Pharmacokinetics: ◦ How drugs are handled by the body

◦ Overview followed by details!!

Lets say you have a really bad headache or an infection of some kind that needs antibiotics and you have to take some meds –

This illustrates the basic processes in the branch of pharmacokinetics

1. the route of administration - how a drug is taken into the body

2. absorption and distribution - factors affecting its absorption and how it gets

distributed to the brain

3. metabolism (detoxification or breakdown)how a drug is broken down or made into inactive

forms

4. excretion – (elimination)◦ how the drug is eliminated

Knowing about pharmacokinetics tells us critical information about insight into the actions of a drug.

Ex. benzodiazepenesultra short acting, short acting, long acting

lorazepam (Ativan) and triazolam (Halcion) – pharmacokinetics

lorazepam – persists for at least 24 hr triazolam – 6 – 8 hours midazolam – 1 – 2 hrs

Oral Parenteral Buccal Inhalation Rectal Nasal

most common, sometimes referred to as po safe, self administered, economical BUT

blood levels are often irregular (most complicated route of adm)

liquid more readily absorbed than solids

soluble and stable in stomach (not destroyed by stomach enzymes more acidic)

enter intestine; penetrate lining of intestine, pass into bloodstream and reach site of action; intestine is more basic

absorption favored if the drug is nonionized and more lipophilic

◦chemicals in stomach must deal with:◦stomach acids◦digestive enzymes◦first pass metabolism through liver◦other items in stomach ex. tetracycline

Find something about warning label for tetracycline and absorption

◦ Convenient - can be self- administered, pain free, easy to take

◦ Absorption - takes place along the whole length of the GI tract

◦ Inexpensive - compared to most other parenteral routes

disadvantages of oral administration:◦ vomiting/stomach distress◦ variability in dose◦ effect too slow for emergencies◦ unpleasant taste of some drugs◦ unable to use in unconscious patient◦ first pass metabolism

First pass metabolism - term used for the hepatic metabolism of a drug when it is absorbed from the gut and delivered to the liver via the portal circulation.

The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally

first pass metabolism

disadvantages of oral administration:◦ vomiting◦ stomach distress◦ variability in dose◦ first pass metabolism

ex. buspirone (BuSpar) – antianxiety drug 5% reaches central circulation and is distributed to

brain

disadvantages of oral administration: ex. buspirone (BuSpar) – antianxiety drug

5% reaches central circulation and is distributed to brain metabolism can be blocked by drinking grapefruit juice

(suppresses CYPp450 enzyme)

J.Clin. Invest. 99:10, p.2545-53, 1997

Hours

Drugs that are destroyed by gastric juice or cause gastric irritation can be administered in a coating that prevents dissolution in acidic gastric contents (however may also preclude dissolving in intestines)

Controlled – Release Preps -

Sustained Release Controlled Release Extended Release Time or Timed Release

How is this achieved?◦ Embed in a web of substance that the body is slow to

dissolve◦ drug to swell up to form a gel with a nearly impenetrable

surface, wherein the drug slowly exits the semipermeable layer

◦ may have a coating over the active ingredient, ◦ may contain tiny time release beads, individually coated

DA: delayed absorptionDR: delayed releaseEC: enteric coatedER: enteric releaseGC: granules within capsulesSR: slow releaseSSR: sustained release

GI motility- speed of gastric emptying affects rate of absorption◦ ex. migraine and analgesics vs metoclopramide

Malabsorptive States - ◦ GI diseases, ex. Crohn’s disease can affect

absorption

Food - ◦ iron, milk alters tetracycline◦ fats

first pass metabolism

chemicals delivered with a hypodermic needle; ◦ most commonly - injected into vein, muscle or

under the upper layers of skin, in rodents also intraperitoneal cavity

requirements for parenteral: must be soluble in solution (so it can be injected)

