Drug absorption is defined as the passage of a drug from its site of administration into the blood stream.
Factors that modify drug absorption:
1. Solubility:
• Drugs with higher lipid solubility are absorbed at a greater rate.
• Drugs given in aqueous solution are more rapidly absorbed than these given in oily solution, suspension or solid form.
2. Degree-of ionization:
Greater the degree of ionization, lesser the absorption. Drugs which are lipid soluble are in unionized form, and readily absorbed, while the water soluble drugs are in ionized form and can be absorbed if they have very small molecular size.
Pka: Pka is the pH at which drug is ionized to the extent of 50%.
3. Pharmaceutical Preparations:
• Solution are better absorbed than suspensions.
• Smaller the particle size of powders the more efficient their absorption.
4. Route of Administration:
Absorption form intramuscular route is rapid than from subcutaneous route Absorption from parenteral route is rapid than oral route.
5. Surface Area
Grater the surface area, larger will be the amount of drug absorbed e.g. surface area of mucous membrane of small intestine is greater than that of buccal or gastric mucosa, thus providing large area for absorption.
6. Concentration of Drug:
Greater the concentration of the drug, greater will be the conc. Gradient across the cell membrane, and thus higher the rate of absorption.
7. Local Blood Flow:
Rate of absorption is directly proportional to the local blood circulation.
Factors modifying absorption from Gut
Solubility, surface area and local circulation are already discussed. Other factors are:
• Motility of the Gut:
Motility of the gut helps in dissolution of tablets, therefore increased motility also increase rate of absorption.
• pH of the Gut:
Most of the drugs are either weak acids or weak base. Weak acids are mostly unionized in acidic medium and therefore better absorbed in acidic medium while the weak bases are unionized in alkaline medium and therefore better absorbed in it.
• Disease Conditions:
Different disease conditions also effect the rate of absorption e.g. in congestive cardiac failure edema of the gut delays absorption.
• Presence of other substances in Gut:
Food or other substances present in the gut may delay the absorption e.g. Tetracyclines are absorbed if given with calcium or iron salts.
DISTRIBUTION OF DRUGS
After the drug is absorbed it is distributed through different tissues and the body fluid compartments such as plasma, extracellular and intracellular and intracellular fluid depending upon its physicochemical properties.
The drugs are not equally distributed in the body. There are four basic patterns of drug distribution.
• Substances of high molecular weight like dextran almost remain in plasma water.
• Drugs that can pass the capillary wall but cannot pass across the cell membrane are localized mainly in extracellular fluid e.g. mannitol after IV administration.
• Some drugs are concentrates especially in one or more tissues of the body e.g. iodide in thyroid gland, chloroquine in liver and calcium in bone.
FACTORS THAT DETERMINE DRUG DISTRIBITION
1. Protein blinding.
2. Blood flow.
3. Membrane permeability
4. Tissue solubility (lipid solubility).
Protein Binding:
After entering the blood, a drug maybe bound to plasma proteins (chiefly albumin) to varying extent; this is called plasma protein binding of drug. The binding of drugs to albumin is reversible and may show low or high capacity. Albumin has strongest affinity for anionic drugs and neutral drugs do not bind to albumin. Following are the properties of protein bound drug.
• Binding is reversible, bound form does not go out into tissue; it remain in blood.
• The protein bound fraction of drug is inactive ( not available for interaction with
receptors ) and acts as deposit from which a small proportion of drug is constantly released to maintain equilibrium with free drug which is being utilized.
• Bound form if not freely filtered from the renal glomeruli.
• Only the unbound or free drug is liable to degradation, utilization and excretion.
• When two drugs are given, each with high affinity for albumin, they compete for available sites. Protein bound drug can be displaced by another drug that competes for protein binding e.g. when sulfonamide is given with tolbutamide, sulfonamide compete s with tolbutamide for albumin biding and displaces tolbutamide from albumin binding sites resulting in rapid rise in plasma tolbutamide level than can be very harmful for the body. This type of drug interactions is clinically very significant.
Blood Flow:
Blood flow determines how rapidly drug molecules are delivered to a given tissue and how effectively the concentration gradient between blood and tissue is maintained. Therefore, drugs equilibrate rapidly between the blood and organs with a high blood flow.
