Pharmacokinetics

Pharmacokinetics

Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. It studies the processes of absorption, distribution, metabolism and excretion of drugs (how the body affects the drugs; movement or disposition of drugs in the body). It quantifies the fate of a drug by measurement of its concentration and metabolites in blood and urine over a period of time after its administration.
Intensity of response of a drug is related to its concentration at the site of action, which in turn is dependent on its pharmacokinetic properties.
Pharmacokinetic considerations, therefore, determine the route (s) of administration, dose, latency of onset, time of peak action, duration of action – frequency of administration of a drug.
ABSORPTION OF DRUGS:
Dosage form: The term describes the pharmaceutical preparation in which the
active principle is introduced into or onto the body. Whether this is solid, liquid,
gaseous or any state in between, the prime requisite for pharmacological activity
is that the drug leaves the dosage form and goes into solution in the immediately
adjacent body water: insoluble drugs are pharmacologically inert.
Body water (which is approximately 70% of the body by weight) is found to exist
in several compartments like intracellular fluid (ICF) and extra cellular fluid (ECF).
Clearly, drugs have to cross these boundaries (biological membranes) if they are
to penetrate throughout the body water.

Nature of Biological membranes:
These functionally important components (comprising organelle, cytoplasmic and
plasma membranes) account for about 80% of the dry weight of a cell.
The plasma membrane, which is the interface between a cell and the ECF,
possesses features and properties which allow movement of solutes into and out
of the cell.
The membrane is now visualized as a cholesterol-containing, double layer of
phospholipids molecules arranged perpendicular to the surfaces. The outer layer
has its polar groups directed to the ECF while the inner layer presents its polar
groups towards the ICF. Individual lipids can move laterally, endowing the
membrane with fluidity, flexibility, imperviousness to polar molecules, and high
electrical resistance. The lipid molecules can even flip from one bilayer of the
membrane to the other.
In this model (fluid mosaic model), proteins integral to the membrane are a
heterogenous set of globular molecules, each arranged in an amphipathic
structure, i.e. with their ionic and highly polar groups located largely on
membrane surfaces in contact with the extra- and intra-cellular aqueous media
and with their non-polar residues sequestered from contact with water in the
membrane interior. These proteins are partially embedded in a discontinuous,
fluid bilayer of phospholipids that forms the matrix of the mosaic.
Aqueous channels appear to be present in the core of the globular intrinsic
(integral) proteins and may be gated (i.e. channels may open and close) by
conformational changes in the proteins.
Biological membranes behave as if they were lipoids punctured by aqueous
pores and allow drugs and physiological materials to cross by passive or carrier
mediated processes.
Drug Passage across Membranes:
1. Passive Diffusion:
The drug diffuses across the membrane in the direction of its
concentration gradient, the membrane playing no active role in the process. This
is the most important mechanism for majority of the drugs.
Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the
membrane, the rate of transport being proportional to lipid
:water partition
coefficient of the drug. A more lipid soluble drug attains higher concentration in
the membrane and diffuses quickly. Also, greater the difference in the
concentration of the drug on two sides of the membrane, faster is its diffusion.
2. Filtration:
Filtration is passage of drugs through aqueous pores in the membrane or
through paracellular spaces. This can be accelerated if hydrodynamic flow of the
solvent is occurring under hydrostatic or osmotic pressure gradient, e.g. in most
capillaries including glomeruli. Lipid insoluble drugs cross biological membranes
by filtration if their molecular size is smaller than the diameter of the pores.
Majority of cells (intestinal mucosa, RBC etc.) have very small pores (4
Å) and
drugs with MW>100 or 200 are not able to penetrate. However, capillaries
(except those in brain) have larger pores (40
Å) and most drugs (even albumin
can filter through these).

