Lecture 3 - Drug Absorption - 9 Sep 2006

DRUG ABSORPTION

Introduction  A drug may be defined as a therapeutic substance intended to affect the structure or function of the body in order to restore abnormal function to normal.

 For a drug to produce a therapeutic effect, it must reach to its target and it must accumulate at that site to reach to the minimum concentration required to produce the required effect.

 The effects of drugs depend upon the ability of the drug to reach the site of action.

 This ability is influenced by a number of phenomena like translocation and disposition.

Translocation of Drug Molecules  For a drug to reach its site of action in the body, it must cross numerous biological membranes, including the cellular membranes.

 These membranes include the gastrointestinal mucosa (if given orally) or lung mucosa (if inhaled), the lymphatic or capillary wall, and the cell wall.

 There are 4 ways by which small molecules cross cell membranes: 1. By diffusion through the membrane lipid 2. By diffusion through aqueous pores 3. By combination with a carrier molecule 4. By pinocytosis

 Drugs in general pass through cells rather than in between them.  Plasma membranes thus represent   the common barrier.  Most drugs cross membranes by passive diffusion.

Diffusion through lipid  The drug molecule penetrates membranes by passive diffusion along its concentration gradient by virtue of its solubility in the lipid bilayer.

 Such transfer is directly proportional to the magnitude of the concentration gradient and the Lipid: Water partition coefficient of the drug.

 The greater the partition coefficient of the drug, the higher is the concentration of the drug in the membrane and the faster is its diffusion.

pH and ionization  Most drugs are weak acids or weak bases that are present in solution as both the ionized and non-ionized form.

 Non-ionized molecules are usually lipid soluble and can diffuse across cell membranes

 In contrast, ionized molecules are usually unable to penetrate the lipid membrane because of their low lipid solubility.

 The ratio of ionized to unionized species depends on the pKa of the drug and the pH of the membrane environment, and can be calculated from the Henderson-Hasselbalch equation.

Base + BH

B+H

Acid AH

A +H

+

-

+

 The acid (low pH) nature of the stomach generally results in a higher degree of ionization for weak bases than for weak acids. i.e. Weak acids will be more unionized and thereby absorbed more readily.

 In the small intestine, the pH is about 5.0-8.0 and the reverse situation holds true.

 When there is relative “acidity” of distal tubular urine, there is tendency to increase the ionization of weak bases thereby hastening their renal elimination whereas weak acids passively diffuse (in the unionized form) back into the circulation.

 “Alkalinization” of urine (for example with NaHCO3) would tend to reverse this situation whereas further “acidification” (for example with NH4Cl) would amplify these mechanisms.

 In a similar manner, certain physiologic secretions will tend to concentrate certain ions. For example, breast milk (pH 6.7) is slightly acidic and tends to concentrate weak bases.

 Thus the pain-relieving narcotic meperidine, which is a weak base, when given during labor and delivery will be present in breast milk

Summary Drug is weak acid:

AH

A- + H+

Acidic environment: protonated, non-ionized, lipid-soluble Basic environment: un-protonated, ionized, water-soluble

Drug is weak base: BH+ B + H+   Acidic environment: protonated, ionized, water-soluble Basic environment: un-protonated, non-ionized, lipid-soluble

Drug absorption

 Absorption is the passage of a drug from its site of administration into the plasma (circulation).

The main routes of drug administration are: Enteral: oral, sublingual, rectal Parenteral: intravascular (intravenous), intramuscular, subcutaneous Other: inhalation, intranasal, intrathecal, topical, transdermal

Oral 1. Easy, practical and reliable way 2. Drug is first dissolved in GI fluids, absorbed through epithelial lining of the GI tract, and enters into blood vessels.  little absorption in the large intestine

3. Most of the drug is absorbed in the small intestine. Why?

 small intestine has a much larger surface area for absorption (∼200 m2) as compared to the stomach (∼1-3 m2).

 drug spends more time in the small intestine (∼4 hrs) than the stomach (∼0.5-1 hrs).