◦ Intravenous◦ Intramuscular◦ Subcutaneous◦ Intracranial◦ Epidural◦ Intraperitoneal

absorption more rapid than SC

◦ less chance of irritation;

ways to speed up or slow down absorption

depot injections -

extremely rapid rate of absorption

adv: useful when you need rapid response or for irritating substances

Disadv: rapid rate of absorption

contingent on blood flow SO◦ IV, intraperitoneal, IM, SC

increasing or decreasing blood flow affects drug absorption

Drugs leave bloodstream and are exchanged between blood capillaries and body tissues

bolus or depot shots

related - drugs that accumulate in fat◦ ex. THC

nasal, oral, buccal

medications include: nitroglycerine, fentanyl –(1998) , nicotine gum, lozenges, buprenorphine

cocaine –

snuff, cigars

◦Advantages: rapid absorption avoid first-pass effect

◦Disadvantages: inconvenient small doses unpleasant taste of some drugs

1990’s – several medications incorporated into transdermal patches:◦ estrogen, nicotine, fentanyl, nitroglycerin,

scopolamine

controlled slow release for extended periods of time

Novel approaches…..Audra Stinchcomb

usually suppository form

for unconscious, vomiting or unable to swallow

disadv: not very well regulated dose; absorbed plus irritation (yikes)

not really used for psychotropics

intravenous 30-60 seconds inhalation 2-3 minutes sublingual 3-5 minutes intramuscular 10-20 minutes subcutaneous 15-30 minutes rectal 5-30 minutes ingestion 30-90 minutes transdermal (topical) variable (minutes to

hours)

Route for administration -Time until effect-

The rate at which a drug reaches it site of action depends on:◦Absorption - involves the passage of the drug from its site of administration into the blood

◦Distribution - involves the delivery of the drug to the tissues

Factors which influence the rate of absorption◦ routes of administration◦ dosage forms◦ the physicochemical properties of the drug◦ protein binding

Factors which influence the rate of absorption◦ routes of administration◦ dosage forms◦ the physicochemical properties of the drug◦ protein binding◦ circulation at the site of absorption◦ concentration of the drug

Mostly a passive process - ◦ from higher conc to lower (in blood)

Concentration GradientConcentration Gradient

[DRUG] [DRUG] receptorsreceptors ≈ [DRUG] ≈ [DRUG] circulationcirculation

Drug goes from higher concentration to lower concentration

Distribution

Drug molecules may be found in different places in the blood.

1. Plasma–more likely with water soluble drugs2. Platelets–more likely with lipid soluble drugs3. Attached to proteins (e.g., albumin)–bound vs. free

Pharmacokinetics

Mostly a passive process - ◦ from higher conc to lower (in blood)

Binding to plasma proteins◦ results in a store of bound drug in plasma

examples - 95-99% - chlorpromazine, diazepam, imipramine 90 - 95% - valproate, propanolol, phenytoin

Renal insufficiency last trimester of pregnancy drug interactions (other drugs that bind to

proteins) diseases

Blood brain barrier-◦ layer of thickly packed epithelial cells and

astrocytes that restrict access of many toxins/drugs to the brain

Lipid solubility – how soluble the drug is in fats

◦ cell membranes are lipid bilayers◦ similar characteristics allow drugs to cross brain

as to cross into cells

Lipid solubility

Size of molecule

Ionization – whether the degree has a charge (+ or -)

pKa – the pH at which ½ of the molecules are

ionized most drugs are either weakly basic or

weakly acidic

Basic drugs are highly ionized in acidic environment

Acidic drugs are highly ionized in basic environment

pKa – the pH at which ½ of the molecules are

ionized

the closer the pKa of the drug is to the local tissue pH, the more unionized the drug is.

ex. morphine – pKa of 8stomach ~ pH ~ 3

caffeine – pH .5

◦ Distribution half-life: the amount of time it takes for half of the drug to be distributed throughout the body

◦ Therapeutic level: the minimum amount of the distributed drug necessary for the main effect.

Until this time, drug movement has been mostly passive from regionsof higher concentration to lower concentration.

Elimination of drugs usually requires more of an active process (except gaseous drugs).

