Pk - Absorption of drugs

Pharmacokinetics

Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. Pharmacokinetics deals with the movement of drugs. A drug that is administered must be absorbed, distributed, metabolized and excreted. Pharmacokinetics deals with absorption, distribution, metabolism and excretion of drugs. In simple words it is described as what the body does to the drug. The intensity of response is related to concentration of the drug at the site of action, which in turn is dependent on its pharmacokinetic properties. Pharmacokinetic considerations, therefore, determine the route of administration, dose, latency of onset, time of peak action, duration of action and frequency of administration. Pharmacokinetic information is helpful in determining and adjusting the drug dosage schedules and in interpreting drug concentration data. A drug that is administered must move through different parts of the body and for this movement it must pass through various membranes.

            Drug Administration

            For a drug to act and produce its characteristic systemic effects, it must first be absorbed and then attain an effective concentration at its site of action (Biophase). Absorption is the movement of drug from the site of administration to circulation. Not only the fraction of the administered dose that gets absorbed, but also the rate of absorption is important. Except with intravenous administration, the drugs have to cross the biological membranes for entering the systemic circulation.

Factors affecting absorption in general include - aqueous solubility, concentration of the drug, area of the absorbing surface, vascularity of the absorbing surface and route of administration.

Routes of administration

Absorption of a drug is very much depending on the routes of administration. Routes of drug administration can be broadly divided into two categories: 1. Topical, 2. Systemic administration.

The choice of the route and technique of administration is generally based on several factors viz.,

physicochemical properties of drugs & the formulation to be used,

the therapeutic indication (site of desired action),

the physiopathology of the disease condition,

species of animal involved,

ease of handling & controlling the animal,

rate and extent of absorption of the drug from different routes,

rapidity with which the response is required,

accuracy of dosage required,

condition of the patient &

economic factors – repetitive dosing or mass medication of a herd / flock.

Topical Application of drugs:

Drugs are placed directly on to the affected site as cream / ointment on skin and mucous membrane or drops in ears, eyes; in rare instances a drug impregnated patch is placed on to skin for gradual absorption. Application of drugs on the skin and mucous membrane is useful for localized effect.

            Topical administration of drugs is restricted to readily accessible organs and structures such as skin, eyes, ears, body orifices, body cavities and mammary glands. Many dosage forms (ointment, cream, paste, dusting powder, lotion, spray, liniment, poultice, gargle, plasters, etc.) have been developed to deliver active principles to the site of application in order to produce local effects. Absorption through the skin can also be enhanced by occlusive dressings, inunction ( suspending the drug in oily vehicle and rubbing the resulting preparation in to the skin) or the use of Di Methyl Sulphoxide (DMSO) as a carrier. Several drugs are deliberately applied to the skin with the anticipation of systemic effects following transdermal absorption. E.g., External parasiticides available as “Pour on” formulations, medicated ear tags, nitroglycerines ointment, and a trans dermal patch device-containing scopolamine.

            Drugs are applied locally to mucous membranes (eyes, mouth, throat, urethra, vagina, rectum, bladder) to achieve anti-infective, anti-inflammatory, decongestant, astringent, or anaesthetic effects. Drugs forms most frequently administered by the mucosal route include solutions, suspensions & suppositories. Less commonly used forms include creams, ointments, tablets, powders, sponges and tampons. Intra mammary infusion of ointments containing antibacterial & anti-inflammatory agents is frequently employed for the treatment of bovine mastitis.

Commonly used dosage forms for dermal application include ointments, creams, pastes, dusting powders, lotions, sprays, liniments and poultices. Specialized dosage forms like "pour-on", "spot-on" formulations, medicated ear tags, collars, transdermal patches are also available. Dusting powders and solutions are useful for superficial activity. Oily ointments enhance the penetration of drugs into the dermis and lipophilic substances can pass through the skin. Absorption can be increased by inunction (rubbing with friction) or iontophoresis. DMSO (dimethylsulphoxide) facilitates penetration through the skin. Damaged, inflammed and hyperemic skin allows drugs to pass through readily. In general, skin is an efficient barrier and little systemic absorption of topically applied drugs is seen. Systemic absorption from such a site will vary with the nature of the drug, characteristics of the vehicle and the degree of hydration of the stratum corneum of the skin and the location. However, organophosphorous insecticides in cattle and organochlorine insecticides in cats constitute a considerable toxic hazard. Topical application should be used with particular care in cats because of their extensive grooming habits. Drugs are rapidly absorbed through wounds. Transdermal delivery systems release drug through a rate controlling membrane into the skin and so into the circulation. Fluctuations in plasma concentration associated with other routes of administration are largely avoided, as is first-pass elimination in the liver. These are in the form of adhesive patches of various sizes and shapes. The drug is held in a reservoir between an occlusive backing film and a rate controlling micropore membrane, the under surface of which is smeared with an adhesive impregnated with priming dose of drug that is protected by another film to be peeled off just before application.

