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

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

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 hoursmidazolam 1 2 hrs

OralParenteralBuccalInhalationRectalNasal

most common, sometimes referred to as posafe, 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 basicabsorption favored if the drug is nonionized and more lipophilic

chemicals in stomach must deal with:stomach acidsdigestive enzymesfirst pass metabolism through liverother items in stomachex. tetracycline

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 distressvariability in doseeffect too slow for emergenciesunpleasant taste of some drugsunable to use in unconscious patientfirst 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:vomitingstomach distressvariability in dosefirst pass metabolismex. buspirone (BuSpar) antianxiety drug5% reaches central circulation and is distributed to brain

disadvantages of oral administration:ex. buspirone (BuSpar) antianxiety drug5% reaches central circulation and is distributed to brainmetabolism can be blocked by drinking grapefruit juice (suppresses CYPp450 enzyme)

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

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 ReleaseControlled ReleaseExtended ReleaseTime or Timed Release

How is this achieved?Embed in a web of substance that the body is slow to dissolvedrug to swell up to form a gel with a nearly impenetrable surface, wherein the drug slowly exits the semipermeable layermay have a coating over the active ingredient, may contain tiny time release beads, individually coated

DA: delayed absorption DR: delayed release EC: enteric coated ER: enteric release GC: granules within capsules SR: slow release SSR: sustained release

GI motility- speed of gastric emptying affects rate of absorptionex. migraine and analgesics vs metoclopramide

Malabsorptive States - GI diseases, ex. Crohns disease can affect absorption

Food - iron, milk alters tetracyclinefats

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)

IntravenousIntramuscularSubcutaneousIntracranialEpiduralIntraperitoneal

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 SOIV, 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 fatex. THC

nasal, oral, buccal

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

cocaine

snuff, cigars

Advantages:rapid absorptionavoid first-pass effect

Disadvantages:inconvenientsmall dosesunpleasant taste of some drugs

1990s 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 secondsinhalation 2-3 minutessublingual 3-5 minutesintramuscular 10-20 minutessubcutaneous 15-30 minutesrectal 5-30 minutesingestion 30-90 minutestransdermal (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 bloodDistribution - involves the delivery of the drug to the tissues

Factors which influence the rate of absorptionroutes of administrationdosage formsthe physicochemical properties of the drugprotein binding

Factors which influence the rate of absorptionroutes of administrationdosage formsthe physicochemical properties of the drugprotein bindingcirculation at the site of absorptionconcentration of the drug

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

Concentration Gradient [DRUG] receptors [DRUG] circulationDrug goes from higher concentration to lower concentration

DistributionDrug molecules may be found in different places in the blood.Plasmamore likely with water soluble drugsPlateletsmore likely with lipid soluble drugsAttached to proteins (e.g., albumin)bound vs. freePharmacokinetics

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

Binding to plasma proteinsresults in a store of bound drug in plasma

examples -95-99% - chlorpromazine, diazepam, imipramine90 - 95% - valproate, propanolol, phenytoin

Renal insufficiencylast trimester of pregnancydrug 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 bilayerssimilar 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 of the molecules are ionizedmost drugs are either weakly basic or weakly acidic

Basic drugs are highly ionized in acidic environmentAcidic drugs are highly ionized in basic environment

pKa the pH at which 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 bodyTherapeutic 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

Excretion - removal of drug to outside world

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

role of livermost significant organ in biotransformation

role of livermost significant organ in biotransformationlargest organ in bodyserves many functionstransforms molecules via enzymes

deactivating the molecule

ionize the molecule

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 InhibitionSome 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 bodyFilter 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 excretionfluid 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 muscariaIn 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 muscariaIn 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

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

Sex differences

Age

Interspecies differences rabbits belladonna (deadly nightshade)

Intraspieces differences

Disease states

Nutrition

Biorhythm

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

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 life is 2 hours?

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

brainbloodfirst pass metabolism

**Metoclopramide increases the rate at which the stomach and intestines move during digestion. It also increases the rate at which the stomach empties into the intestines and increases the strength of the lower esophageal sphincter (the muscle between the stomach and esophagus). *************