Membrane permeability and tissue solubility
Already discussed in previous section.
PASSAGE OF DRUG TO CNS
The passage of drug into the CNS is limited by the blood brain barrier. Only non-ionized lipid soluble drugs can pass through that barrier, while soluble drugs do not reach the CSF because blood brain barrier has not intercellular pores that are necessary for the passage of water-soluble drugs.
REDISTRIBUTION:
Termination of drug effect is usually by its metabolism and excretion but it may also result form redistribution of the drug from its site of action into other tissues or sites. Redistribution is a factor in termination drug affects primarily when a highly lipid-soluble drug affects primarily when a highly lipid-soluble drug that acts on the brain or CVS is administered rapidly by l/V or by inhalation.
Example
Intravenous anesthetic thiopental is a highly lipid soluble drug. Because blood flow to the brain is so high, the drug reaches its maximum concentration in train within a minute after it is injected intravenously. After injection is stopped, the plasma concentration falls as thiopental diffuses of drug follows that of plasma, because there is little binding of drug to brain constituents.
VOLUME OF DISTRIBUTION (Vd)
Volume of distribution is a relation between amount of drug in the body to the concentration of drugs in the blood or plasma.
V/d =
Total drug in the body Cone. of drug in the blood
Vd = Volume of distribution.
Volume of distribution depends upon the:
• PKa of the drug
• Degree of plasma protein binding
• Degree of binding to other tissue within the body.
Example
Total body water =42liters
Plasma volume =5.5liters
When a drug in the body of a person is 400mg and plasma conc. Of this drug is 40mg/lit then the
volume of distribution will be:
V/d =
400 mg
40mg/lit
= 10liters
Now consider that
• If Vd 5.5 liter, then the whole drugs will remain in plasma and no portion will go to the tissues.
• If the Vd is 11liters, then half of drug will remain in plasma and half is distributed to the tissues.
• If the Vd of drug is 42 liters, It will be distributed in the whole body fluid -----5.5liters in plasma and remaining to the tissue. i.e. major portion of the drug is distributed to the tissue and concentration of drug in the blood is less.
• If Vd is 300liters, then very little drug is present in blood and maximum is concentrated i
the tissues i.e. drug with short plasma half life has high volume of distribution.
Note: As I have mentioned above that the distribution of drug mainly depends on protein binding. Therefore the drug that has tendency to extensively bind to plasma protein, will be retained in the blood, distribution to the tissues is least and therefore the volume of distribution will also be towards lower limit e.g. 7liters, 9liters. The drug which has greater affinity for tissue proteins than that of plasma protein will be very less cons. In blood and major portion will be distributed to the tissues and then the volume of distribution will also be towards upper limit e.g. 40liters, 300liters.
BIOAVAILABILITY
Bioavailability is the extent of absorption of a drug following its acministration by routes other than intravenous injection. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100mg of a drug is administered unchanged , the bioavailability is 70%.
Bioavailability is determined by comparing plasma levels of drug after a particular route of administration (e.g. oral) with plasma drug levels achieved by intravenous administration.
FACTORS AFFECTING BIOAVAILABILITY
• Route of administration
When a dose of a drug is given intravenously, the whole drug reaches in circulation and the bioavailability is equal to one.
When a drug is administered through other route (such as orally) bioavailability maybe less than one for the following reasons:
• Incomplete absorption
• Solubility of drug
After oral administration, a drug maybe incompletely absorbed because of too hydrophilic that cannot pass through the lipid cell membrane, or too lipophilic that the drug is not soluble enough to cross the water layer adjacent to the cell.
• First-pass hepatic metabolism
Metabolism liver prior to entry into the systemic circulation is called first-pass metabolism. After absorption in the gut drug enters in to the portal circulation. If the drug is rapidly metabolized by the liver, the amount of unchanged drug that enter into
the systemic circulation is decreased. Drugs such as propranolol and nitrates undergo significant hepatic metabolism during a single passage through the liver.
• Chemical instability
Some drugs such as penicillin G is unstable in the of gastric contents.
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