For application on the mucus membrane preparations available include solutions, suspensions, suppositories or pessaries, creams, ointments, powders, sponges and tampons. Drugs can be applied on the oral, nasal, conjunctival, vaginal, rectal and urethral mucous membrane for local effect. Intra mammary administration is useful when localized therapy is needed as in mastitis. However, absorption into systemic circulation may occur following intramammary administration depending on the pKa of the drug and pH of milk. Dosage forms used for intramammary administration include solutions and creams.

Advantages: Usually simple and convenient; usually painless; safest route of administration, unless there is a major hypersensitivity reaction; drug is administered directly on the site of action; drug concentrations at the at the site of action can be 100s – 1000s of times greater than the maximum concentration that could be achieved at the site following I.M. / oral / I.V. administration; No significant absorption, hence, no systemic effects.

            Disadvantages: only possible for a limited number of conditions that require drugs; may be quite messy and stain clothing and skin; some topical drugs wash off easily and do not last long; systemic effects may occur due either to licking of the applied medication / to percutaneous drug absorption, which often takes place especially when the skin is damaged / inflammed (burns, ulcers, wounds, dermatitis, etc.).

Systemic administration

            This is classified into two broad categories: 1. Enteral & 2. Parenteral route of administration.

            Enteral route of administration: here the drug is placed directly in the GIT either by placing it under the tongue (sublingual route of administration) or by swallowing (oral route of administration) or by rectal administration.

Oral administration: Drug is given by mouth and swallowed. Usually called as “per os”; abbreviated “P.O.” on medical records. It is the most common route of administration. In some situations drug may be given by stomach tube. Common Dosage forms available for oral use include powders, tablets, enteric-coated tablets, capsules, granules, syrups, electuaries, solutions, suspensions, and pastes. Powders, granules, and pellets, and soluble powders and liquid forms are used for medicating feeds and drinking water, respectively. In these preparations a variety of inert fillers, binders, lubricants, disintegrants, vehicles, and diluents are used. These adjuvants and excipients may influence the chemical stability of the formulation and the drug’s clinical effectiveness. The rates of disintegration and dissolution of solid dosage forms within the GIT are also determined by these ingredients and may vary between different manufacturers’ products. Such discrepancies in pharmaceutical availability lead to generic or therapeutic inequivalence between supposedly identical preparations. This problem is now well recognized and in large measure has been rectified by regulatory requirements.

In addition to the standard dosage forms, a number of specialized delivery systems are also available. These include enteric-coated tablets and sustained-action or controlled-release preparations. These time-release formulations provide delayed or gradual escape of active ingredient in several ways. The methods include micro encapsulation, embedding in a slowly eroding matrix or inert carrier, formation of poorly soluble chemical complexes, and the use of ion-exchange resins.

Orally administered drugs are exposed to low pH ranges, digestive enzymes, enteric microflora, and ingesta that vary greatly between species. Moreover, when a drug is absorbed from the stomach or intestinal tract it enters the portal circulation and passes through the liver before reaching the systemic circulation. During this time a high degree of metabolic transformation may occur – the “First pass” effect / pre-systemic metabolism.

Advantages: Convenient & safe procedure; Economical; Relatively simple for owner;

No need for sterile equipment; Systemic distribution can be achieved; the danger of acute drug reaction is not great; Painless administration; Self administration is possible in humans; Absorption takes place in large surface area with rich blood supply.

Disadvantages: Absorption may be variable; Gastric irritation may cause vomiting; Not useful if animal is vomiting; Requires cooperation of patient; Drugs may be destroyed by gastric acidity, gut flora, mucosal enzymes and liver enzymes; Onset of effect is usually slow; Drug gets diluted in the voluminous ruminal contents; A larger dose is required; A transit time that may be modified by GI disturbances; Poor technique or the presence of dysphagia may lead to intratracheal delivery and subsequent bronchopneumonia; The extent to which orally administered drugs can elicit the oesophageal groove reflex determines the pH of the medium into which the drug enters; When antimicrobials are administered to ruminants orally for a longer duration of time, they may bring about an alteration in the microbial ecosystem of the rumen resulting in gastrointestinal disturbance.

