Monday, March 31, 2014

Pharmacokinetics


1.  INTRODUCTION

What is Pharmacology?
The term derived from “Pharmacon” meaning a ‘drug’ and “logos” meaning a ‘science’. So, in short, Pharmacology can also be defined as a science of Drugs.
Definitions:
Pharmacology is the study of how drugs exert their effects on living systems. Pharmacologists work to    identify drug targets in order to learn how drugs work. Pharmacologists also study the ways in which drugs are modified within organisms. In most of the pharmacologic specialties, drugs are also used today as tools to gain insight into both normal and abnormal function.  
Divisions of Pharmacology
i.              Pharmacokinetics
ii.             Pharmacodynamics
i.Pharmacokinetics
 Is what the body does to the drug?  The magnitude of the pharmacological effect of a drug depends on its concentration at the site of action. 
•          Absorption
•          Distribution
•          Metabolism
•          Excretion
ii.Pharmacodynamics
Is what the drug does to the body? 
Drug-Receptor Interactions
–        Binding
Dose-Response
–        Effect
  What is Drug?
Drugs can be defined as chemical agents that uniquely interact with specific target molecules in the    body, thereby producing a biological effect.
WHO definition of Drug-“any substance or product that is used for or intended for used to modify or explore physiological systems or pathological states for the benefit of the recipient”
Drug categories:  Drug fall into two categories 
a. Non- Prescription Drug (OTC Drug)
   These are safe and can be sold over the counter without prescription, e.g. Vitamins, antacids etc.

b. Prescription Drugs

   These are classified in various schedules and are used under medical supervision and dispensed by an order of a registered medical practioner, e.g. antibiotics, anxiolytics, antidepressants etc.

 

Drug Nomenclature: Every drug has three types of names

  1. Chemical Name:
This is a name given according to the chemical constitution of a drug. It is cumbersome to use in a prescription sometimes a code name, e.g. SKF-525-A may be given by the manufacturer for convince before an approved name is allotted to the drug: but this is neither a chemical nor a official name.
Non-Proprietary or Generic Name:
The United States Adopted Name (USAN) council assigns these names, only when the drug has been found to be of potential therapeutic usefulness. These names are used uniformly al over the world by an International agreement through the WHO.When include in an official pharmacopoeia, the non –proprietary name is very frequently referred to as generic name.
Proprietary Name or Brand Name: The trade name or Brand Name selected by Pharmaceutical Company.

2. NATURE AND SOURCES OF DRUGS


a. Synthetic source

Presently the majority of drugs are obtained synthetically or semi- Synthetically. Some of the drugs that were earlier obtained from plant or animal source are today synthesized in the laboratories. The Advantages Being:
  1. Their quality can be better controlled
  2. The process is easier and cheaper
  3. The chemical structure of the prototype drug can be modified in search of better, more potent and safer drug because the pharmacological activity of a drug is a function of its chemical structure and physical properties.

b. Vegetable source

Drug belong to the categories are usually obtained from vegetable source.
1. Alkaloids
These are nitrogenous heterocyclic bases derived from plants. Alkaloids as such are insoluble in water but being alkali-like, they form salts with acids, which are water-soluble.
Alkaloids are pharmacologically active principal plants. e.g. atropine from Atropa belladona
2. Glycosides
 Glycosides are those plant products, where a sugar moiety is joined to a non- sugar moiety with an ether linkage (-o-). However, if the sugar moiety is glucose, the glycoside is called a glycoside and if it is an amino sugar then it is called as amino glycoside.
3. Oils
The following three types of oils are generally used for various medical purposes.
A. Essential oils (or Volatile oils)
These are obtained from leaves or flower petals by steam distillation. These are obtained from steam volatile, have aroma, have no caloric or food value, do not form soaps with alkalis and do not become rancid. e.g. eucalyptus oil, clove oil.
B. Fixed oils
These are non-volatile, have caloric or food value, from soaps with alkalis and become rancid after prolonged stay. These are obtained by solvent extraction of crushed seeds.
C. Mineral oil
These are mostly petroleum products and are obtained by dry distillation of woods. These have no food value and do not become rancid.
4. Gums
These are colloidal exudates of the plants. They either swell, or dissolve or form adhesive mucilage in water. These are used as emulsifying or suspending agents, e.g. gum acacia and gum tragacanth.
5. Tannins
These are non- nitrogenous phenolic derivatives from plant source and are soluble in water. Mainly used as astringents, e.g. tinct. catechu and tinct. 
6. Resins
These are polymers of volatile oil and are insoluble in water, e.g. benzoin, tinct. Benzoin colophony and shellac.
c. Animal source
 Many drug are obtained from animal source and these comprise hormones, vitamins vaccines and sera e.g. insulin from pancreas, vitamin B12 from liver.
d. Micro Biological source
Some of the fungi, moulds and bacteria are important source of many lives saving drugs e.g. penicillin from Penicilium notatum, Chloramphenicol from Streptomyces venezuelae.
e. Mineral source
Many minerals are also used in Pharmacology, e.g. ferrous sulphate in anemia, magnesium sulphate as purgative.
f. Genetically engineered drugs
This relatively new methodology involves the blending of discoveries from molecular biology.






 



















 

3. ROUTES OF DRUG ADMINISTRATION


The route of administration (ROA) that is chosen may have a profound effect upon the speed and efficiency with which the drug acts, the possible routes of drug entry into the body may be divided into two classes:
A.
Enteral routes
1.    Oral
2.    Sublingual
3.    Rectal
B. Par-Enteral routes
i. Injection
  1. Intravenous
  2. Intramuscular
  3. Intraperitoneal
  4. Intrathecal
  5. Intra- arterial
  6. Intramedullary
  7. Intra-articular
  8. Subcutaneous
  9. Intra dermal
  10. Intra Cardiac
ii.            Inhalation
C. Topical routes
1.    Transdermal
2.    Conjunctival
3.    Vaginal and urethral
4.    Inunctions


A. Enteral - Drug placed directly into the GI tract:
1. Sublingual/Buccal- Placed under the tongue

Some drugs are taken as smaller tablets, which are held in the mouth or under the tongue.

