HOW DO DRUGS GET INTO THE BODY?

This Lecture power point is courtesy of Dr. Edwin Jackson, American Society of Pharmacology and Experimental Therapeutics

WHY BE CONCERNED ABOUT HOW DRUGS GET INTO BODY?

This issue importantly affects:
Bioavailability - % of dose that gets into body Bioequivalence - similarity between two formulations of same drug Speed of Drug Onset - how long it takes the drug to begin working Dosing Interval - how often the drug should be given Site of Action - whether the drug stays local or acts systemically

HOW DO DRUGS GET INTO THE BODY?

Unless injected directly into the blood stream, drugs must be absorbed.

WHAT IS DRUG ABSORPTION?

The movement of drug molecules across biological barriers (mostly layers of cells) from the site of administration to the blood stream.
BIOLOGICAL BARRIER

Site of Administration
DRUG

Vascular System

WHAT AFFECTS DRUG ABSORPTION?

The rate of drug absorption will be affected by:
Rate of release of drug from pharmaceutical preparation Membrane permeability of drug Surface area in contact with drug Blood flow to site of absorption Destruction of drug at or near site of absorption

WHAT DETERMINES RATE OF RELEASE OF DRUG FROM PHARMACEUTICAL PREPARATION?

A: DOSAGE FORM
Solutions: No Delay, Immediate Release Capsules & Tables: Delay (Dissolution) Followed by Rapid Release Creams, Ointments & Suppositories: No Delay, but Slow Release

WHAT DETERMINES RATE OF RELEASE OF DRUG FROM PHARMACEUTICAL PREPARATION?

B: ADDITIVES (EXCIPIENTS)
Decrease Rate of Dissolution Binders Lubricants Coating Agents Increase Rate of Dissolution Disintegrants Variable Effects on Rate of Dissolution Diluents Coloring Agents Flavoring Agents

WHAT DETERMINES RATE OF RELEASE OF DRUG FROM PHARMACEUTICAL PREPARTAION?

C: MANUFACTURING PARAMETERS
Tablet Compression - Hard tablets dissolve more slowly Tablet Shape - Round tablets dissolve more slowly Tablet Size - Large tablets dissolve more slowly

WHAT DETERMINES RATE OF RELEASE OF DRUG FROM PHARMACEUTICAL PREPARATION?

D: DELAYED RELEASE PREPARATIONS
Enteric Coating - Dissolve in intestines, not stomach

WHAT DETERMINES RATE OF RELEASE OF DRUG FROM PHARMACEUTICAL PREPARATION?

E: SUSTANED RELEASE PREPARATIONS
Reservoir Diffusion Products - Drug diffuses from pill core through membrane shell Matrix Diffusion Products - Drug diffuses through matrix in which it is embedded Matrix Dissolution Products - Drug released as matrix dissolves Osmotic Tablets - Drug pumped out of tablet by osmotic forces Ion-Exchange Products - Drug bound to resin exchanges with endogenous ions

WHAT DETERMINES MEMBRANE PERMEABILITY OF DRUGS?

A: LIPOPHILICITY increases membrane permeability
Presence of Aliphatic and Aromatic Structures Absence of Polar Groups

WHAT DETERMINES MEMBRANE PERMEABILITY OF DRUGS?

B: IONIZATION decreases membrane permeability
Weak acids in intestines are mostly ionized (intestinal pH ranges from 6.6 to 7.5) Weak bases in stomach are mostly ionized (stomach pH ranges from 1 to 2) For other polar molecules, see next slide

Factors Affecting Drug Absorption

Transport
active vs. passive ATP

pH Physical factors
blood flow surface area contact time A good example of pH effect is illustrated in next slide

ADP + Pi

ABH+

Ion Trapping: Anesthesia Correlation: Placental transfer of basic drugs Placental transfer of basic drugs from mother to fetus: local anesthetics fetal pH is lower than maternal pH (what does this mean?) lipid-soluble, nonionized local anesthetic crosses the placenta converted to poorly lipid-soluble ionized drug
gradient is maintained for continual transfer of local anesthetic from maternal circulation to fetal circulation in fetal distress, acidosis contributes to local anesthetic accumulation

ION TRAPPING (a form of sequestration) Ion Trapping Occurs when a drug is ionized across a cell membrane and the pH of the transmembrane medium favors retaining the ionized form of the molecule: a gradient is established The ion is said to be trapped or enters a sink

WHAT DETERMINES SURFACE AREA FOR ABSORPTION?