Enteric coated preparations: Drugs that are destroyed by the gastric juice or that cause gastric irritation can be administered orally with a coating that prevents dissolution in the acidic gastric contents. It is important that they do dissolve once they reach the duodenum. Onset of drug action is considerably delayed with enteric-coated tablets.

Sublingual tablets: Absorption directly from the oral cavity is sometimes useful when a rapid response is required, particularly when the drug is either unstable at gastric pH or rapidly metabolized by the liver. Eg. Glyceryl trinitrate. Only drugs that are lipid soluble and non-irritating can be administered sublingually. Drugs absorbed by mouth pass directly into the systemic circulation without entering the portal system and so escape the first-pass metabolism. This type of tablet is useful in the treatment of angina pectoris where the drug enters directly into the systemic circulation and provides immediate effect. Once the required effect has been achieved, the excess tablet can be spit off.

Timed release preparations: Timed release preparations are designed to produce slow uniform release and absorption of the drug over a period of 8 hours or more. They are also known as spansules or timesules.

Advantages: Less frequent administration; Lasts overnight; Drug levels are more constant and do not peak after each administration (less toxic effects); Good for short-acting drugs

Disadvantages: Marketed preparations are sometimes not reliable; Dissolution rates may be irregular; Not needed for long acting drugs; Not good for a brief therapeutic effect

Rectal administration: This route of administration is useful when the animal is unconscious or vomiting. Rectal absorption is often incomplete and erratic. Drugs can be administered rectally in the form of enema or suppository. Irritant and unpleasant drugs can be administered per rectum. However, rectal inflammation may occur due to highly irritant drugs.

Parenteral administration: While considering parenteral administration, the points of importance include: 1. Volume to be administered; 2. Concentration of the drug; 3. pH;

4. Toxicity; 5. Viscosity; 6. Particle size if suspension is used; 7. Adjuvant used in the preparation

In general, parenteral administration requires skill and use of sterile equipment. Parenteral preparations are normally used as solutions or suspensions. Several novel approaches have been introduced for parenteral delivery of drugs like microspheres, microcapsules, liposomes, microsponges, resealed carrier erythrocytes and projectile biodegradable missiles. Additionally monoclonal antibodies have been utilized to carry highly selective bound drugs to specific target tissues or even cells.

Intravenous administration

Injection of a drug directly into the blood stream gives a more predictable concentration of the drug in plasma and produces immediate plasma concentrations, which can produce a pharmacologic response. The entire dose of the drug is administered directly into the systemic blood stream rather than being administered extravascularly and requiring the drug to be absorbed from the injection site into the systemic circulation. This is of major importance in emergency situations and for drugs, which may be irritant if injected into muscle or subcutaneous tissue. Except where a rapid onset of effect is required, i.v. injections are usually made slowly with constant patient monitoring. Slow infusions can be used to maintain the plasma concentration at some fixed level.

Advantages: Extremely rapid onset of action; Initial absorption step is by-passed; Drug levels can be controlled more accurately; Suitable for irritant drugs; Suitable for large volumes of drugs

Disadvantages: Most dangerous route as toxicity can easily occur (as a general rule even the injection of a small volume should be made over a period of one circulation time); Drugs must be in aqueous solution; Must be performed slowly; Once injected, drug cannot be removed; Drugs formulated as suspensions or oily solutions cannot be given by i.v.injection; with some drugs, problems with vein irritation may predispose to thrombus formation, which may also be associated with the presence of catheters.

Subcutaneous administration (Hypodermoclysis): This route is useful when slow and continuous absorption is required. The formulation must be isotonic and at physiological pH. Certain drugs that are irritating can cause severe pain and necrosis. The rate of distribution of the drug is largely dependent on blood flow and it can, therefore, be slowed by including a vasoconstrictor. Warmth or vigorous massage will increase distribution. Addition of hyaluronidase can enhance drug dispersion. This enzyme hydrolyses the hyaluronic acid polymers, which comprises the intercellular cement and thus facilitates diffusion through the tissues. Specialized subcutaneous preparations include dermojet and pellet implantation. Dermojet is a process where no needle is used. A high velocity jet of the drug solution is projected from a microfine orifice using a gun like implement. The solution passes through the superficial layer and gets deposited in the subcutaneous tissue. It is essentially painless and suitable for mass inoculation.

Pellet implantation provides sustained release of the drug over weeks or months. The pellet impregnated with the drug is implanted in the subcutaneous tissue. Sialistic (non biodegradable) and biodegradable implants are used. Crystalline drug is packed in tubes made of suitable material and implanted under the skin. Constant blood levels can be maintained as the drug is released uniformly over a period of time. If non-biodegradable implant is used, it should be removed after the specified period of time.