Advantages
  1. Rapid absorption  ii. Drug stability  iii. Avoid first-pass effect




Disadvantages

      i.        Inconvenient    ii. Small doses   iii. Unpleasant taste of some drugs


2. Oral: swallowing a drug through mouth.

Advantages

  1. Convenient - can be self- administered, pain free, easy to take
  2. Absorption - takes place along the whole length of the GI tract
  3. Cheap - compared to most other parenteral routes



Disadvantages

  1. Sometimes inefficient - only part of the drug may be absorbed
  2. First-pass effect - drugs absorbed orally are initially transported to the liver via the portal vein
  3. Irritation to gastric mucosa - nausea and vomiting
  4. Destruction of drugs by gastric acid and digestive juices
  5. Effect too slow for emergencies
  6. Unpleasant taste of some drugs
  7. Unable to use in unconscious patient
First-pass Effect

The first-pass effect is the term used for the hepatic metabolism of a pharmacological agent 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







3. Rectal:  Absorption through the rectum

Advantages

  1. Unconscious patients and children
  2.  If patient is nauseous or vomiting
  3.  Easy to terminate exposure
  4.  Absorption may be variable
  5.  Good for drugs affecting the bowel such as laxatives

Disadvantages
i.              Chances of rectal inflammation
ii.             Absorption is unreliable
iii.            Inconvenient and embarrassing to the patient.
iv.           Irritating drugs contraindicated

B. Parenteral Routes




Injection Routes: I. Intravascular: For the intravenous route, a needle is inserted directly into a vein. A solution containing the drug may be given in a single dose or by continuous infusion.
Advantages
i.              Absorption phase is bypassed
 (100% bioavailability)
  1. Precise, accurate and almost immediate onset of     action, 
  2. Large quantities can be given, fairly pain free

  1. By Pass first pass effect.

  1. Can be employed unconscious patients.

  1. Amount of drug can be controlled.
Disadvantages
i.              Strict aseptic condition is needed.
ii.             Painful
iii.            Drugs once injected cannot be withdrawal
iv.           Oil suspensions drug cannot be administered
v.            Depot injection not possible.
vi.           Necrosis can be chances.

II. Intramuscular:

The Intramuscular route is preferred to the subcutaneous route when larger volumes of a drug product are needed. Because the muscles lie below the skin and fatty tissues, a longer needle is used. Drugs are usually injected into muscle in the upper arm, thigh, or buttock. How quickly the drug is absorbed into the bloodstream depends, in part, on the blood supply to the muscle: The sparser the blood supply, the longer the drug takes to be absorbed. The blood supply is increased during physical activity.
Advantages
                                          i.        Very rapid absorption of drugs in aqueous solution
                                         ii.        Depot injection is possible.


Disadvantages

i.              Pain at injection sites for certain drugs
ii.             Perfect aseptic conditions are needed.
iii.            Chances of Nerve damage.
iv.           Large volume cannot be injected.

III. Subcutaneous: For the subcutaneous route, a needle is inserted into fatty tissue just beneath the skin. The drug is injected, then moves into small blood vessels (capillaries) and is carried away by the bloodstream or reaches the bloodstream through the lymphatic vessels. Protein drugs that is large in size, such as insulin

Advantages
i.              Smooth but slower absorption.
ii.            Depot injection is possible.
Disadvantages

  1. Slow and constant absorption
  2. Absorption is limited by blood flow affected if circulatory problems exist 
  3. Concurrent administration of vasoconstrictor will slow absorption
IV. Intrathecal: (Intra spinal) For the intrathecal route, a needle is inserted between two vertebrae in the lower spine and into the space around the spinal cord. The drug is then injected into the spinal canal. A small amount of local anesthetic is often used to numb the injection site. This route is used when a drug is needed to produce rapid or local effects on the brain, spinal cord, or the layers of tissue covering them (meninges)—for example, to treat infections of these structures. Anesthetics are sometimes given this way.

 

V. Intramedullary: Injection into the tibial or sternal bone marrow.e.g. Bone marrow transplantation.
VI. Intraperitoneal: Into the peritoneal space. Lesser in use except for giving anti rabies injection or peritoneal injection.
VII. Intra- arterial: Into the lumen of the desired artery.e.g. Radio opaque contrast media for coronary angiographies and cerebral angiographies.
VIII. Intra- articular: Injection directly into the joint space.e.g. Hydrocortisone or gold chloride injection.

Inhalation: Gaseous and volatile agents and aerosols Rapid onset of action due to rapid access to circulation

        a. Large surface area
        b. Thin membranes separate alveoli from circulation 
        c. High blood flow
Particles larger than 20 micron and the particles impact in the mouth and throat. which cause problem, Smaller than 0.5 micron and they aren't retained.  
  1. Respiratory system. Except for IN, risk hypoxia.
  2. Intranasal (snorting) Snuff, cocaine may be partly oral via post-nasal dripping. Fairly fast to brain, local damage to septum. Some of the volatile gases also appear to cross nasal membranes.
  3. Smoke (Solids in air suspension, vapors) absorbed across lung alveoli: Nicotine, opium, THC, freebase and crack cocaine, crystal meth. Particles or vapors dissolve in lung fluids, and then diffuse. Longer action than volatile gases. Tissue damage from particles, tars, CO.
  4. Volatile gases: Some anesthetics (nitrous oxide, ether) [precise control], petroleum distillates. Diffusion and exhalation (alcohol).
  5. Lung-based transfer may get drug to brain in as little as five seconds.
C.
Topical
Mucosal membranes (eye drops, antiseptic, sunscreen, callous removal, nasal, etc.) 
1. Skin

    1. Dermal - rubbing in of oil or ointment  (local action)  
 b. Transdermal - absorption of drug through skin (systemic action)
i.              Stable blood levels
ii.             No first pass metabolism
iii.            Drug must be potent or patch becomes to large
2.    Vaginal Route: Some drugs may be administered vaginally to women as a solution, tablet, cream, gel, or suppository. The drug is slowly absorbed through the vaginal wall. This route is often used to give estrogen to women at menopause, because the drug helps prevent thinning of the vaginal wall, an effect of menopause
3.    Ocular Route: Drugs used to treat eye disorders (such as glaucoma, conjunctivitis, herpes simplex infection, and injuries) can be mixed with inactive substances to make a liquid, gel, or ointment, so that they can be applied to the eye. Liquid eye drops are relatively easy to use but may run off the eye too quickly to be absorbed well. Gel and ointment formulations keep the drug in contact with the eye surface longer. Solid inserts, which release the drug continuously and in slow amounts, are also available, but they may be hard to put and keep in place. Ocular drugs are almost always used for their local effects. For example, artificial tears are used to relieve dry eyes.