3. Specialized Transport (Carrier – Mediated Transport):
When the rate of movement of molecules across a membrane is greater
than can be accounted for by the operation of conventional laws of diffusion, the
existence of a carrier-mediated transport system can be suspected. Such
systems are well known in physiology, e.g. in glucose uptake into erythrocytes
and sodium ion expulsion from erythrocytes.
Carrier-mediated transport across membranes implies a rapidly reversible
interaction between components of the membrane and the transported
substance. The drug combines with a carrier present in the membrane and the
complex then translocates from one face of the membrane to the other. This kind
of transport shows relative selectivity toward the chemical nature of the
substance moved across the membrane. Since a carrier (membrane component)
is involved in transport, the process is saturable, and substances of a similar
chemical nature may compete for the carrier. Competitive inhibition is a
characteristic of carrier-mediated transport.
The carriers for polar molecules appear to form a hydrophobic coating
over the hydrophilic groups and thus facilitate passage through the membrane.
Substances permitting transit of ions across membranes are called
ionophores.
Carrier-mediated transport is of two types i.e. active transport and facilitated
diffusion.

(i) Active transport:
Movement occurs against the concentration gradient, needs energy and is
inhibited by metabolic poisons. It results in selective accumulation of the
substance on one side of the membrane. Drugs related to normal metabolites,
e.g. levadopa and methyldopa are actively absorbed from the gut by aromatic
amino acid transport process. The rapid transfer into urine and bile of drugs that
are strongly acidic or basic as well as most drug metabolites takes place by
active transport. It is also responsible for removal of certain drugs (e.g.
penicillins) from the central nervous system (CNS) at the choroids plexus. This is
now believed to be accomplished through reverse transport from the CSF back
into the bloodstream by the
p-glycoprotein pump. Generation of pH gradient
across a biological membrane is also an active process.
(ii) Facilitated diffusion:
It is neither an energy-dependent process nor does it move substances
against a concentration gradient. Transport is facilitated, however, by attachment
to a carrier and is more rapid than simple diffusion and translocates even nondiffusible substrates. Entry of glucose into most cells takes place by facilitated
diffusion (enhanced by insulin), but its passage across the GI mucosa and
excretion by renal tubular cells are active processes.
Phagocytosis and Pinocytosis of drugs:
Cells have the ability to engulf either particles (phagocytosis) or droplets
(pinocytosis). If the engulfed material is not susceptible to enzyme degradation it will
persist, e.g. particles of talc or droplets of liquid paraffin. In relation to drugs, this
possibility is of more histopathological than pharmacological interest at present.
The absorption of immunoglobulins through the gut mucosa of young calves
depends on pinocytosis.

ROUTES OF DRUG ADMINISTRATION:
Factors governing choice of route of administration of drugs:
(i) Physical and chemical properties of drugs (solid/ liquid/ gas; solubility, stability,
pH, irritancy).
(ii) Site of desired action – localized and approachable or generalized or not
approachable.
(iii) Rate and extent of absorption of the drug from different routes.
(iv) Effect of digestive juices and first pass metabolism on the drug.
(v) Rapidity with which the response is desired (routine treatment or emergency).
(vi) Accuracy of dosage required (i.v. and inhalational can provide fine tuning).
(vii) Condition of the patient (unconscious, vomiting) etc.
LOCAL ROUTE :
Systemic absorption from these routes is minimal.
Systemic side effect is minimized.
Desired localized action.
Topical Route:
(a) Skin: Ointment, cream, lotion, paste, powder, dressings, spray etc.
(b) Mucous membranes:
(i) Mouth & Pharynx – Paint, mouth wash, gargles etc.
(ii) Eye, ear, nose – Drops, ointment, nasal spray etc.
(iii) GI tract – As non-absorbable drugs given orally, e.g. Mg(OH)
2, sucralfate,
neomycin etc.
(iv) Bronchi and lungs – As inhalations, aerosols (nebulized solution or fine
powder), e.g. salbutamol, cromolyn sodium.
(v) Urethra – As jellys e.g lidocaine; irrigating solutions.
(vi) Vagina – As pessaries (vaginal suppositories), vaginal tablets, inserts,
cream, powders, douches.
(vii) Anal canal – As ointment, suppositories.
SYSTEMIC ROUTES :
Intended to be absorbed into blood and distributed all over through systemic
circulation.
1. Oral route:
Oldest and commonest mode of drug administration.
Safer and more convenient.
Medicament need not be sterile, so cheaper.
Solid dosage forms: Powders, tablets, boluses, capsules
Liquid dosage forms: Elixirs, syrups, emulsions, mixtures etc.