4. Solubility of the drug in the GI tract 5. Time in the GI tract. Any pathological condition that changes that either increase or decrease the passage time of the drug in the GI tract will change the quantity of absorption.

6. Food in the stomach can decrease absorption.  Food may cause changes in transit time, increase release of fluids into the stomach, interactions between drug and food particles.

 If food causes problems with a certain drug, it should be taken 2 hrs after food intake and 1 hr before the next food intake.

7. Drugs may be metabolized by enzymes of GI mucosa or enter the hepatic portal circulation and undergo metabolism by liver enzymes which may result in their inactivation.

Sublingual  Good absorption through capillary bed under tongue  Drugs are easily self administered

 Because the stomach is bypassed, acid-lability and gut-permeability is not important

 Drugs are absorbed from the mouth straight into the systemic circulation without entering the portal system and so escape first-pass metabolism by the liver.

Rectal  Useful for unconscious or vomiting patients and small children  Absorption is unreliable

Intravenous  Rapid onset of action because the drug is injected directly into the bloodstream

 Useful in emergencies and in patients that are unconscious

 The drug avoids the GI tract and first-pass metabolism by the liver

Intramuscular  Drug passes through capillary walls to enter the blood stream.

 Rate of absorption depends on formulation (oil-based preparations are absorbed slowly, aqueous preparations are absorbed rapidly).

Subcutaneous  Drug is injected beneath the skin and permeates capillary walls to enter blood stream.  Absorption from the site of injection is dependent on local blood flow.

Inhalation  Inhalation provides the rapid delivery of a drug across the large surface area of the mucous membranes of the respiratory tract and pulmonary epithelium, producing an effect almost as rapidly as by intravenous injection.

 This route of administration is used for drugs that are gasses (for example some anesthetics) or those that can be dispersed in an aerosol (for example some asthma drugs).

 The route is particularly effective and convenient for patients with respiratory complaints (for example asthma or chronic obstructive pulmonary disease) as drug is delivered directly to the site of action and systemic side effects are minimized.

Topical  Useful for local delivery of drugs, particularly those which have toxic effects if administered systemically  Used for most dermatologic and ophthalmologic preparations

For example, clotrimazole is applied as a cream to the skin in the treatment of dermatophytosis, and atropine is instilled directly into the eye to dilate the pupil and permit measurement of refractive errors.

First-Pass Effect  Since drugs are absorbed from the gastrointestinal tract into the portal circulation, some drugs may be extensively metabolized in the liver or in the intestinal mucosa before reaching the systemic circulation.

 This “first-pass effect” can substantially decrease the amount of active drug reaching the systemic circulation and thus, its bioavailability.

Example: Lidocaine is a drug with a first-pass effect that is so great that oral administration is not practical.

 In the case of propranolol, a significant portion of the orally administered dose is metabolized through a first-pass effect;

 therefore, a much larger oral dose is required to achieve the same therapeutic response as that obtained from a dose administered intravenously.

Gastric emptying  The rate of drug absorption after an oral dose can be altered by altering the rate of gastric emptying.

 Ingestion of a solid dosage form with a glass of cold water will accelerate gastric emptying.

 This will expose the drug to the upper intestine with a higher pH and a much larger surface area (better absorption).  Some drugs can also increase gastric emptying.

 Conversely, ingestion of a drug with a fatty meal or an acidic drink will slow gastric emptying.  Drugs with anti-cholinergic effects can also slow gastric emptying.

SUMMARY  When a drug is to be administered to a patient to achieve a therapeutic blood level Consideration must be given to:

 Route of administration (as determined by chemical nature of the drug and/or the clinical circumstances)  Desired time of onset of action (as determined by the route of administration and the dose)

 Since most drugs are given orally, the factors which can alter absorption characteristics must be also considered i.e., dissolution rate, dosage form, changes in pH of GI tract and transit time as a result of :

 The clinical state of the patient  Presence of other drugs or substances that interfere with absorption (breakdown or binding of drug, formation of insoluble compounds)  Individual differences of absorption rates