4.    Nasal Route: If a drug is to be breathed in and absorbed through the thin mucous membrane that lines the nasal passages, it must be transformed into tiny droplets in air (atomized). Once absorbed, the drug enters the bloodstream. Drugs taken by this route generally work quickly. Some of them irritate the nasal passages. Drugs that can be taken by the nasal route include nicotine

5.    Cutaneous Route: Drugs applied to the skin are usually used for their local effects and thus are most commonly used to treat superficial skin disorders, such as psoriasis, eczema, skin infections (viral, bacterial, and fungal), itching, and dry skin. The drug is mixed with inactive substances. Depending on the consistency of the inactive substances, the formulation may be an ointment, a cream, a lotion, a solution, a powder, or a gel
6. Transdermal Route: Some drugs are delivered body wide through a patch on the skin. These drugs, sometimes mixed with a chemical (such as alcohol) that enhances penetration of the skin, pass through the skin to the bloodstream without injection. Through a patch, the drug can be delivered slowly and continuously for many hours or days or even longer. As a result, levels of a drug in the blood can be kept relatively constant. Patches are particular useful for drugs that are quickly eliminated from the body, because such drugs, if taken in other forms, would have to be taken frequently. However, patches may irritate the skin of some people. In addition, patches are limited by how quickly the drug can penetrate the skin. Only drugs to be given in relatively small daily doses can be given through patches. Examples of such drugs include nitroglycerin
Route for administration -Time until effect-
  1. Intravenous 30-60 seconds
  2. Intraosseous 30-60 seconds
  3. Endotracheal 2-3 minutes
  4. Inhalation 2-3 minutes
    v.        Sublingual 3-5 minutes
  1. Intramuscular 10-20 minutes
  2. Subcutaneous 15-30 minutes
  3. Rectal 5-30 minutes
  4. Ingestion 30-90 minutes
  5. Transdermal (topical) variable (minutes to hours)



Time-release preparations

Oral - controlled-release, timed-release, sustained-release
Designed to produce slow, uniform absorption for 8 hours or longer
Better compliance, maintain effect over night, and eliminate extreme peaks and troughs
Depot or reservoir preparations - parental administration (except IV), may be prolonged by using insoluble salts or suspensions in non-aqueous vehicles.
The ROA is determined by the physical characteristics of the drug, the speed that the drug is absorbed and/ or released, as well as the need to bypass hepatic metabolism and achieve high conc. at particular sites

Through the Skin
4. PHARMACOKINETICS INTRODUCTION
Pharmacokinetics (in Greek: "pharmacon" meaning drug and "kinetics" meaning putting in motion,  is a branch of pharmacology . Pharmacokinetics is often divided into several areas including, but not limited to, the extent and rate of Absorption, Distribution, Metabolism and Excretion. This sometimes is referred to as the ADME scheme.Pharmacokinetics is sometimes abbreviated as "PK".

The LADME scheme

LADME describes the pharmacokinetic processes which follow a given dosage regimen.
  • L = Liberation, the releases of the drug from its dosage form.
  • A = Absorption, the movement of drug from the site of administration to the blood circulation.
  • D = Distribution, the process by which drug diffuses or is transferred from intravascular space to extra vascular space (body tissues).
  • M = Metabolism, the chemical conversion or transformation of drugs into compounds, which are easier to eliminate.
  • E = Excretion, the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes.
LADME processes can be divided into two classes, drug input and drug output.
Input processes are:
  • L = Liberation, the releases of the drug from its dosage form.
  • A = Absorption, the movement of drug from the site of administration to the blood circulation. The term commonly used to describe the rate and extent of drug input is bioavailability. Drugs administered by intravenous routes exhibit essentially 100% bioavailability.
Output processes, or dispositions of drug are:
  • D = Distribution, the process by which drug diffuses or is transferred from intravascular space to extra vascular space (body tissues).
  • M = Metabolism, the chemical conversion or transformation of drugs into compounds those are easier to eliminate.
  • E = Excretion, the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes.



5.
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





Mechanisms of solute transport across membranes

  1. Passive diffusion
  2. Filtration and bulk flow
  3. Endocytosis
  4. Ion-pairing

  1. Active Transport



Movement of Drugs across Biological Membranes (Biotransport)
Biotransport is the translocation of a solute from one phase to another phase without a change in the form of the solute.  Process of Biotransport are resposible
a. Molecular size and shape
b. Lipid solubility
i. Partition coefficient - relation to lipid solubility
ii. Weak acids - weak bases
II. Mechanism of Biotransport
A. Passive Processes
1. Passive diffusion is the direct movement of a solute through a biologic barrier from the phases of higher concentration to a phase of lower concentration. There is no requirement of energy. This is the most common mechanism of transport. The rate of diffusion is related to lipid solubility and polarity, pH, etc. previously discussed. The concentration gradient is the most important factor in determining rate. The rate of diffusion can be expressed by the following equation
(Ficks Law of Diffusion)
Rate of diffusion = KA (C1 - C2)/d
K = diffusion constant, (M.W., shape of molecule degree of ionization, lipid solubility).
A = surface area available
d = thickness of membrane
C1-C2 =concentration gradient
NOTE: For a given membrane A and will be constant
Lipid-Water Partition Coefficient
The ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (representing the membrane); and an aqueous buffer, pH 7.4 (representing the plasma)


The higher the lipid/water p.c. the greater the rate of transfer across the membrane
  1. Increasing Polarity of a drug, by increasing ionization will   decrease   the lipid/ water p.c.
  2. Decreasing Polarity of a drug, suppression of ionization will increase the lipid/ water p.c.


A.2. Filtration
Involves the bulk flow of water related to osmotic and hydrostatic pressures. This process transports small water soluble, polar and non-polar, substances. It is most probable that these substance pass through spaces between cells rather than across the cell membrane. It is a purely physical process and the most important force is a pressure gradient. Examples include water and urea.
B. Specialized Transport Mechanisms or Carrier mediated Transport
Specialized transport mechanisms give the membrane selectively so that it can control the transport of specific substances into and out of the cell or across the cell membrane.
1. Facilitated diffusion or (Down-Hill transport)
This is a carrier mediated transport system characterized by:
Selectivity, Competitiveness, Saturability, Concentration gradient
Lower conc.
 
No energy is required for this transport. The rate of transport is at first related to the concentration gradient but as the gradient but as the gradient increased the rate reaches a limiting or maximal rate.
Carrier
 
 Higher conc.           
Drug
 
Carrier-Drug
 
Drug
 
                                 Lower Con
 


a.    Carrier can move a drug substrate along its concentration gradient only
b.    As in passive diffusion, no extra cellular energy required for translocation of drug.
c.    It is capacity limited process. The rate of diffusion depends upon and carrier and is limited by the availability of carrier.

2. Active transport (Up-Hill transport)
This too is a carrier mediated transport system, but energy is required and the transport is against a concentration gradient. It too, however, is characterized by saturability, selectivity, and competitiveness.
Higher conc
 
Lower conc.
 
Carrier
 
Drug
 
 






3. Pinocytosis
A transport mechanism that requires energy. The transport mechanism is by invagination of the cell membrane to form a vesicle and the engulfing of the invagination Pinocytosis
Stages of Pinocytosis. Macromolecular solutes in contact with the membrane are trapped in microscopic cavities or cups - invaginations - formed on the surface of the membrane. The membrane fuses around and completely encloses the fluid to form a vesicle. The vesicle is pinched off, passing some fluid and solutes, across the membrane into the interior of the cell.