Intramuscular administration: Drugs in aqueous solution are rapidly absorbed after intramuscular administration. However, very slow constant absorption occurs if the drug is administered in oil or suspended in other repository vehicles as depot preparations. It can be used for relatively irritant drugs and such drugs must be administered deep intramuscularly. Intramuscular injections are always painful and large volumes cannot be injected. A disadvantage of this route is the possibility of improper deposition in nerves, blood vessels, fat or between muscle bundles & in connective tissue sheaths. Whenever drugs are administered intramuscularly, it is always advisable to confirm that the needle is not in the blood vessel.

Intra peritoneal administration: This route is particularly useful in laboratory animal medicine and neonatal animals and for the administration of large volumes. There is a very large absorbing area and absorption is rapid. Absorption is via the portal system, so it is not useful for drugs that are removed by the liver. There is danger of infection and peritoneal adhesions are not uncommon. So it is not used routinely. Peritoneal dialysis is becoming more frequently used in small animals with short-term renal failure and renal insufficiency.

Intra dermal administration: This route is used mainly for diagnostic purposes e.g. for Tuberculine testing in cattle and also   for   hypersensitivity   testing   before   administering   some   drugs   known   to   induce hypersensitivity.

Intra thecal administration: In this route the drug is administered through the membranes enclosing the central nervous system in the lumbar area or into the cisterna magna. It is occasionally used for radiographic examinations and chemotherapy of central nervous system infections and neoplasms.

Epidural administration: This route is mainly used to anaesthetize animals for surgery like parturition in cattle. The drug is administered between the first and second coccygeal vertebrae.

Intra articular administration: This route is used to administer antiinflammatory agents into the joint capsule.

The other parenteral routes of drug administration rarely used are intra arterial, intra medullary, intra testicular, intra cardiac etc.

Respiratory system: This is the site of absorption of atmospheric pollutants. Volatile anaesthetics are administered by inhalation. Absorption is very rapid as the alveoli have an enormous surface area and is rich in blood supply. Drugs that can be nebulized can be given by inhalation, but particle size is extremely important for efficient administration. Ideally particles should be less than l mm in diameter. Inhalation therapy is useful for administering drugs that are poorly absorbed from other route. Thus, lung infections can be treated with high, localized concentrations of antibiotics and bronchoconstriction can be treated with corticosteroid levels that would normally have unacceptable side effects. Nasal administration of drugs is commonly practiced and drugs are readily absorbed through the nasal mucous membrane. They also by-pass the liver. Drugs can be applied as gases, vapours, snuff, spray, solution or nebulized solution.

Special drug delivery systems: Drug delivery systems have become the much sought for research in Pharmacology. Some of the special drug delivery systems include biologically erodable microspheres, pro-drugs, antibody-drug conjugates and packaging in liposomes.

Biologically erodable microspheres: Microspheres of biologically erodable polymers can be engineered to adhere to mucosal epithelium in the gut. Such microspheres can be loaded with drugs, including high molecular weight substances as a means of improving absorption, which occurs through mucosal absorptive epithelium and also through epithelium overlying Payer's patches.

Pro-drugs: Pro-drugs are inactive precursors, which are metabolized to active metabolites. Some pro-drugs confer no obvious benefits while some have advantages. Cyclophosphamide an anticancer drug becomes active only after it undergoes metabolism in the liver and hence severe damage to the gastrointestinal epithelium can be avoided.

Antibody-drug conjugates: One of the aims of cancer chemotherapy is to improve the selectivity to cytotoxic drugs. One interesting possibility is to attach the drug to an antibody directed against tumour specific antigen, which will bind selectively to tumour cells.

Packaging in liposomes: Liposomes are minute vesicles produced by sonication of an aqueous suspension of certain phospholipids. They can be filled with non-lipid soluble drugs or nucleic acid sequences, which are retained until the liposome is disrupted. Liposomes are mainly taken up by the reticuloendothelial cells especially in the liver. They are also concentrated in the malignant tumour and there is a possibility of achieving selective delivery of drugs in this way.

 

Transport of drugs across biological membranes

All pharmacokinetic processes involved transport of the drug across biological membranes.

