Pharmacokinetics and Interactions 3.2

What does pharmacokinetics examine?

How drugs move through the body

What are the basic components of pharmacokinetics?

ADME

absorption, distribution, metabolism, excretion

Absorption refers to

How a drug enters the body

Distribution refers to

How a drug travels to its target tissue

Metabolism refers to

How the body converts a drug to a form that can be used or eliminated

Excretion refers to

How a drug leaves the body

What does absorption dictate?

The routes and why they can't be interchanged

The peak action is

The point at which its concentration in the body is at its highest, leading to the maximum therapeutic effect

Onset of action is very closely linked to

Absorption, the faster the absorption, the faster the onset

Which is the fastest route of administration for absorption?

IV, then IM (because the muscle has many more blood vessels than subq tissue), Subq, PO, skin

Why is IV the fastest?

Straight into the bloodstream

Makes it also the most dangerous

Why are mediations usually given away from meals?

So it doesn't affect absorption

What does absorption involved?

How the drug enters the body and makes its way into the bloodstream, how it makes its way across cells, membranes, or moves through body fluids

What are the most common sites of absorption?

Lining of the stomach and small intestine but other membranes such as pulmonary, vaginal, rectal or mucous membranes offer potential locations of absorption as well as

What is a drug's onset of action?

Amount of time it takes for a drug effect to start

The faster the rate of absorption, the

Faster the onset of action

What is a key property that influences absorption?

A drug's bioavailability which is the portion of the drug that is actually available to produce a systemic effect

What are bioavailability and thus absorption influenced by?

For oral meds how quickly a drug dissolves (the faster it dissolves the faster it can be absorbed)

Since a majority of oral meds are absorbed in the small intestine, what's in the GI tract and how well the GI tract is functioning

The oral route usually has a slower onset of action followed by

Drugs absorbed through the skin

Why do the inhalation, sublingual and rectal routes have rapid onset?

Because they take advantage of the rich supply of capillaries close to the surface, which facilitates entry into the bloodstream faster

Many drugs are specifically formulated to shorten or lengthen absorption rates which explains

Why some drugs are formulated to delay their dissolving such as enteric coated medications or those that delay absorption to extend their action

Are all drugs able to pass barriers?

No, placenta and blood brain barrier are meant to be protective

Can alcohol pass through the placenta?

Yes

Why are eye drops the route for any eye disorders?

The eyes are a sequestered organ

What does distribution include?

Blood flow so ischemia affects distribution (patient is going into shock and vasoconstriction so an IM might not be the best option since the blood is being shunted)

What does protein binding have to do with distribution?

Many drugs bound to proteins in order to move around the blood

The percentage of the drug bound to the protein

Becomes inactive

An example of protein binding is warfarin:

Warfarin is 99% protein bound, so the standard dose (99% of it) binds to a protein and has no action, the 1% is the swimmer that can go out and have an effect on target tissues and receptors

If someone has a low albumin level, this means less plasma proteins to bind to, so

More swimmers and the more likely it is to be toxic

Once a drug is absorbed and makes its way into the bloodstream, distribution

Is how a drug moves through the body to reach its target action

Why do conditions that impair blood flow impair distribution?

Because blood circulation is primarily responsible for distribution

A shock will _____ distribution

Delay

Patients in shock experience peripheral vasoconstriction, making medications given IM

Difficult to distribute

What are the barriers?

Blood brain and placenta, they don't stop all substances which is why drugs used to treat CNS disorders must be able to cross the blood brain barrier

Normal dosages of highly protein bound drugs are based on

Normal protein levels and the degree of binding (have to be careful with people with low albumin levels)

Key player in metabolism is

Liver

Why do the elderly need dose adjustments?

Blood flow through the liver reduces as you age and the liver isn't as good at metabolizing

What is the site of drug metabolism?

Liver

Disorders that affect the _______ can and do affect drug metabolism

Liver

Metabolism is

How a drug is broken down to a form that can be easily removed from the body (called biotransformation)

The primary metabolic pathway in the liver is the

Hepatic cytochrome P450 enzyme system

What do the enzymes in the hepatic cytochrome P450 system do?

Inactivate drugs and enhance their excretion

What do the hepatic P450 system enzymes do to the drugs?

Metabolize them as conjugates and conjugates are the ones that leave the liver and have their effects on tissues

What does metabolised mean?

It is changed

What is the process of pharmacokinetics?

Administered, dissolved, goes to the liver, is metabolised, then target tissue, then kidney to be eliminated

What do inducers and inhibitors do?

Alter the rate of metabolism

What does the inducer do

Pushes the drug out the liver faster so the amount for the target tissue is decrease

What does the inhibitor do?