How drugs are absorbed

 

A. Absorption via Gastrointestinal tract

The digestive tract is the system of organs within multicellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste. The major functions of the GI tract are ingestion, digestion, absorption, and excretion.
The GI tract differs substantially from animal to animal. Some animals have multi-chambered stomachs, while some animals' stomachs contain a single chamber. In a normal human adult male, the GI tract is approximately 6.5 meters (20 feet) long and consists of the upper and lower GI tracts. The tract may also be divided into foregut, midgut, and hindgut, reflecting the embryological origin of each segment of the tract.

Upper gastrointestinal tract

The upper GI tract consists of the mouth, pharynx, esophagus, and stomach.
  • The mouth contains the buccal mucosa, which contains the openings of the salivary glands; the tongue; and the teeth.
  • Behind the mouth lies the pharynx, which leads to a hollow muscular tube, the esophagus.
  • Peristalsis takes place, which is the contraction of muscles to propel the food down the esophagus which extends through the chest and pierces the diaphragm to reach the stomach.

 Lower gastrointestinal tract

The lower GI tract comprises the intestines and anus.
§      Rectum
   B.  Absorption via Parentral sites
                                 Drug when injected intravenously are completely absorbed and rapiodly distributed as they reach the blood stream directley withoyt crossing any membrane. Absorption following Iintramuscular and subcutaneous injections usually occurs by pasive diffusion from the injection site to the plasma or lymph. Filtration through channels in the endothelial capillary membrane is also very efficient.
 C. Absorption via Lungs
                                 Lipid soluble drugs when given in a vapourised form or as aqueous solution spray or as spray of suspended micro fined particles are absorbed by simple diffusion from the mucous mambrane of trachea and lungs. Absorption is rapid because of the large surface area and hiigh vascularity
. Factor that modify absorption:
A.   Pharmaceutical factor
B.   Pharmacological factor
A. Pharmaceutical factor
1. Physicochemical factors for Bio transport of Drug
                         Oral Administration of Drug
     (Dosage form: Tab/Cap/Powder/Solution/Suspension)
1. Disintegration
 
Available for absorption through GIT
 
 









2. Drug product -Form of preparation administered drug solubility, ease of dissolution, concentration administered, tablet, capsule, solution, suspension, etc.
3. Physical state: Drugs in the form of liquids are well absorbed   than solids. Gases are quickly absorbed through lungs.
4. Particle size: Smaller the particle size better is the absorption of drug. lf the particle size is large, the drug is slowly absorbed and  hence the action is delayed.
 5. Solubility: An easily soluble drug is quickly absorbed. ·Also drug in the form of solutions are quickly absorbed than solids.
6. Concentration: Concentrated forms of drugs are quickly absorbed than dilute solutions
7. Salt Form:  Salts of weakly acidic drugs as a rule are highly water soluble. Free acidic drug is precipitated from these salts in a microcrysaline from which has faster dissolution rate and hence enhanced bioavaiability, e.g sodium tolbutamide and sodium secobarbital have better bioavailability than tolbutamide and secobarbital.
8. Crystal form: The absorption rate and bioavailability of a drug depends on its crystalline form also e.g amorphous chloramphenicol palmitate and amourphousnovobiocin have faster dissolution rate and better bioavailability compared to their crystalline forms.
B. Pharmacological factor
1. Area of absorbing surface: Greater the area of absorbing surface, quicker is the absorption of a drug for example; lungs and peritoneal cavity are large surface areas from where drugs can be quickly absorbed.
2. Circulation to site of absorption: Increased blood flow to the area of absorption can increase the absorption of a drug. This can be achieved by massage or local application of heat. Vasoconstrictors decrease blood flow and so decrease the absorption of a drug.
 3. Route of administration: This is a very important factor which determines drug absorption. Some drugs are absorbed only on   parenteral administration and they fail to get · absorbed on oral administration e.g. insulin. So it is necessary to carefully choose the route of administration of a drug.
4. Gastric Emptying: Accelerate gastric emptying, permit drugs to reach the large absorptive surface area of small intestine sooner and increase the bioavailability.
5. Gastro intestinal Disease: Achlorhydria gastric acid secretion is decreased with concomitant increase in gastric Ph.
6. First Pass effects: All drugs taken orally, first of all pass through GIT wall and then through portal system before reaching systemic circulation. First pass effect means the drug degradation occurring before the drug enters the systemic circulation.
7. Drug -drug interaction: Differences in bioavailability can also be observed due to drug-drug interactions.

Bioavailability Drug

 

Bioavailability

Definition: Is defined as per U.S.FDA as “the rate at which and the extent at which the active concentration of the drug is available at the desired site of action”

Absolute bioavailability

Absolute bioavailability measures the availability of the active drug in systemic circulation after non-intravenous administration (i.e., after oral, rectal, transdermal, subcutaneous administration).
In order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (IV) and non-intravenous administration. Therefore, a drug given by the intravenous route will have an absolute bioavailability of 1 (F=1) while drugs given by other routes usually have an absolute bioavailability of less than one.

 Relative bioavailability

This measures the bioavailability of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute bioavailability.

 Factors influencing bioavailability

The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e. F<1). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation,
Such factors may include, but are not limited to:
  • poor absorption from the gastro-intestinal tract
  • degradation or metabolism of the drug prior to absorption
  • hepatic first pass effect

Bioequivalence

Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same. For example, between two products such as a commercially-available Brand product and a potential to-be-marketed Generic product, pharmacokinetic studies are conducted whereby each of the preparations are administered in a cross-over study to volunteer subjects.