Biological Membrane

Biological membranes may be viewed as mosaics of functional units composed of lipoprotein complex. Most membranes are composed of a fundamental structure called the unit membrane or plasma membrane. This boundary, which is 80 to 100 A° thick, surrounds single cell and nuclei. More complex barriers such as the intestinal epithelia and the skin are composed of multiples of this functional structure. The plasma membrane consists of a bilayer of amphipathic lipids with their hydrocarbon chains oriented inward to form a continuous hydrophobic phase and their hydrophilic heads oriented outward. Individual lipid molecules in the bilayer can move laterally, endowing the membrane with fluidity, flexibility, high electrical resistance and relative impermeability to highly polar molecules. The known fluidity of the phospholipids in the bilayer explains the mobility of cell surface compounds such as the receptors. This view of membrane structure is known as the fluid mosaic model and is wholly compatible with the known behaviour of drugs at membranes. Membrane protein embedded in the bilayer serves as receptors to elicit electrical or chemical signaling pathways and provide selective targets for drug action. Glycoprotein or glycolipids are formed on the surface by the attachments to polymeric sugars, amino sugars or sialic acids. The proteins are able to freely float through the membrane and some of the intrinsic ones, which extend through the full thickness of the membrane, surround fine aqueous pores. Paracellular spaces or channels also exist between certain epithelial or endothelial cells and other proteins have enzymatic or carrier properties. Biological membranes behave as if they were lipoids punctured by aqueous pores and allow drugs and physiological materials cross by passive or carrier mediated process. Which mechanism operates is determined by the physicochemical properties of drugs and the options available in the membrane in question.

Drugs are transported across the membrane by:

1.   Passive diffusion

2.   Filtration

3.   Facilitated diffusion

4.   Active transport

5.   Pinocytosis & Phagocytosis

Passive Diffusion: It is a random movement of drug molecules from an area of higher concentration to an area of lower concentration. When a drug is injected into the body, it passively diffuses from the injection site to areas of lower concentration, eventually reaching a blood capillary and entering the systemic circulation. In this process no cellular energy is expended and no active transport process is performed by the body to direct the movement of drug molecules. Hence the term passive diffusion is used.

Many drugs pass through the biological membranes such as cell membranes by passive diffusion. For a drug to diffuse from one side to another, the drug must dissolve in the membrane, which is composed of phospholipids, and diffuse down the concentration gradient. Thus, if a drug can dissolve in a cell membrane, it readily passes through the membrane by passive diffusion without any energy expended by the cell to move the drug molecules. Passive diffusion continues until enough molecules have passed from an area of higher concentration to an area of lower concentration to equalize the concentrations. At that point, the concentration gradient is very small and little differences exist in drug concentration in the areas of formerly high concentration and formerly low concentration. Drug molecules continue to move, however, such that an equal number move into and out of both the areas. At that point the drug concentrations are at equilibrium. This is the most important mechanism for majority of 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 a higher concentration in the membrane and diffuses quickly. Also the greater is the difference in the concentration of the drug on the two sides of the membrane, faster is its diffusion. Passive diffusion is mostly dependent upon:

1.   Concentration gradient

2.   Drug molecular size (smaller molecules move more rapidly than bigger molecules)

3.   Lipophilic nature of the molecule

4.   Temperature

5.   Thickness of the membrane (the thicker the membrane the slower the diffusion)

Filtration: Filtration is the 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 the hydrostatic or osmotic pressure gradient. Lipid insoluble drugs cross biological membranes by filtration if their molecular size is smaller than the diameter of the pores. Majority of the cells have very small pores and drugs with higher molecular weight are not able to penetrate. However capillaries (except those in brains) have large pores and most drugs can filter through these pores. Passage of drugs across capillaries is dependent on the rate of blood flow through them rather than on lipid solvability of the drug or pH of the medium. Neutral or uncharged molecules pass most readily since the pores are believed to be electrically charged. Within the alimentary tract pores are largest and most numerous in jejunal epithelium. Filtration seems to play almost a minor role in drug transfer within the body except for glomerular filtration, removal of drugs from CSF and passage of drugs across hepatic sinusoidal membrane.

Carrier mediated transport: In this transport mechanism the drug combines with a carrier present in the membrane and the complex then translocates from one side of the membrane to the other. The carriers for polar molecules appear to form a hydrophobic coating over the hydrophilic groups and thus facilitate passage through the membranes. Substances permitting transit of ions across membranes are called ionophores. Carrier transport is specific, saturable and competitively inhibited by analogues, which utilize the same carrier. Intestinal absorption sometimes depends on carrier mediated transport. Levodopa is taken up by a carrier that normally transports phenylalanine, flurouracil is transported by the system that carries natural pyrimidines (thymine and uracil), iron is absorbed via a specific carrier on the surface of the mucosal cells in the jejunum and calcium is absorbed by means of a vitamin D dependent carrier system. This carrier mediated transport is of two types, namely facilitated diffusion and active transport.