ANATOMY
Low Surface Area: eyes, nasal cavity, buccal cavity, rectum, stomach, large intestines High Surface Area small intestines, lungs, liver Low surface area: generally smooth Large surface area: villi and cavitation

Internal Structure of Small Intestine showing increase of surface area for absorption

Note the folds of lining of intestine =Nutrient Absorption Note the capillary network Villi

Epithelial cells Note the microvilli

WHAT DETERMINES TISSUE BLOOD FLOW?

A. PHYSIOLOGY
Low Blood Flow: eyes, stomach, large intestines, rectum, subcutaneous tissue High Blood Flow small intestines, lungs, muscle, buccal cavity, nasal cavity, liver, brain

WHAT DETERMINES TISSUE BLOOD FLOW?

B. PHARMACOLOGY
Some Drugs Are Vasoconstrictors Some Drugs Are Co-Administered With Vasoconstrictors Some Drugs Are Vasodilators In other words, some drugs alter their own absorption and distribution

WHAT DETERMINES WHETHER A DRUG IS DESTROYED AT OR NEAR SITE OF ADMINISTRATION?

BIOCHEMISTRY
Liver - hepatic enzymes (first pass effect) Colon - intestinal microflora Stomach - digestive enzymes and acids

THINKING CAP TIME

QUIZ: What molecular group of drugs will NOT likely survive as an intact molecule when in the stomach? What molecular group of drugs will NOT be absorbed from the stomach?
(possible answers: proteins, lipids, weak bases, strong bases, weak acids, strong acids, carbohydrates, ionic molecules)

WHAT ARE THE ROUTES OF ADMINISTRATION FOR DRUGS?

ENTERAL
(Digestive tract)

PARENTERAL
Intravenous (IV) Intra-arterial (IA) Subcutaneous (SC) Intradermal (ID) Intramuscular (IM) Intraperitoneal (IP) Lungs (Inhalation) Skin (Topical) Nose (Intranasal) Eye (Opthalmic) Ear (Otic) Vagina Urethra Urinary Bladder Intrathecal Epidural Directly Into Target Tissue

Oral Sublingual Rectal

WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF ORAL, IV, IM AND SC ADMINISTRATION?

SAFETY High Oral > SC > IM > IV Low CONVENIENCE High Oral > SC > IM > IV Low COST High IV > IM > SC > ORAL Low

WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF ORAL, IV, IM AND SC ADMINISTRATION?

BIOAVAILABILITY High and Reliable IV > IM = SC > ORAL Low and/or Variable ONSET OF ACTION Immediate IV > IM > SC > Oral Delayed PATIENT COMPLIANCE High IV > IM > SC > Oral Low

WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF ORAL, IV, IM AND SC ADMINISTRATION?

INTERACTIONS WITH FOOD Risk Oral > IV = IM = SC No Risk COMMERCIAL AVAILABILITY OF DOSAGE FORMS High Oral > IM = SC = IV Low VOLUME OF DRUG High Oral = IV > IM > SC Low

WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF ORAL, IV, IM AND SC ADMINISTRATION?

AVAILABILITY OF SUSTAINED RELEASE DOSAGE FORMS High IM > Oral > SC > IV Low

TOLERANCE TO FUNKY VEHICLES High Oral = IM = SC > IV Low

WHY CONSIDER OTHER ROUTES OF ADMINISTRATION?