1. Biotransformation (metabolism)

chemical transformation of a drug into a different compound in the body (metabolite)

Most biotransformation takes place in the liver

2. Excretion - removal of drug to outside world

***Drug elimination may be by both or either of these mechanisms

role of liver◦ most significant organ in biotransformation

role of liver◦ most significant organ in biotransformation◦ largest organ in body◦ serves many functions

transforms molecules via enzymes

1. deactivating the molecule

2. ionize the molecule

3. make it less lipid soluble

** product of biotransformation is called a metabolite

located primarily in hepatocytes

important for metabolism of alcohol, tranquilizers, barbiturates, antianxiety drugs, estrogens, androgens, PCBs and other agents

oxidative metabolism – makes drugs more water soluble (so more easily excreted)

There are about 12 CYP families.◦ CYP1, 2, and 3 = most common for drug metabolism.◦ CYP2D6 and CYP3A (especially 3A4) metabolize over

50 percent of drugs.

Cytochrome p450 enzyme family

CYP enzymes -◦ enzyme induction -

liver produces extra enzyme to break down drug with continued exposure

Examples and Consequences:St. John's Wort: (with active ingredient hyperforin) stimulates a receptor (SXR in humans, PXR in nonhumans) in the liver to induce CYP3A, CYP3A breaks down many other drugs: theophylline (asthma), warfarin (anticlotting),

birth control pills, and immunosuppressant

cyclosporin.

Pharmacokinetics

CYP enzymes -◦ enzyme induction -

liver produces extra enzyme to break down drug with continued exposure

Genetics

Pharmacokinetics

Estimates that there is a 10-year gap between medically relevant bio-technological advances and appropriate application, or translation into routine medical practice

Enzyme Inhibition◦ Some drugs inhibit CYP enzymes and

increase their own levels, as well as levels of any other drug metabolized by that enzyme. Can produce toxicities.

◦ Example: Inhibition of antipsychotic medication by SSRIs.

Pharmacokinetics

CYP enzymes -◦enzyme induction - liver produces extra enzyme to break

down drug with continued exposureGenetics

Liver disease

cirrhotic liver

In some cases, biotransformation can be to another psychoactive compound

ex. benzodiazepenes

diazepam nordiazepam oxazepam

Excretion ◦ Primarily accomplished by kidneys.

2 organs (about the size of a fist) located on either side of the spine in the back.

Keep the right balance of water and salt in the body

Filter everything out of blood and then selectively reabsorb what is required.

Can be useful for eliminating certain drugs in overdose.

Pharmacokinetics

all drugs not in gaseous state need to use fluid routes of excretion◦ fluid routes include -sweat, tears, saliva, mucous,

urine, bile, human milk

◦ amount of drug excreted in each of these fluids is in direct proportion to amount of fluid excreted SO…….

Sometimes drugs are not metabolized and are excreted intact.◦ Lithium ◦ Mushroom amanita muscaria

In large doses it is toxic and lethal; small amounts are hallucinogenic.

Hallucinogenic ingredients are not greatly metabolized and are passed to the urine. Siberian tribespeople discovered this and recycled the drug by drinking their urine.

Pharmacokinetics

Sometimes drugs are not metabolized and are excreted intact.◦ Lithium ◦ Mushroom amanita muscaria

In large doses it is toxic and lethal; small amounts are hallucinogenic.

Hallucinogenic ingredients are not greatly metabolized and are passed to the urine. Siberian tribespeople discovered this and recycled the drug by drinking their urine.

Pharmacokinetics

absorption, distribution and excretion do not occur independently

1. Body weight - smaller size • concentration of drug based on body fluid

2. Sex differences

3. Age

4. Interspecies differences rabbits – belladonna (deadly nightshade)

5. Intraspieces differences

6. Disease states

7. Nutrition

8. Biorhythm

half-life - time takes for the blood concentration to fall to half its initial value after a single dose

½ life tells us critical information about how long the action of a drug will last

How long would it take for a drug to reach 12.5% remaining in blood if its ½ life is 2 hours?

How long would it take for a drugto reach 12.5% remaining in blood if its ½ life is 100 hours?

brainblood

first pass metabolism