dose (mg)
• Plasma concentration (mg/mL)

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Sample Problem

• 500 mg of Newdrug was administered to a 70 kg 25
  year old medical student. The plasma
  concentration, shortly after its administration,
  was 0.01 mg/mL. What is the volume of
  distribution?
• Lets do the calculation!

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Sample Problem

• How do we explain this?
• EITHER
• He is a very large water balloon
• OR
• The drug is hiding somewhere.
• BUT WHERE?????

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Drugs Hidden From Measurement

• Drugs can hide if they
• Dissolve well in fat and are stored there
• Bound to PROTEINS in the blood
• Volume of distribution is a THEORETICAL volume
  not an actual volume.
• Why do we use it?
• Gives us estimate of where drug is in body!

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Drug Distribution depends on blood flow!!

• Blood flow is large to
• Heart
• Liver
• Kidneys
• Brain
• But. Lets think for a minute about this

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This is your brain on drugs

• Brain
• Very special place
• Has a very, very, tight blood-brain barrier
• Guarded by tightly bound cells in the capillary
  walls
• Have to be special to get in
• Small, lipid soluble
• Not bound to protein
• Or actively pumped

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Ive been working on the railroad not just at
the end!

• As drug travels, may encounter
• Site of action can work there
• Plasma protein (albumin)
• Can bind there or remain free
• IF IT IS BOUND, CANNOT EXERT AN EFFECT
• Only free, unbound drug can act

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SAMPLE Question

• A drug, Coumadin (makes people bleed on purpose),
  is highly bound to plasma proteins. Only 0.2 is
  free in the blood.
• Your friend administers a drug that displaces
  0.2 of the bound drug from the protein because
  it too binds there.
• What happens to the concentration of drug in the
  plasma?

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Sample Question ANSWER

• Go from 0.2 free to 0.4 free!
• YOUR FRIEND HAS DOUBLED THE DRUG AVAILABLE TO
  EXERT A THERAPEUTIC EFFECT oops!
• Be aware of drug-drug interactions!

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Drug Distribution - REVIEW

• How drug gets to tissues and fluids of the body
  and what tissues and fluids it gets to!
• We talked about
• Water Compartments in the body
• Volume of Distribution
• Depends on several factors
• Blood flow
• Solubility
• Protein Binding

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THE LIFE OF A DRUG Drug Metabolism

• Pharmacokinetics

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Drug METABOLISM

• Metabolism Biotransformation
• Metabolism Change
• Changes from the form in which it was
  administered to a more WATER-SOLUBLE
  (hydrophilic) form!
• WHY? Cause you can pee it out better!

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Metabolism ENZYMES

• Lets take a simple chemical reaction
• X Y ? A B
• This reaction takes place in 18 days, 12 hours,
  and 14 minutes (to half completion) in a room at
  37 deg C.
• In our body, at 37 deg C, this reaction is
  instantaneous.
• THIS IS WHAT ENZYMES DO!

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Metabolism

• Majority of drugs metabolized by enzymes in the
  liver
• Some kidney, brain, plasma, membranes of
  intestine, lungs
• Some drugs inhibit or compete for enzymes
  gtgtDRUG-DRUG INTERACTIONSltlt
• Some drugs induce or activate enzymes that
  metabolize drugs
• BEWARE OF DRUG-DRUG INTERACTIONS!

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Other things affect Metabolism

• Your book talks about
• Disease conditions (liver disease, heart
  disease)
• Genetics
• Environment (eg. Smoke, stress)
• Age
• Always watch-out for the very young and very old!

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P450 Enzyme System Induction

• Cytochrome (add oxygen) P450
• Found in the liver, GI tract
• In smooth endoplasmic reticulum
• Cyt P450 induction (increase activity)
• Most common way increase production of enzyme
• Eg. Phenobarbital

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P450 Enzyme System Induction

• Eg. Alcoholic who is taking acetaminophen and it
  isnt working?
• Alcohol induces CYP2E1
• Acetaminophen is metabolized by CYP2E1
• Therefore serum concentration is lower!