2. Sublingual or buccal route:
Only lipid soluble and non-irritating drugs can be used.
Absorption – rapid.
The chief advantage is that the liver is bypassed and drugs with high first pass
effect can be absorbed into systemic circulation directly. For example,
Nitroglycerine, isoprenaline, clonidine, methyltestosterone.
3. Rectal route:
Certain irritant and unpleasant drugs can be put into rectum as suppositories
for systemic effect.
This route is used when the patient is having recurrent vomiting.
Route is inconvenient and embarrassing.
Absorption is slower, irregular and often unpredictable.
Rectal inflammation can result from irritant drugs.
Examples: Aminophylline, endomethacin, paraldehyde, diazepam etc. are
sometimes given rectally.
4. Cutaneous route:
Highly lipid soluble drugs can be applied over the skin for slow and prolonged
absorption.
Liver is also bypassed.
Example: Ointments.
5. Inhalational route:
Absorption takes place from the vast surface of alveoli – action is very rapid.
When administration is discontinued, the drug diffuses back and is rapidly
eliminated in expired air. Thus, controlled administration is possible.
Examples: Volatile liquids and gases (General anaesthetics).
6. Nasal route:
The mucous membrane of the nose can readily absorb many drugs; digestive
juices and liver are bypassed.
Only certain drugs like GnRH agonists and desmopressin applied as spray or
nebulized solution have been used by this route.

7. Parenteral route: (par – beyond, enteral – intestinal)
It refers to injection of drug directly into tissue fluid or blood without having to
cross the intestinal mucosa.
The limitations of oral administration are circumvented.
Action is faster and surer (valuable in emergencies).
Liver is bypassed.
Disadvantage: The preparation has to be sterilized, so costlier. The technique
is invasive and painful, so assistance of other persons is required.
(i) Subcutaneous (s.c.):
The drug is deposited into the loose subcutaneous connective tissue which is
richly supplied by nerves (so, irritant drugs can’t be injected) but is less
vascular (absorption is slower).
Repository (depot) preparations – oily solutions (like vaccines) or aqueous
suspensions can be injected for prolonged action.
(ii) Intramuscular (i.m.):
The drug is injected in one of the large skeletal muscles (like deltoid, triceps,
gluteus maximus, rectus femoris
etc.).
Muscle is less richly supplied with sensory nerves (mild irritants can be
injected) and
more vascular (absorption is faster).
It is less painful. Deep injection is needed.
Depot preparations can be injected by this route.
(iii) Intravenous (i.v.):
The drug is injected as a bolus or infused slowly after hours in one of the
superficial veins.
The drug directly reaches into the blood stream and effects are produced
immediately (great value in emergencies).
The intima of veins is insensitive and drug gets diluted with blood, therefore
even highly irritant drugs can be injected
i.v., but hazards are –
thrombophlebitis of the injected vein and necrosis of adjoining tissues if
extravasation occurs.
Only aqueous solutions are injected (not suspensions).
Dose of the drug is smallest in this route and bioavailability is 100%.
Response of the drug can be accurately measured.
It is the most risky route – vital organs like heart, brain etc. get exposed to
high concentrations of the drug.
(iv) Intradermal:
The drug is injected into the skin by raising a bleb (e.g. BCG vaccine,
sensitivity testing) or
scarring/ multiple puncture of the epidermis through a
drop of the drug (small pox vaccine) is done.
This route is employed for specific purposes only.

(v) Intraperitoneal (i.p.):
This route is of importance in large animal practice for the administration of
large volumes, because of great absorbing surface of the peritoneum and
because the absorption rate is rapid.
The injection is made via the sub-lumbar fossa, care being taken to avoid
delivering the solution into an abdominal organ.
The risk of causing peritoneal adhesions should also be borne in mind.
(vi) Other parenteral routes are:
Intrathoracic and intracardiac injections.
Intrathecal injection.
Epidural injection.
Intra-articular injection.

 

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