6. DISTRIBUTION

 

Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible transfer of drug from one location to another within the body.
The distribution of a drug between tissues is dependent on permeability between tissues (between blood and tissues in particular), blood flow and perfusion rate of the tissue and the ability of the drug to bind plasma proteins and tissue.
Distribution of Drug in Special Compartments
Blood Brain Barrier
n  These barriers influence the distribution of drugs. The blood brain barrier is of particular significance since it is desirable to attain therapeutic concentrations in the brain tissue of certain drugs. On the other hand, it is not desirable for many drugs. The BBB is formed by the single layer of endothelial cells that line the inner surfaces of capillaries in the brain.
n  It is a semi-permeable capillary membrane; that is, it allows some materials to cross, but prevents others from crossing. In most parts of the body the capillaries, are lined with endothelial cells. The endothelial tissue has small spaces between each individual cell so substances can move readily between the inside and the outside of the vessel. However, in the brain, the endothelial cells fit tightly together and substances cannot pass out of the bloodstream. (Some molecules, such as glucose, are transported out of the blood by special methods such as active transport.)
n  The BBB has several important functions:
n  Protects the brain from "foreign substances" in the blood that may injure the brain.
n  Protects the brain from hormones and neurotransmitters in the rest of the body.
n  Maintains a constant environment for the brain.
n  General Properties of the BBB
n  Large molecules do not pass through the BBB easily.
n  Low lipid (fat) soluble molecules do not penetrate into the brain. However, lipid soluble molecules rapidly cross the BBB into the brain.
n  Molecules that have a high electrical charge to them are slowed.
n  Therefore:
n  The BBB is selectively permeable to :Oxygen, Carbon dioxide and glucose
n  The BBB is not permeable to  hydrogen ions
Blood –CSF Barrier- Cerebrospinal fluid is secreted by the epithelial cells of the choroid plexus and these are by occluding zonulae. Here only nonionnisable lipid soluble drug can cross CSF- brain barrier.
 Placental Barriers
The placenta also acts as a barrier between the maternal circulation and the fetal circulation. The same principles applied here as for other membranes. Lipid soluble drugs diffuse across more rapidly than polar compounds. Constant levels of a drug in the maternal circulation will eventually each equilibrium with the fetal circulation. Fortunately, this requires time. The fastest possible time is estimated to be 40 minutes. Certain parts of the brain do not have a barrier to the entrance of polar substance. N-acetyl-4-aminoantipyrine, a compound having a low lipid-solubility, enters the CSF and brain slowly but penetrates the area postrema, the intracolumnar tubercle, the anterior and posterior pituitary and the pineal gland at the same rate as it penetrates liver and muscle. It has been suggested that these tissues are not really part of the brain but merely contiguous with it; in fact, the cells of these areas are not said to be non-neuronal

Vascular permeability

Vascular permeability characterizes the capacity of a blood vessel wall to pass through small molecules (ions, water, and nutrients) or even whole cells (lymphocytes on their way to the site of inflammation). Blood vessel walls are lined by a single layer of endothelial cells. The gaps between endothelial cells (cell junctions) are strictly regulated depending on the type and physiological state of the tissue.

Plasma protein binding

A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ globulins.
A drug in blood exists in two forms: bound and unbound. Depending on a specific drug's affinity for plasma protein, a proportion of the drug may become bound to plasma proteins, with the remainder being unbound. If the protein binding is reversible, then a chemical equilibrium will exist between the bound and unbound states, such that:
Protein + drug ⇌ Protein-drug complex
Notably, it is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be metabolized and/or excreted. Protein binding can influence the drug's biological half-life in the body. The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. Since the unbound form is being metabolized and/or excreted from the body, the bound fraction will be released in order to maintain equilibrium.

 

Types of Plasma Protein

Globulins are of three types- alpha, beta and gamma.
Other types of blood proteins include:
  1. Lipoproteins (chylomicrons, VLDL, LDL, HDL)
  2. Transferrin   3. Prothrombin
The main influence of plasma proteins on drugs is in their distribution. The most important plasma proteins in this context are albumin, acid-glycoprotein and beta globulin. Since albumin is basic, acidic and neutral drugs will primarily bind to albumin. If albumin becomes saturated, then these drugs will bind to lipoprotein. Basic drugs will bind to the acidic alpha-1 acid glycoprotein. This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins. Only the unbound fraction of the drug undergoes metabolism in the liver and other tissues. As the drug dissociates from the protein more and more drug undergoes metabolism. Changes in the levels of free drug change the volume of distribution because free drug may distribute into the tissues leading to a decrease in plasma concentration profile.
What is the effect of protein binding on drug action?
For a drug showing little protein binding, the plasma acts simply as a watery solution in which the drug is dissolved. Where protein binding does occur the behavior of the drug may be influenced in several ways:
1. Extensive plasma protein binding will increase the amount of drug that has to be absorbed before effective therapeutic levels of unbound drug are reached. For example, acidic dugs (such as acetyl salicylic acid – aspirin) are often substantially bound to albumin.
2. Elimination of a highly bound drug may be delayed. Since the concentration of free drug is low, drug elimination by metabolism and excretion may be delayed. This effect is responsible for prolonging the effect of the drug digoxin.
3. Changes in the concentration of plasma proteins will influence the effect of a highly bound drug. A low plasma protein level may occur in old age or malnutrition. It may also be caused by illness such as liver disease (remember that most plasma proteins are made in the liver), or chronic renal failure where there is excessive excretion of albumin. In each case the result is a smaller proportion of drug in bound form and freer drug in the plasma. The greater amount of free drug is able to produce a greater therapeutic effect and reduced drug dosages may be indicated in these cases
4. Drugs may compete for binding with plasma proteins leading to interactions. This is significant for highly bound drugs such as the anticoagulant warfarin since even a small change in binding will greatly affect the amount of free drug. Such an effect is produced by the concurrent administration of aspirin, which displaces warfarin and increases the amount of free anticoagulant. 
 
Drug Distribution Factors
·         Blood Flow
The rate at which a drug reaches different organs and tissues will depend on the blood flow to those regions. Equilibration is rapidly achieved with heart, lungs, liver, kidneys and brain where blood flow is high. Skin, bone, and depot fat equilibrate much more slowly. 
·         Lipid Solubility
Lipid solubility will affect the ability of the drug to bind to plasma proteins and to cross lipid membrane barriers.
Very high lipid solubility can result in a drug initially partitioning preferentially into highly vascular lipid-rich areas. Subsequently these drugs slowly redistribute into body fat where they may remain for long periods of time. 
·         Effects of pH
Effects of pH on the partitioning or "trapping" of drugs will not be as dramatic as those seen between the stomach and plasma since the pH differences are not as great. Nevertheless, even small pH differences have significant effects and so acidic drugs will still tend to accumulate where the pH is higher while bases do the reverse.
The rate of movement of a drug out of circulation will depend on its degree of ionization and therefore its pK.
Changes in pH occuring in disease may also affect drug distribution. For example, blood becomes more acidic if respiration is inadequate. Also, the pH of milk can increase as much as 0.7 of a pH unit in animals with mastitis.
  • Capillary Permeability
The ability of a drug to reach various tissues will depend on the permeability of the capillaries at the site in question. For example, the capillaries in liver are extremely permeable, while those at the blood-brain barrier lie at the other extreme. Drugs can pass through the epithelial cells or between them through the gap junctions. Thus, molecular size is the major factor affecting the permeability of water-soluble drugs across capillaries.
Passage of drug into the CNS
The largest pores are extremely permeable, allowing the passage of all but the largest of proteins. In contrast, the pores in muscle allow only very small amounts of albumin to pass.
Drugs can pass into the CNS through the capillary circulation (through the blood-brain barrier) or via the cerebrospinal fluid (through the choroid plexus). In both cases, the barriers are similar to those encountered for the entry of a drug into the cytoplasm of a typical cell. Thus, except when a drug has a specific uptake mechanism, only small, lipid-soluble drugs are able to enter the CNS. Inflammation of the epithelial layer may increase its permeability and allow charged and, therefore, normally impairment drugs (for example, penicillin and streptomycin) to attain therapeutic concentrations in meningitis.