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P450 Enzyme System Inhibition

• P450 3A4 present in GI tract
• Responsible for 1st pass metab of some drugs
• GRAPEFRUIT JUICE inhibits P450 3A4
• Cyclosporins, statins metabolized by this enzyme
• Levels in serum are ELEVATED!

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Drug METABOLISM Review

• Metabolism change biotransformation
• Several possible outcomes activate, inactivate,
  maintain activity
• Most common inactivate, make more polar
• Goal deal with toxins (/drugs), prepare for
  excretion

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THE LIFE OF A DRUG Drug Excretion

• Pharmacokinetics

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Drug EXCRETION

• Concepts
• Where are drugs gotten rid of?
• Clearance
• Half-life
• Has implications for drug dose
• If it is cleared by an organ, when to give?
• How much?
• What if liver or kidney or lung disease? Etc.
  Etc.

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Clearance

• Describes the efficiency of irreversible
  elimination of a drug from the body.
• Elimination means to leave the body or to convert
  to an inactive form.

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Clearance

• Volume of blood cleared of drug per unit time
• Liters per hour
• Milliliters per minute
• Can be specific (organ, process) or whole body
• Total body clearance is sum total of all the
  different clearances

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Clearance

• Another definition
• Elimination rate clearance x Pl drug conc
• (mg/hour) (L/hour) (mg/L)
• But who really cares?
• WE DO! Because
• Elimination rate maintenance dose rate

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Clearance

• Maintenance dose CL Css
• (mg/hour) (L/h) (mg/L)
• Css Steady state concentration of drug
• Every drug has a therapeutic range
• You wanna be in it!
• You use maintenance dosing to do that!

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LungsCount backwards from 100

• 100 99 98. Zzzzzzz..
• Anesthetic gases
• Remember clearance can be applied to any organ!

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Liver

• Biotransformation
• Main Function make things more soluble in water
• WHY?? To make them easier to pee!
• Remember Kidney can only excrete water soluble
  substance!

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Kidney

• Where blood is filtered and pee is made
• Why is the liver so important?
• Only water soluble substances
• Most drugs excreted have been changed
• More polar, more easily pee-d out
• Kidney also site of biotransformation!
• Some drugs 100 kidney elimination!

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Get out of my way! I have been flexing my urethra
for an hour!

• The urinary tract is one of the many organ
  systems involved in HOMEOTHERMY in mammals.

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Kidney
Diaphragm
Kidneys
Ureters
Urinary bladder
Urethra
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Half-life

• The amount of time required to rid the body of
  half of the initial concentration of the drug
• t1/2 0.693VD
• CL
• What happens if VD goes up?
• What happens if CL goes up?

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Half-life What it looks like!
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Half-life

• 5 HALF-LIFE RULE! V/IMP!
• Takes 5 half lives to reach Css!
• Takes 5 half lives to rid body of drug!!
• Half-life is a combination of volume of
  distribution and clearance!

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Who cares about half-life?

• Duration of action after a single dose
• Time required to reach steady state
• Dosing frequency required to avoid large
  fluctuations

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Clearance again!
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The marathon is almost over

• Just a couple of more minutes

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Onset, Peak, Duration

• Onset
• The time interval from administration to
  therapeutic effect
• Peak
• Reached when absorption rate elimination rate
• Not always time of peak response
• Duration
• Length of time drug produces therapeutic effect

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Dosing Schedules
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Dosing Schedules
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PHARMACOKINETICS

• The life of a drug in the body
• Route of Administration
• Absorption taken into the body
• Distribution moved into tissues
• Metabolized changed so can be excreted
• Excreted removed from the body

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CONGRATULATIONS!!!

• Youve made it through a marathon lecture on
  pharmacokinetics. You will have most of the
  evening to digest this material. Study it
  carefully and call on us to ask questions. This
  is not difficult material but there is a lot of
  information here please dont hesitate to ask
  for help.