Facilitated diffusion: Facilitated diffusion is a passive transport mechanism across biological membranes that involve a special "carrier molecule" in the membrane that facilitates the movement of certain drug molecules across the membrane. As in passive diffusion, facilitated diffusion involves no energy expended by the cell to move the drug molecules and the direction of the drug movement is determined by the concentration gradient. In addition, once the equilibrium is attained, the number of drug molecules crossing the membrane is either direction via the carrier remains the same. This proceeds more rapidly than simple diffusion and even translocates non-diffusible substrates, but along their concentration gradient, therefore does not need energy. Vitamin B12 is absorbed from the gut by this process.

Active transport: Like facilitated diffusion, active transport of drug molecule involves a specialized carrier molecule. However, in active transport a drug molecule comes in contact with a specialized carrier molecule in the membrane and the cell expends energy to move the drug molecules across or to reset the carrier molecule after transport so that it may transport again. Unlike diffusion in which the direction of net drug movement is determined by the concentration gradient, active transport can move drug molecules against the concentration gradient from areas of lower concentration to areas of higher concentration within a cell or body compartment. Glucose entry within cell is facilitation diffusion while passage across gastric mucosa and excretion by proximal renal tubular cells is active transport. Drugs related to normal metabolites are actively absorbed from the gut by aromatic amino acid transport processes.

Drugs actively transported may potentially reach such high concentration within cells that they exert a toxic effect, such as that seen with aminoglycoside antibiotics. Because active transport requires cellular energy, anything that disrupts the cell's production of energy such as toxins or certain drugs, prevents active transport of drug molecules across biological membranes. Nonspecific active transport of drugs, their metabolites and some endogenous products occurs in renal tubules and hepatic sinusoids, which have separate mechanisms for organic acids and organic bases. Certain drugs have been found to be actively transported in the brain and choroid plexus also. Examples for active transport include 5-fluorouracil, iron by gut, levodopa crossing the blood brain barrier and secretion of many organic acids and bases by renal tubular cells.

Pincytosis (Cell drinking) and phagocytosis (Cell eating)

Drug molecules may enter a cell by being physically engulfed by the cell. In both pinocytosis and phagocytosis, a portion of the cellular membrane surrounds the drug molecule and takes it within the cell. In these processes transport across the cell membrane is facilitated by formation of vesicles. This is an active process and requires the cell to expend energy. If the engulfed particle is not susceptible to enzyme degradation, it will persist like particles of talc or droplets of liquid paraffin. Pincytosis and phagocytosis are especially important for movement of large drug molecules such as complex proteins or antibodies that would otherwise be unable to enter a cell or pass intact through a membrane barrier. The absorption of immunoglobulins through the gut mucosa of young calves depends on phagocytosis. Pinocytosis and phagocytosis are more of histopathological interest than pharmacological interest.

Effect of transport mechanisms on drug molecule movement

Transport mechanisms determine the direction of drug molecule movement and the rate at which the molecules move from one compartment to other, or through a membrane barrier. In facilitated diffusion and active transport, wherein a carrier is involved, the transport mechanism can only move a limited member of drug molecules at one time. If the transport system becomes overloaded or saturated, some drug molecules waiting to be transported begin accumulating. In contrast to these carrier transport systems, the rate of passive diffusion is not limited because drug molecules simply diffuse through any part of the biological membrane. Pinocytosis and phagocytosis are relatively slow mechanisms for drug transport.

Absorption of drugs from the gastrointestinal tract: Before a drug can be absorbed, it must dissolve in the aqueous contents of the gut. Thus the actual amount of the drug present in a dose is only one of the factors that will affect the amount of drug actually absorbed or available.

Factors affecting absorption include

1. Molecular size and shape of the drug and its concentration.
2. Degree of ionization (ionization depends on the pKa of the drug and pH of the medium. In stomach the pH is 1 - 2, rumen 5.5 - 6.5 and intestine 7 - 8, and hence degree of ionization of drugs varies in different regions and species of the gastrointestinal tract).
3. Lipid solubility of the neutral or nonionized form of the drug.
4. Chemical or physical interaction with co-administered preparations and food constituents.
5. Pharmaceutical preparation and dosage form, especially their disintegration rate and dissolution rate.
6. Morphological and functional difference in the gastrointestinal tract among various species.
7. Gastric motility and secretion as well as gastric emptying.
8. Intestinal motility and secretion as well as intestinal transit time.
9. Fluid volume within the gastrointestinal tract.
10. Osmolality of the intestinal contents.
11.  Intestinal blood and lymph flow.
12.  Disruption of the functional and structural integrity of the gastric and intestinal epithelium.
13.  Drug biotransformation within the intestinal lumen by micro flora or within the mucosa by host enzymes.
14.  Volume and surface area of the absorbing surface. Stomach has a relatively small surface area compared to the duodenum. Hence absorption is more in the duodenum.
15. Presence of food in the stomach. Normally in full stomach there is a delay in absorption because the drug gets diluted in the stomach contents.