 Passage of drug across the placenta
The placenta is not an effective parries to most drugs. This is why the utmost care must be taken when administering drugs to pregnant animals. Only highly ionized drugs and drugs with low lipid solubility are excluded. Drugs such as oxytocin are vulnerable to placental enzymes and so do not pose such a risk to the fetus
Drug Dilution in Body Water
Body water constitutes as much as 75% of the total body weight of very lean animals and as little as 45% in very fat ones. The average is about 60%. This is distributed between intracellular fluid (~35% of body weight), interstitial fluid (~18%), blood plasma (~5%), and transcellular fluid (~2%). Transcellular fluids are separated from the interstitial fluid by an epithelium. They include:
The distribution of drugs between these body water compartments will depend on their volume and the barriers (for example, lipid membranes, plasma binding proteins, pH gradients) they encounter. Accumulation at Other Sites
Cells
Many drugs accumulate in muscle and other cells. Since the pH difference between the cytoplasm (7.0) and the extra cellular space (~7.4) is small, there is little pH trapping. Accumulation is either due to active transport or, more commonly, to binding.
Fat
Highly lipid soluble drugs accumulate in fat (for example, chlorinated hydrocarbons). Larger doses of lipid-soluble drugs may be necessary in obese animals.
Bone
Some drugs (for example, lead, fluoride, tetracycline’s) are deposited in bone and teeth.

Drug Reservoirs
Sites other than the site of action can act as reservoirs for a drug. For example, plasma proteins can sequester digitoxin and phenytoin, fat can sequester thiopental and organ chlorine pesticides, and bone can sequester tetracyclines and lead. The rate at which a drug is released from a reservoir is governed by the same factors as those described for its distribution. Such reservoirs can be useful in achieving a prolonged effect with an other-wiseshort-actingdrug.

Drug Residues in Food Animals
The existence of drug reservoirs and sites of prolonged sequestration is a major concern in food animals. Residues can be found in muscle, milk, eggs, liver, etc. For this reason, many drugs are not approved for use in food animals. For example, a drug will not be approved for use in milking dairy cattle if drug residues can be detected for longer than 96 hours (8 milkings) in milk.
Volume of distribution = Dose / drug concentration
Of course, the human body is not a glass beaker. Drug is distributing in and out of many tissue compartments while it is simultaneously being eliminated. This complex and continually changing environment must be simplified in order to mathematically model the human body. Therefore, the body is usually divided into two spaces, a central and a tissue compartment.

Volume of distribution

The volume of distribution (VD) , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication throughout the body after oral or parenteral dosing. It is defined as the volume in which the amount of drug would need to be uniformly distributed in to produce the observed blood concentration.
Volume of distribution may be increased by renal failure (due to fluid retention) and liver failure (due to altered body fluid and plasma protein binding). Conversely it may be decreased in dehydration.
The initial volume of distribution describes blood concentrations prior to attaining the apparent volume of distribution and uses the same formu  Equations
The volume of distribution is given by the following equation:
Therefore the dose required to give a certain plasma concentration can be determined if the VD for that drug is known. The VD is not a real volume; it is more a reflection of how a drug will distribute throughout the body depending on several physicochemical properties, e.g. solubility, charge, size, etc.
The units for Volume of Distribution are typically reported in (ml, liter, or liter)/kg body weight. The fact that VD is a ratio of a theoretical volume to a fixed unit of body weight explains why the VD for children is typically higher than that for adults, even though children are smaller and weigh less. As body composition changes with age, VD decreases.
The VD may also be used to determine how readily a drug will displace into the body tissue compartments relative to the blood:
Where:
Central volume of distribution (Vc) may be calculated as:
D. Redistribution
Redistribution involves the sequestration of a drug in a tissue, the fat, liver, etc. These drugs reach equilibrium with the plasma and as a drug is loss from the plasma it is replaced by drug from the tissue. At times sequestration of a drug in a tissue may lead to local toxicity. If the drug s released from the tissue in adequate amounts it may serve as a reservoir; if too slowly released, it may be simply ineffective.

 

7. METABOLISM

Metabolism is the enzymatic conversion of one chemical compound into another. Most drug metabolism occurs in the liver, although some processes occur in the gut wall, lungs and blood plasma.
Overall, metabolic processes will convert the drug into a more water-soluble compound by increasing its polarity. This is an essential step before the drug can be excreted in the body fluids such as urine or bile. Only a few drugs can be excreted without being metabolized first (See the tutorial on drug excretion for more information).
On the whole, as drugs are metabolized their therapeutic effect diminishes.
Prodrug:
•          Pharmacologically inactive
•          Converted rapidly to active metabolite (usually hydrolysis of ester or amide bond)
•          Maximizes the amount of active species that reaches site of action
Definition: “Biotransformation of drug is defined as the conversion from one chemical form to another”. The term is used synonymously with metabolism.
•       Pharmacologic Inactivation of Drug
•       Ex:  Active Drug                  Inactive Drug
      Salicylic Acid                Salicyluric Acid
•       Active Metabolite From An Inactive Drug
•       Ex.   Inactive(Prodrug)               Active
•                    Aspirin                             Salicylic Acid
   
•       No Change in Pharmacologic Activity
•       Ex.     Active                           Active Drug
             Codeine                        Morphine
  

Stages of Metabolism

Metabolism is often divided into two phases of biochemical reaction - phase 1 and phase 2. Some drugs may undergo just phase 1 or just phase 2 metabolisms, but more often, the drug will undergo phase 1 and then phase 2 sequentially.