Sublingual - Rapid absorption that bypasses liver Rectal - Great for patient that is vomiting or cannot (will not) swallow medication

WHY CONSIDER OTHER ROUTES OF ADMINISTRATION?

IS OFTEN DESIRABLE TO CONCENTRATE MEDICATION AT TARGET SITE TO INCREASE EFFICACY AND DECREASE TOXICITY Lungs (Inhalation) Skin (Topical) Nose (Intranasal) Eye (Opthalmic) Ear (Otic) Vagina Urethra Urinary Bladder Intrathecal Epidural Directly Into Target Tissue

(The purpose here is to limit systemic absorption)

HOW DO DRUGS GET INTO THE BODY?

Now you know!!

WHERE DO DRUGS GO?

WHY BE CONCERNED ABOUT WHERE DRUGS GO?

Where drugs go determines Where Drugs Act:
Ciprofloxacin [Cipro] penetrates the prostate gland and therefore is effective in bacterial prostatitis, whereas most antibiotics do not enter the prostate and are therefore ineffective in prostatitis. Fexofenadine [Allegra] is largely excluded from the brain and therefore is a nonsedating antihistamine, whereas most antihistamines freely enter the brain and cause marked drowsiness.

WHY BE CONCERNED ABOUT WHERE DRUGS GO?

Where drugs go influences Where Drugs Are Eliminated:
Penicillin is actively transported into the proximal tubules and is therefore rapidly excreted by the kidneys. Can be influenced by PROBENECID Probenecid inhibits secretion and keeps penicillin in blood Inhalation anesthetics distribute to alveolar spaces and therefore are eliminated by the lungs.

WHY BE CONCERNED ABOUT WHERE DRUGS GO?

Where drugs go influences How Long Drugs Last In the Body :
Raloxifene [Evista]) (for treatment of osteoporosis in postmenopausal women) is transported by the liver into the intestines where it is reabsorbed (enterohepatic recirculation). This greatly increases the time raloxifene lasts in the body. Iodine is sequestered in the thyroid gland Lipid-soluble drugs stay sequestered in adipose tissues for a long time before being slowly released into the blood for action and metabolism in the liver

WHAT ARE THE DETERMINANTS OF WHERE DRUGS GO? Determinants of Drug Distribution:
Organ blood flow Barriers to drug diffusion Adipose tissue Tissue protein binding Plasma protein binding Drug transport Ion trapping

WHAT IS THE EFFECT OF ORGAN BLOOD FLOW ON DRUG DISTRIBUTION?

Organs with high blood flow will have larger amounts of drug delivered to them per unit time. Organs with high blood flow will experience initial high concentrations of drug, but these high concentrations will diminish as the drug is redistributed throughout the body to sites with lower blood flow.

WHAT IS THE EFFECT OF ORGAN BLOOD FLOW ON DRUG DISTRIBUTION?

Organs with high blood flow will experience larger initial effects. Many sedative/hypnotics, such as benzodiazepines (e.g., diazepam [Valium]) will produce initial, but short-lived, profound CNS effects following IV administration.

WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG DISTRIBUTION?

Most capillaries have pores between the endothelial cells lining the capillaries. These pores allow for rapid diffusion of most drugs into the interstitial space. In some capillary beds, however, the endothelial cells are closely connected by tight junctions, and such capillaries do not have pores between the endothelial cells.

WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG DISTRIBUTION?

In capillaries with tight junctions, drug molecules must diffuse across (transcellular), rather than around (paracellular) the endothelial cells. Only lipophilic drugs rapidly diffuse across capillary beds with tight junctions, whereas hydrophilic drugs are mostly excluded.

WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG DISTRIBUTION? The blood-brain barrier (BBB) is a special case:
Capillaries in brain have tight junctions that contribute to the BBB. Capillaries in brain are wrapped by pericapillary glial cells that further contribute to the BBB. The endothelial cells in brain capillaries have P-glycoprotein that pumps drugs out of endothelial cells, and this also contributes to the BBB.

WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG DISTRIBUTION? The blood-brain barrier (BBB) is a special case:
In general, the BBB restricts the movement of hydrophilic drugs into brain; however, the BBB is broken by ischemia and inflammation. The BBB can be exploited to develop drugs with reduced CNS adverse effects. HOW?

WHAT IS THE EFFECT OF ADIPOSE TISSUE ON DRUG DISTRIBUTION?

Lipophilic drugs will distribute into adipose (fat) tissue. Distribution of lipophilic drugs into fat may necessitate a larger initial bolus of drug to achieve the desired effect. Large depots of drug in fat may necessitate a longer period of time for drug to be removed from the body. The distribution of lipophilic drugs will be different in thin versus obese patients.

QUIZ TIME Describe how knowledge of factors affecting entry of drugs into the brain can be used to design drugs that can concentrate in the brain. Based on the above information, how will you design a drug that will have primarily peripheral effect? SUBMIT YOUR ANSWERS NEXT WEEK TUESDAY FOR GRADING

WHAT IS THE EFFECT OF TISSUE PROTEIN BINDING ON DRUG DISTRIBUTION?

Some

drugs are highly bound to tissue proteins.

Binding of drugs by tissue may necessitate a larger initial bolus of drug to achieve the desired effect. Large depots of drug in tissue may necessitate a longer period of time for drug to be removed from the body.

WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION?

Some drugs are highly bound (> 90%) to plasma proteins. Acid drugs bind to albumin and basic drugs bind to alpha1-acid glycoprotein. Binding of drugs by plasma proteins limits the distribution of drugs out of the vascular compartment, necessitating more drug initially to achieve the desired effect.

WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION?

Binding of drugs may limit the delivery of drugs to drug elimination mechanisms (for example excretion by the kidney or metabolism by the liver), and this increases the time required for the drug to be removed from the body.

WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION?

Displacement of a highly plasma-protein bound drug by another drug may lead to drug-drug interactions because of a rapid increase in the availability of free (unbound) drug. Displacement of unconjugated bilirubin from albumin by drugs may precipitate bilirubin encephalopathy in newborns.

WHAT IS THE EFFECT OF DRUG TRANSPORT ON DRUG DISTRIBUTION?

Transport mechanisms may increase or decrease the distribution of drugs to certain tissues. For example, most diuretics are transported by the proximal tubules into the nephron, a process that delivers the diuretics to their site of action. Competition for transport may result in drug-drug interactions. For example, probenecid ( a drug used for gout) blocks the transport of diuretics into the proximal tubule and thereby markedly blunts the effects of diuretics on salt and water excretion.

WHAT IS THE EFFECT OF ION TRAPPING ON DRUG DISTRIBUTION?

BIOLOGICAL BARRIER (= plasma membrane)

Compartment with Low pH

Unionized Weak Acid

Compartment with High pH

Unionized Weak Acid

Ionized Weak Acid

Ionized Weak Acid

Higher total concentration of weak acid

WHAT IS THE EFFECT OF ION TRAPPING ON DRUG DISTRIBUTION?

BIOLOGICAL BARRIER

Compartment with Low pH

Unionized Weak Base

Compartment with High pH

Unionized Weak Base

Higher total concentration of weak base

Ionized Weak Base

Ionized Weak Base

WHAT IS THE EFFECT OF I0N TRAPPING ON DRUG DISTRIBUTION?

Ion trapping can be used to distribute drugs into the urinary compartment to increase the urinary excretion of poisons. Example: Alkalinization of the urine with systemic administration of sodium bicarbonate is useful for the treatment of overdoses of aspirin and phenobarbital. (Explain this) Example: Acidification of the urine with systemic administration of ammonium chloride is useful for the treatment of amphetamine overdoses.

WHERE DO DRUGS GO?

Now you know!!