Effect of a drug's lipophilic or hydrophilic nature on drug movement

Biologic membranes are largely composed of fats. Therefore to move across a membrane, drug molecules must be in a form that dissolves in fat or oil. Fat loving form is known as lipophilic form. Some drug molecules dissolve readily in water and are called hydrophilic. Drug molecules that are polarized or ionized readily dissolve in an aqueous medium and so are hydrophilic. Non­polarised, non-ionized drugs are less soluble in water and can pass through lipid membranes.

Drugs can be conveniently classified into three groups as follows in the physicochemical sense. They are

1.  Drugs that are charged or uncharged according to the environmental pH (electrolytes),

2. Drugs that are incapable of assuming a charge, whatever is the environmental pH (non-polar) and

3. Drugs that are permanently charged whatever is the environmental pH (polar)

Electrolytes: Many drugs are weak electrolytes i.e., their structural groups ionize to a greater or lesser extent, according to environmental pH. Usually most molecules are present partly in the ionized and partly in the un-ionized state. The degree of ionization influences lipid solubility and in turn their absorption, distribution and elimination. Most of the drugs are either weak acids or bases. The degree to which these drugs are lipid soluble (nonionized, the form in which drugs are able to cross membranes) is determined by their pKa and the pH of the medium containing the drug. pKa of a drug is the pH at which 50% of the drug is ionized and 50% is non-ionized. In monogastric animals with a low stomach pH, weak acids such as aspirin with a pKa of 3.5 tend to be better absorbed from the stomach than the weak bases because of the acidic conditions. Weak bases are poorly absorbed from the acidic environment of the stomach because they exist mostly in the ionized state. Weak bases are better absorbed from the small intestine where the environmental pH is more alkaline.

Henderson Hasselbach equation is used to calculate the percent of a drug that exists in ionized form or to determine the concentration of a drug across the biologic membrane.

concentration of nonionized acid

For weak acid, pKa = pH + log------------------------------------------

concentration of ionized acid

concentration of ionized base

For weak base, pKa = pH + log------------------------------------------

concentration of nonionized base

It can also be expressed as

                                                            100

For a weak acid, % ionized = ---------------------------------

                                                 1 + antilog (pKa – pH)

                                                            100

For a weak base, % ionized = ---------------------------------

                                                1 + antilog (pH – pKa)

Effect of pH gradient on distribution of a weak organic acid (pKa 3.5) between blood plasma and gastric juice

           

                                                Biologic membrane

Plasma (pH 7.4) pKa = pH + log U/I 3.5 = 7.4 + log U/I -3.9 = log U/I Taking antilog on both sides 0.01         = U/I If U = 1 then I = 10,000 10,001 units of the drug on this side of the membrane at equilibrium

Gastric fluid (pH 1.5) pKa = pH + log U/I 3.5 = 1.5 + log U/I 2 = log U/I Taking antilog on both sides 100 = U/I If U = 1then I 0.01 1.01 units of the drug on this side of the membrane at equilibrium

I = Ionized form; U = Unionized form.

At equilibrium

a. the concentration of unionized drug (HA) is the same on both the sides of the membrane

b. there is more total drug (unionized + ionized) on the side of the membrane where the degree of ionization is the greatest (ion trapping).

Because of the relationship between pH and degree of ionization, a relatively small change will produce a large change in the proportion of drug present in non-ionized form, particularly when the pH of the solution is numerically close to the pKa of the weak organic electrolyte.

Acidic urinary reaction of the carnivorous species promotes passive reabsorption of acidic drugs from the distal portion of the nephron. Conversely urinary alkalinisation promotes their excretion.

Weak acids like aspirin and phenylbutazone are well absorbed from the gastrointestinal tract of dogs and cats. Weak organic bases like tetracyclines administered parenterally diffuse into the rumen of cattle and sheep and into the colon of horses. Basic drugs tend to concentrate in fluids that are acidic relative to plasma such as intracellular fluid (pH 7.0)

Non-polar : Eg. Digoxin, chloramphenicol. These drugs have no ionisable group. They are not affected by pH. Lipid solubility favours diffusion of these drugs across tissue boundaries. Drugs with high lipid to water coefficient can diffuse more rapidly through the gastrointestinal epithelium.