Keeps it in the body longer because the inhibitor holds it in the liver more

What is an inhibitor of the CYP450 system?

Grapefruit

What is the first pass effect?

Almost exclusively reserved for oral medications, the oral drugs are absorbed via the stomach or small intestine and immediately go through the hepatic portal vein which takes it straight to the liver, then they are metabolized and the conjugates leave the liver weaker or less active than originally before going into systemic circulation and going to the target tissue, then it will pass through the liver again later

What is the non-oral route pathway?

Enter systemic circulation (however they were absorbed), distribute throughout the body, only later pass through the liver for metabolism during normal circulation

What are metabolized drugs called?

Conjugates

How do drug conjugates leave the liver?

More water soluble which enables the kidneys to readily eliminate them

What does the first pass through the liver increase?

Excretion of the drug

What are the routes that bypass the first pass effect?

Nasal

Inhalation

Ophthalmic

Buccal/sublingual

Rectal/vaginal

What must routes that bypass the first pass effect do?

Delay their passage through the liver

What are all elimination routes?

Kidney, lungs, sweat, mammary glands

How are the lungs a way to eliminate?

Breathalyser, we eliminate alcohol in a gaseous form

What is special about bile as an eliminator?

A portion of that drug is going to get reabsorbed, so it stays in the body longed

Once a drug is metabolized it is available for

Excretion

What is excretion

How a drug leaves the body

Most drugs are eliminated in the

Urine therefore kidney function affects the rate of drug elimination

What are the three mechanisms of drug clearance utilized by the kidneys?

Glomerular filtration

Active or passive movement into tubule

Renal failure diminishes excretion

What is glomerular filtration?

Drugs can be filtered through the glomerulus and get directly excreted in urine

What is active or passive movement into tubule?

They may actively or passively move from the blood to the renal tubule

Why does renal failure diminish excretion?

Because they will be less able to excrete medications and the drugs will remain in circulation for extended periods of time, therefore dosages are reduced for patients with renal failure

What are other organs of excretion

Respiratory, glands, bile

If a drug is converted to a gaseous form it can be eliminated by the

Lungs

Drugs are eliminated using glands such as

Sweat or mammary glands in breast milk

Where is bile created and stored

Lover, galbladder

When bile is released into the small intestines, a portion of it gets

Reabsorbed therefore drugs that use bile as a mechanism of elimination tend to recirculate many times which prolongs their action

What is the plasma half life?

Amount of time it takes for plasma levels of a drug to be reduced by half

What is plasma half life a measure of?

A drug's duration of action

What does plasma half life explain?

Why it takes time for some drugs to reach an effective level

The longer the half life, the longer it would take to

Reach the steady state

What is the half life of warfarin

72 hours

What is warfarin

Anticoagulant

What is a steady state required for?

Not all medications, but yes for the ones you take every day

What is a loading dose?

Bigger initial dose and then maintenance doses

What are loading doses usually given for?

Anticonvulsants because you can't wait for the medicine to have several doses if they are seizing

What is half life closely associated to?

How frequently a drug is administered

Shorter half-life of drug

The shorter the time it takes to excrete it so the more frequently it can be administered

What is steady state?

When the amount of a drug taken equals the amount excreted

What is a drug's therapeutic range?

Drugs must achieve a certain level in the blood to exert their effect

Do all drugs have to stay in the therapeutic range to exert their effectiveness?

No, but some do, others like PRN reach their therapeutic level do their job and then leave

What is it called when there is an initial larger dose to achieve a therapeutic level faster?

Loading dose

How is the therapeutic level maintained with a loading dose?

With smaller doses given at regular intervals called maintenance dises

What is a drug interaction?

Any modification of action of one drug by another drug or substance

Are drug interactions beneficial?

Some are but most of the time we are concerned about the harmful effects of drug interactions

What are the three different drug interactions?

Indifferent

Additive

Synergistic/potentiate

What is an indifferent interaction?

Two drugs that have no effect on each other, neither good or bad

What is the sign for indifferent interaction?

1+1=0

Most drugs are _____ to each other

Indifferent

What is an additive interaction?

When the sum of two drugs equals the expected combined response of two drugs (like taking aspirin and acetaminophen together for better pain relief)

Can an additive interaction be harmful?

Yes if the side effects are additive as well

What is the sign for additive?

1+1=2

What are synergistic/potentiate interactions?

Two terms often used interchangeably because they both refer to a greater than expected net affect when two drugs are taken tigether

What is synergistic

Greater effect produced by two drugs taken together from the same or similar drug classes such as when two antibiotics are given concurrently to achieve greater antimicrobial action

What is the sign for synergism?

1+1=3

What does potentiate refer to?

Two drugs from different classes used together to produce a greater therapeutic effect