• Pharmacokinetics: – How drugs are handled by the body

Lets say you have a headacheand you need to take some meds –

This illustrates the basic processes in the branch of pharmacokinetics

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. anti-anxiety drugs – • benzodiazepenes

– ultra short acting, short acting, long acting

• Examples of BZ

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

Drug Absorption

• Absorption – the process by which a drug enters the bloodstream without being chemically altered or

• The movement of a drug from its site of application into the blood

What are the routes of drug administration?

oral administration

• 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

What do orally administered drugs have to deal with?

– chemicals in stomach must deal with:– stomach acids– digestive enzymes– first pass metabolism through liver– other items in stomach

• ex. tetracycline

Advantages of oral administration

– 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

oral administration

• 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

• 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

oral administration

• 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– metabolism can be blocked by drinking grapefruit

juice (suppresses CYPp450 enzyme)

Grapefruit Juice Increases Felodipine Oral Availability in Humans by

Decreasing Intestinal CYP3A Protein Expression

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

Hours

Some additional interesting points regarding oral adm

• 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 dissolution in intestines)

• Controlled – Release Preps -

Factors that affect rate of absorption following PO route

• 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

Factors that affect rate of absorption following PO route

• Food - – iron, milk alters tetracycline– fats

• first pass metabolism

Parenteral or Injection• 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)

B. Parenteral (Injection)– Intravenous– Intramuscular– Subcutaneous– Intracranial– Epidural– Intraperitoneal

Intramuscular

• not typical for drugs of abuse• absorption more rapid than SC

– less chance of irritation;

• ways to speed up or slow down absorption

• depot injections -

Intravenous

• extremely rapid rate of absorption

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

• Disadv: rapid rate of absorption

Absorption for parenteral route

• 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

Mucosal membranes

• nasal, oral, buccal

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

• cocaine –

• snuff, cigars

Advantages and Disadvantages of Buccal

– Advantages:• rapid absorption• avoid first-pass effect

– Disadvantages:• inconvenient• small doses• unpleasant taste of some drugs

transdermal or transcutaneous

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

scopolamine

• controlled slow release for extended periods of time

Rectal Administration

• usually suppository form

• for unconscious, vomiting or unable to swallow

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

Inhalation

• 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-

Drug Absorption

• 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

Drug Absorption

• 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

Distribution

• drugs are distributed throughout body by blood • very little at site of action at any one time• role of passive diffusion, concentration gradient

Absorption• 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

Additional issue for drugs to reach the CNS

• Blood brain barrier-– layer of thickly packed epithelial cells and

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

3 Factors that affect how well a drug can cross the blood brain barrier (or placental barrier)

• 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

3 Factors that affect how well a drug can cross the blood brain barrier

• 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 and therapeutic levels

– 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).

How are drugs eliminated?

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

Biotransformation

• role of liver– most significant organ in biotransformation

Biotransformation

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

• transforms molecules via enzymes

Liver enzymes biotransform drugs (and other compounds) by

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)

Cytochrome p450 enzyme family

Can metabolism rate be altered?

• CYP enzymes -– enzyme induction -

• liver produces extra enzyme to break down drug with continued exposure

Can metabolism rate be altered?

• CYP enzymes -

– enzyme induction - • liver produces extra enzyme to break down drug with

continued exposure

• Genetics

Can metabolism rate be altered?

• CYP enzymes -– enzyme induction -

• liver produces extra enzyme to break down drug with continued exposure

• Genetics

• Liver disease

In some cases, biotransformation can be to another psychoactive compound

ex. benzodiazepenes

diazepam nordiazepam oxazepam

Routes of Excretion- fluid

• 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…….

Kidneys

• numerous functions – – filters out metabolic products

Kidneys• numerous functions – • main function – maintain correct balance

between water and salt in body fluids– filters out metabolic products– blood continuously flowing through kidneys

• factors that influence a substance not being resorbed

– not lipid soluble– ionized

• dialysis –

absorption distribution and excretion do not occur independently

2 Summary Slides

brainblood

first pass metabolism

Other factors that affect drug pharmacokinetics

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

2. Sex differences

3. Age

Other factors that affect drug pharmacokinetics

4. Interspecies differences rabbits – belladonna (deadly nightshade)

5. Intraspieces differences

6. Disease states

7. Nutrition

8. Biorhythm

Time in hours

Blo

od

level

Elimination

Distribution

2 4 6 8 10 12 14

Resultant

• 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?