Polar : Eg. Negatively charged - Heparin, Positively charged - Tubocurarine. These drugs have limited capacity to cross plasma membrane. They are normally not administered orally.

In general

1. The more lipid soluble (less polar) a drug is, the better it is absorbed from the gut and the more widely it is distributed in the body.
2. Weak acids are absorbed best from the stomach.
3. Weak bases are absorbed best from the intestine.
4. However, it is also true that most drug absorption from the gut occurs in the proximal duodenum.
5. Absorption is a dynamic process; absorbed drug is rapidly carried away by blood or lymph.
6. Most drugs are sufficiently water-soluble to be carried away by blood. This blood enters the protal vein and goes to the liver where some or all the drug may be metabolized.
7. Extremely lipid soluble compounds enter the lymphatics.

First pass effect (Pre systemic metabolism)

All drugs that are absorbed from the intestine enter the portal vein and pass through the liver before they are distributed systemically. Some drugs are almost completely removed from the circulation on their first passage through the liver. The drugs that show poor availability when given orally due to their extensive first pass effect include - meperidine, aspirin, morphine, pentazocine, chlorpromazine, lidocaine, nitroglycerine, isoproterenol and propranolol. However some of these drugs are given orally and the required dose is much greater than that for other routes of administration.

Enterohepatic recycling

A drug that is excreted by the liver and arrives at the duodenum in lipophilic form could be reabsorbed across the intestinal wall and transported by the hepatic portal circulation back to the liver, where it is then excreted again by the liver or reenters the systemic circulation. This movement of drug from the liver to the intestinal tract, and back to the liver is referred to as enterohepatic circulation. Drugs that are reabsorbed intact from the intestinal tract can exert a pharmacologic effect on the body, therefore some hepatically excreted drugs appear to have an extended duration of action in the body. Eg. Phenophthalein.

Absorption of drugs from parenteral administration

Drugs injected subcutaneously or intramuscularly should be in the hydrophilic form so that they may readily diffuse through tissue fluid and reach a capillary to be absorbed. Anything that interferes with diffusion of the drug from the site of administration or alters the blood flow to the injection site can delay absorption of the drug. Aqueous solutions of drugs are usually absorbed from intramuscular injection site within 10-30 minutes provided the blood flow is unimpaired. Faster or slower absorption is possible, depending on the concentration and lipid solubility of the drug, vascularity of the site, volume of injection, the osmolality of the solution and other pharmaceutical factors. Absorption of drugs from subcutaneous tissues is influenced by the same factors that determine the rate of absorption from intramuscular sites. Some drugs are absorbed as rapidly from subcutaneous tissues as from muscles, although absorption from injection sites in subcutaneous fat is always significantly delayed. Increasing the blood supply to the injection site by heating, massage or exercise hastens the rate of dissemination and absorption. Spreading and absorption of a large fluid volume that has been injected subcutaneously may be facilitated by including hyaluronidase in the solution.

Absorption of drugs from tracheobronchial surfaces and alveoli

The volatile and gaseous anaesthetics are the most important group of drugs administered by inhalation. These substances enter the circulation by diffusion across the alveolar membranes. Since they all have relatively high lipid water partition coefficients and generally are rather small molecules, they equilibrate practically instantaneously with the blood in the alveolar capillaries. Particles contained in aerosols may be deposited, depending on the size of the droplets, on the mucosal surface of the bronchi or bronchioles, or even in the alveoli.

Absorption of drugs from topical sites of application

Drugs may be absorbed through the skin following topical application. The intact skin allows the passage of small lipophilic substances, but efficiently retards the diffusion of water soluble molecules in most cases. Lipid insoluble drugs generally penetrate the skin slowly in comparison with their rates of absorption through the other body membranes. Absorption of drugs through the skin may be enhanced by inunction or more rarely by iontophoresis if the compound is ionized. Certain solvents may facilitate the penetration of drugs through the skin. The best known of these solvents is dimethylsulphoxide. Damaged, inflamed or hyperemic skin allows many drugs to penetrate the dermal barrier much more readily. The same principles that govern the absorption of drugs through the skin also apply to the application of topical preparations on the epithelial surfaces. Many drugs traverse the cornea at rates that are related to their degree of ionization and lipid solubility. Thus organic bases such as atropine, ephedrine and pilocarpine often penetrate quite readily, whereas the highly polar aminoglycoside antibiotics generally penetrate cornea poorly.

Bioavailability The term bioavailability is used to indicate the proportion of drug that passes into systemic circulation after administration taking into account both absorption and local metabolic degradation.