Phase 1 Metabolism

Phase 1 metabolism can involve reduction or hydrolysis of the drug, but the most common biochemical process that occurs is oxidation. Oxidation is catalyzed by cytochrome P450 enzymes and results in the loss of electrons from the drug
•          introduction of functional group
•          hydrophilicity increases slightly
•          may inactivate or activate original compound
•          major player is CYP or mixed function oxygenase (MFO) system in conjunction with NAD(P)H
•          location of reactions is smooth endoplasmic reticulum

Phase 2 Metabolism

A phase 2 metabolisms involves conjugation - that is, the attachment of an ionized group to the drug. These groups include glutathione, methyl or acetyl groups. These metabolic processes usually occur in the hepatocytes cytoplasm.
The attachment of an ionized group makes the metabolite more water-soluble. This facilitates excretion as well as decreasing pharmacological activity.
•          conjugation with endogenous molecules (GSH, glycine, cystein, glucuronic acid)
•           hydrophilicity increases substantially
•           neutralization of active metabolic intermediates
•           facilitation of elimination
•           location of reactions is cytoplasm
Organ Sites of Drug Metabolism


Ø  •Liver
Ø  •Small intestine
Ø  •Kidney
Ø  •Skin
Ø  •Lungs
Ø  •Plasma
Ø  •All organs of the body

Cellular Sites of Drug Metabolism
-       Cytosol, Mitochondria, Lysosomes, Smooth endoplasmic reticulum (microsomes)



Metabolic enzymes:
1. Microsomal: Found predominately in the smooth Endoplasmic Reticulum of liver
Other areas: Kidney, Lungs, Intestinal mucosa, CYP450, monooxygenases, Flavin monooxygenase
•          Non-synthetic/ Phase I reactions
–        Most oxidation and reduction
–        Some hydrolysis
•          Synthetic/ Phase II reactions
–         ONLY Glucuronide conjugation
•          Inducible
–        Drugs, diet, etc.
2. Non-microsomal: Found in the cytoplasm and mitochondria of hepatic cells ,Other tissues including plasma -Alcohol dehydrogenase , Aldehyde dehydrogenase ,Monoamine and diamine oxidases
Both: Esterases and Amidases , Prostaglandin synthase , Peroxidases
•          Not inducible

•          Non-synthetic/ Phase I reactions
–        Most hydrolysis
–        Some oxidation and reduction
•          Synthetic/ Phase II reactions
–        ALL except Glucuronide conjugation
Why Biotransformation?
Most drugs are excreted by the kidneys. For renal excretion drugs should: have small molecular mass
– be polar in nature
– Not be fully ionized at body pH
• Most drugs are complex and do not have these properties and thus have to be broken down to simpler products.
•   Drugs are lipophilic in nature strongly bound to plasma proteins.
• This property also stops them from getting eliminated.
• They have to be converted to simpler hydrophilic compounds so that they are eliminated and their action is terminated.
When and How?
Biotransformation occurs between absorption and elimination from kidneys. Drugs administered orally can biotransform in the intestinal wall

Phase I Metabolism

Ø  A polar functional group is either introduced or unmasked if already present on the otherwise lipid soluble Substrate,
ü  E.g.  –OH, -COOH, -NH2 and –SH.
Ø   Thus, phase I reactions are called as functionalization  reactions.
Ø  Phase I reactions are Non-synthetic in nature.
Ø  The majority of Phase I metabolites are generated by a common hydroxylating enzyme system known as cytochrome P450.

Ø  Oxidation
ü  Hydroxylation (addition of -OH group)
ü  N- and O- Dealkylation (removal of -CH side chains)
ü  Deamination (removal of -NH side chains)
ü  Epoxidation (formation of epoxides)           
ü  Oxygen addition (sulfoxidation, N-oxidation)
ü  Hydrogen removal
Ø  Reduction
ü  Hydrogen addition (unsaturated bonds to saturated)
ü  Donor molecules include GSH, FAD, NAD(P)H
ü  Oxygen removal
Ø  Hydrolysis- Splitting of C-N-C (amide) and C-O-C (ester) bonds
 

 

 
     D
 
Microsomes and cytosol
 
Phase II Metabolism


•          Glycoside conjugation - glucuronidation
•          Sulfate - sulfation
•          Glutathione (GSH)
•          Methylation
•          Acylation
–        Acetylation
–        Amino acid conjugation
–        Deacetylation
•          Phosphate conjugation

  • OH, -SH, -COOH, -CONH with glucuronic acid to give glucuronides
  • -OH with sulphate to give sulphates
  • -NH2,  -CONH2, aminoacids, sulpha drugs with acetyl- to give acetylated derivatives
  • -halo, -nitrate, epoxide, sulphate with glutathione to give glutathione conjugates
  • all tend to be less lipid soluble and therefore better excreted (less well reabsorbed)


Glycoside conjugation - glucuronidation
UGT= UDP-a-D-Glucuronsyltransferase
 
 

•           Conducted by the soluble enzyme sulfotransferase
•           Endogenous donor molecule to conjugation is 3’-phosphoadenosine-5’-phosphosulfate (PAPS)
•           Conjugates are ethereal in character
•           Noninducible
 
 




FACTORS AFFECTING DRUG METABOLISM

•Age
•Diet
•Genetic Variation
•State of Health
•Gender
•Degree of Protein Binding
•Species Variation
•Substrate Competition
•Enzyme Induction
•Route of Drug Administration


 
Race (CYP2C9; warfarin (bleeding) phenytoin (ataxia) Losartan (less cleared but less activated as well); also fast and slow isoniazid acetylators, fast = 95% Inuit, 50% Brits, 13% Finns, 13% Egyptians). 
Age (reduced in aged patients & children)
Sex (women slower ethanol metabilizers) 




 


  
  

   


    
    

    

–    Pseudocholinesterase- typical enzyme, atypical enzyme




   



 		
 







 


  
  

   


    
    

    

•           Degree of protein binding



–    Conditions that displace bound drug from protein allows more of the drug to be accessible to the enzyme for which it serves as a substrate e.g. uremia,  low plasma albumin




   



 		
 







 


  
  

   


    
    

    

•           Gender 



–    Most studies are performed in the rat. In general, male rats metabolize drugs Faster than female rats








   



 		
 







 


  
  

   


    
    

    

Some Enzymes That Exhibit Genetic Variation




   



 		
 



Genetic variation
 


   Species variation
–    Human beings metabolize amphetamine by deamination;
      rats and dogs metabolize the drug by aromatic hydroxylation
–    Guinea pigs have very little sulfotransferase activity, humans have substantial activity
–    Guinea pigs do not N-hydroxylate substrates; mice, rabbits, dogs do
–    Hexobarbital is metabolized at different rates by different species
 
Substrate competition
–    Two or more drugs competing for the same enzyme can affect the metabolism
of each other; the substrate for which the enzyme has the greater affinity would be preferentially metabolized
 
 















 


Inhibitors and inducers of Microsomal enzymes
•          Inhibitors cimetidine 
   Prolongs action of drugs or inhibits action of those biotransformed to active agents (pro-drugs)
•          Inducers  barbiturates, carbamazepine shorten action of drugs or increase effects of those  biotransformed to active agents
Blockers acting on non-microsomal enzymes (MAOI, anticholinesterase drugs


 
Hydrolysis of organophosphates
fig 6-2b
Oxidation reactions
fig 6-21


Glucuronidation of phenol
Sulfation of phenol and toluene

8. DRUG EXCRETION

Excretion is defined as the process whereby drugs or metabolites are irreversibly transferred from internal to external environment through renal or non renal route. Excretion of unchanged or intact drug is needed in termination of its pharmacological action.      The principal organ of excretion is kidneys.


