Absorption
Absorption is the transfer of the drug from its site of administration to the bloodstream.
The rate and extent of absorption depends on the route of administration, the formulation
and chemical properties of the drug, and physiological factors which can impact the site of absorption.
Administration of a drug by any other route may result in less availability of drug due to incomplete absorption. When a tablet or capsule is swallowed, it must dissolve before its absorption. The process is called as dissolution. Once dissolution has occurred, the drug molecules pass through the membrane of the cells lining GIT to reach the blood stream. The drug will be absorbed by one of the mechanisms mentioned earlier. The rate and extent of absorption of drug is termed as its bioavailability.
Bioavailability
The area under curve (AUC) of plasma concentration versus
time represents the total amount of drug reaching systemic circulation. AUC will have a different shape depending on the route of administration. The AUC obtained after intravenous administration is considered to be 100%. This is termed as absolute bioavailability of a drug. Any other route (intramuscular, subcutaneous, oral, dermal etc.) will have lesser bioavailability. The ratio of AUC for any formulation/ route of administration in.comparison to intravenous formulation is termed as relative bioavailability of a drug.
Factors affecting absorption
A number of patient-specific factors can affect absorption. Proper absorption needs adequate blood flow to the site of administration. Most absorption after oral administration occurs in small intestine because of larger surface area and greater blood flow. If small
intestine is partially removed, as in case of bariatric surgery, impairment of absorption of drugs can occur.
Contact time with epithelial lining of gastrointestinal tract is an important factor in drug absorption. In patients with severe diarrhoea, drug absorption may be adversely affected because of rapid transit time in gastrointestinal tract. Contrary to this, if gastric emptying
time is delayed, as in case of large fatty meal, it may delay and potentially reduce absorption. Some medications exhibit drug-food or drug-drug interactions with other
compounds present in gastrointestinal tract. The interaction between tetracycline and dairy products or antacids is an example. Absence of hydrochloric acid in stomach is called as
achlohydria. It is common in elderly population. Patients with achlorhydria may experience
inadequate tablet dissolution and therefore poor drug absorption.
Distribution
Once a drug is absorbed in systemic circulation, it can be carried throughout the body. This process is called as distribution. It is a reversible process. The delivery of a drug from the blood stream to the site of drug action depends on blood flow, capillary permeability, degree of binding to blood and tissue proteins, and relative lipid-solubility of the drug molecule.
Blood flow to the different organs of the body is unequal. Penetration into central nervous system is yet another factor. The anatomical structure of capillary networking in the brain creates a barrier to passage of many drugs in the CNS. This
is called as blood-brain barrier. Lipid-soluble substances enter the brain very easily.
Factors affecting distribution of drugs
Most drugs reversibly bind to plasma proteins in varying degree. Albumin is the most abundant plasma protein with an ability to bind drugs. Only free fraction of the drug is biologically active. There is an equilibrium between free and bound drug to proteins like albumin. Albumin acts as a reservoir for administered drug. Some drugs may have binding of 95-98% to albumin.
With highly protein bound drugs, low albumin levels may lead to toxicity because of lesser binding
sites.
Competition for binding sites is yet another factor. If two drugs can compete for the same site on albumin and one drug is capable of displacing another drug from the site of binding, then an interesting drug interaction is observed.
Other patient variables that can affect distribution include body composition,heart failure, and age of the patient. These factors affect Vd of a drug.
Dosing of medications in infants and children requires special consideration. It is to be noted that “children are not simply small adults”. Bodies of children/infants contain a high % of water and low % of muscle and fat. Especially in neonates, albumin may be lower. All these variations can alter Vd significantly; hence dosage for
neonates/infants/children should be carefully adjusted.
Metabolism
While the drugs are getting distributed in different parts of body, there are chemical changes in their structures due to interaction with various enzymes or due to other chemical reactions. The process of chemical change is called as biotransformation or metabolism.
Liver is major site for drug metabolism, but specific drugs may undergo metabolism in other
tissues. The purpose of metabolism is to convert the drug into more water soluble
compounds. There are two types of metabolic processes which drugs undergo.
In the first type of reaction, drugs are converted into more polar compounds through
oxidation-reduction reactions or hydrolysis. These reactions use microsomal enzymes
located in the liver, called as cytochrome P450 enzyme system. In enzyme-catalysed reactions, the rate of reaction is accelerated by presence of enzymes. Since the quantum of enzymes is limited, metabolism is considered as a saturable process. Once enzymes are saturated, blood levels of drug increase exponentially which may lead to toxicity. Examples
include metabolism of alcohol or phenytoin.
The second type of metabolism involves conjugation reactions. In this type of reactions,
drugs undergoing metabolism are joined with another substance like glucuronic acid, sulphuric acid, acetic acid or an amino acid. Glucuronidation reaction is the most common.
As a result of conjugation reaction, the drug or its metabolite is converted to more water soluble compound which is easier for kidneys to excrete.
For some drugs initially administered compound, called as pro-drug is not biologically
active. Metabolism converts the pro-drug into the active compound.
Excretion
The complete removal of drug from the body is termed as its elimination. Elimination of the drug includes its metabolism and excretion through kidneys and to a lesser degree into bile. Excretion in urine is one of the most important mechanisms of drug removal.
Drug molecules in blood which are not bound to albumin also get filtered in the glomerular filtrate. When drugs have not been converted to water soluble compounds in the liver, they are likely to be reabsorbed into blood at the end of filtration process and will cycle through the body again. If they are water soluble, they will be excreted in urine.
When a medication is given repeatedly, the total amount of drug in the body will increase up to a point and then stabilise. At this point, the amount being taken by the
patient is equal to the amount being removed by the liver and kidneys. This state of equilibrium is called as steady state.