TYPES OF EXCRETION


  1. RENAL EXCRETION
  2. NON RENAL EXCRETION         
    • Biliary excretion.
    • Pulmonary excretion.
    • Salivary excretion.
    • Mammary excretion.
    • Skin / Dermal excretion.
    • Gastrointestinal excretion.
    • Genital excretion.


1. Renal excretion

The excretion of drugs by the kidney utilizes three processes all that occur in the nephron, the microscopic functional unit of the kidney. These processes are 1) Glomerular filtration, 2) Tubular secretion and 3) Tubule reabsorption.
1. Glomerular   Filtration
It is non selective, unidirectional process. Ionized or unionized drugs are filtered, except those that are bound to plasma proteins. Driving force for GF is hydrostatic pressure of blood flowing in capillaries.
Out of 25% of cardiac output or 1.2 liters of blood/min that goes to the kidney via renal artery only 10% or 120 to 130ml/min is filtered through glomeruli. The rate being called as glomerular filtration rate. Large drugs like heparin or those bound to plasma-protein cannot be filtered and are poorly excreted by glomerular filtration.
2. Active tubular   secretion:
The majorities of drugs do not enter the kidney tubule by glomerular filtration but do so by tubule secretion. This mainly occurs in proximal tubule.  It is carrier mediated process which requires Energy for transportation of compounds against conc. Gradient.
Two secretion mechanisms are identified:
System for secretion of organic acids/anions -E.g. Penicillin, salicylates etc uric acid secreted
System for organic base / cations- E.g. morphine, mecamylamine hexamethonium
Active secretion is Unaffected by change in pH and protein binding.
Drug undergoes active secretion have excretion rate values greater than normal   GFR e.g. Penicillin. The process of tubule secretion can have a big impact on the speed that a drug is eliminated from the body. For example, penicillin readily enters the nephron by tubule secretion and is rapidly excreted from the body in the urine. In a situation where the therapeutic effect needs to be prolonged, agents can be administered that block tubule secretion to slow the excretion of the drug.
3. Tubular Reabsorption
It occurs after the glomerular filtration of drugs. It   takes place all along the renal tubules.
Reabsorption of drugs indicated when the excretion rate values are less than the GFR 130ml/min.e.g. Glucose TR can be active or passive processes. Reabsorption results in increase in the half life of the drug.
  • Concentration: About 99% of the water filtered through the glomerulus’s is reabsorbed in the kidney tubule. This results in a considerable concentrating effect that will lead to passive reabsorption. Increasing the urine flow can reduce this.
  • pH: Urine pH will have significant effects on reabsorption of weak acids and bases. This effect is described by the Henderson Hasselbalch relationship. The excretion of weak acids can be increased significantly by alkalinizing the urine (sodium bicarbonate); excretion of weak bases can be increased by acidifying the uring (ammonium chloride). Weak bases are excreted more efficiently by carnivores (acid urine) and weak acids are excreted more efficiently by herbivores (basic urine).
  • Lipid solubility: Highly lipid-soluble drugs will be rapidly reabsorbed from the kidney tubule.
  • Protein binding: Although many protein-bound drugs are actively secreted into the proximal tubule, reabsorption is generally favored with drugs that are largely protein-bound in plasma. Bottom of Form
Other Routes of Excretion
q  Biliary  Excretion
q  Pulmonary Excretion
q  Salivary Excretion
q  Mammary Excretion
q  Skin/dermal Excretion
q  Genital  Excretion
Biliary Excretion
Bile juice is secreted by hepatic cells of the liver. The flow is steady-0.5 to 1ml /min. Its important in the digestion and absorption of fats.90% of bile acid is reabsorbed from intestine and transported back to the liver for re secretion. Compounds excreted by this route are sodium, potassium, glucose, bilirubin, Glucuronides, sucrose, Insulin, muco-proteins e.t.c. Greater the polarity better the excretion. The metabolites are more excreted in bile than parent drugs due to increased polarity. Phase-II reactions mainly glucuronidation and conjugation with glutathione result in metabolites with increased tendency for Biliary excretion. Drugs excreted in the bile are Chlroamphenicol, morphine and indomethacin. Glutathione conjugates have larger molecular weight and so not observed in the urine. For a drug to be excreted in bile must have polar groups like –COOH, -SO3H. Clomiphene citrate, ovulation inducer is completely removed from the body by BE.
The Enterohepatic Circulation
Some drugs which are excreted as glucuronides/ as glutathione conjugates are hydrolyzed by intestinal/ bacterial enzymes to the parent drugs which are reabsorbed. The reabsorbed drugs are again carried to the liver for re secretion via bile into the intestine. This phenomenon of drug cycling between the intestine & the liver is called Enterohepatic circulation.  
Pulmonary Excretion
Gaseous and volatile substances such as general anesthetics (Halothane) are absorbed through lungs by simple diffusion. Pulmonary blood flow, rate of respiration and solubility of substance effect PE. Intact gaseous drugs are excreted but not metabolites. Alcohol which has high solubility in blood and tissues are excreted slowly by lungs.
Salivary Excretion
The pH of saliva varies from 5.8 to 8.4. Unionized lipid soluble drugs are excreted passively. The bitter after taste in the mouth of a patient is indication of drug excreted. Some basic drugs inhibit saliva secretion and are responsible for mouth dryness. Compounds excreted in saliva are Caffeine, Phenytoin, and Theophylline.
Mammary Excretion
Milk consists of lactic secretions which is rich in fats and proteins. 0.5 to one litre of milk is secreted per day in lactating mothers. Excretion of drug in milk is important as it gains entry in breast feeding infants. pH of milk varies             from 6.4 to 7.6.Free un-ionized and lipid         soluble drugs diffuse passively. Highly plasma bound drug like Diazepam is less secreted in milk. Since milk contains  proteins. Drugs excreted can bind to it. Amount of drug excreted in milk is less than 1% and fraction consumed by infant is too less to produce toxic effects. Some potent drugs like barbiturates and morphine may induce toxicity.
Adverse Effects       
Discoloration of teeth with tetracycline and jaundice due to interaction of bilirubin with sulfonamides. Nicotine is secreted in the milk of mothers who smoke.
Skin Excretion

            Drugs excreted through skin via sweat follows pH partition hypothesis. Excretion of drugs through skin may lead to urticaria and dermatitis. Compounds like benzoic acid, salicylic acid, alcohol and heavy metals like lead, mercury and arsenic are excreted in sweat.
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