METABOLISM OF DRUGS

METABOLISM

Biotransformation means chemical alteration of the drug in the body. It is needed to render nonpolar (lipid-soluble) compounds polar (lipidinsoluble) so that they are not reabsorbed in the renal tubules and are excreted. Most hydrophilic drugs, e.g. streptomycin, neostigmine, pancuronium, etc. are little biotransformed and are largely excreted unchanged. Mechanisms which metabolize drugs (essentially foreign substances) have developed to protect the body from ingested toxins.

The primary site for drug metabolism is liver; others are—kidney, intestine, lungs and plasma. 

Biotransformation of drugs may lead to the following. 

(i) Inactivation Most drugs and their active metabolites are rendered inactive or less active, e.g. ibuprofen, paracetamol, lidocaine, chloramphenicol, propranolol and its active metabolite 4-hydroxypropranolol. 

(ii) Active metabolite from an active drug Many drugs have been found to be partially converted to one or more active metabolite; the effects observed are the sum total of that due to the parent drug and its active metabolite(s). 

e.g; codeine → morphine

(iii) Activation of inactive drug Few drugs are inactive as such and need conversion in the body to one or more active metabolites. Such a drug is called a prodrug. The prodrug may offer advantages over the active form in being more stable, having better bioavailability or other desirable pharmacokinetic properties or less side effects and toxicity. Some prodrugs are activated selectively at the site of action.

e.g; levodopa → dopamine

Biotransformation reactions can be classified into: 

(a) Nonsynthetic/PhaseI/Functionalization reactions: a functional group is generated or exposed— metabolite may be active or inactive. 

(b) Synthetic/Conjugation/ Phase II reactions: an endogenous radical is conjugated to the drug— metabolite is mostly inactive; except few drugs, e.g. glucuronide conjugate of morphine and sulfate conjugate of minoxidil are active.

Nonsynthetic reactions 

(i) Oxidation: This reaction involves addition of oxygen/negatively charged radical or removal of hydrogen/positively charged radical. Oxidations are the most important drug metabolizing reactions. Various oxidation reactions are: 

a) Hydroxylation

Phenytoin → hydroxyphenytoin

b) Dealkylation

Codeine → morphine

c) S oxidation

Cimetidine → cimetidine sulfoxide

Oxidative reactions are mostly carried out by a group of monooxygenases in the liver, which in the final step involve a cytochrome P-450 haemoprotein, NADPH, cytochrome P-450 reductase and molecular O2. More than 100 cytochrome P-450 isoenzymes differing in their affinity for various substrates (drugs), have been identified.

(ii) Reduction: This reaction is the converse of oxidation and involves cytochrome P-450 enzymes working in the opposite direction. Alcohols, aldehydes, quinones are reduced. Drugs primarily reduced are chloralhydrate, chloramphenicol, halothane, warfarin. 

(iii) Hydrolysis: This is cleavage of drug molecule by taking up a molecule of water

 

Similarly, amides and polypeptides are hydrolysed by amidases and peptidases. In addition, there are epoxide hydrolases which detoxify epoxide metabolites of some drugs generated by CYP oxygenases. Hydrolysis occurs in liver, intestines, plasma and other tissues. Examples of hydrolysed drugs are choline esters, procaine, lidocaine, procainamide, aspirin, carbamazepine-epoxide, pethidine, oxytocin. 

(iv) Cyclization: This is formation of ring structure from a straight chain compound, e.g. proguanil.

(v) Decyclization: This is opening up of ring structure of the cyclic drug molecule, e.g. barbiturates, phenytoin. This is generally a minor pathway.

Synthetic reactions: 

These involve conjugation of the drug or its phase I metabolite with an endogenous substrate, usually derived from carbohydrate or amino acid, to form a polar highly ionized organic acid, which is easily excreted in urine or bile. Conjugation reactions have high energy requirement. 

(i) Glucuronide conjugation: This is the most important synthetic reaction carriedout by a group of UDP-glucuronosyl transferases (UGTs). Compounds with a hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid which is derived from glucose. Examples are— chloramphenicol, aspirin, paracetamol, diazepam, lorazepam, morphine, metronidazole. Not only drugs but endogenous substrates like bilirubin, steroidal hormones and thyroxine utilize this pathway. Glucuronidation increases the molecular weight of the drug which favours its excretion in bile. Drug glucuronides excreted in bile can be hydrolysed by bacteria in the gut—the liberated drug is reabsorbed and undergoes the same fate. This enterohepatic cycling of the drug prolongs its action, e.g. phenolphthalein, oral contraceptives. 

(ii) Acetylation Compounds having amino or hydrazine residues are conjugated with the help of acetyl coenzyme-A, e.g. sulfonamides, isoniazid, PAS, dapsone, hydralazine, clonazepam, procainamide. Multiple genes control the N-acetyl transferases (NATs), and rate of acetylation shows genetic polymorphism (slow and fast acetylators). 

(iii) Methylation The amines and phenols can be methylated by methyl transferases (MT); methionine and cysteine acting as methyl donors, e.g. adrenaline, histamine, nicotinic acid, methyldopa, captopril, mercaptopurine. 

(iv) Sulfate conjugation The phenolic compounds and steroids are sulfated by sulfotransferases (SULTs), e.g. chloramphenicol, methyldopa, adrenal and sex steroids. 

(v) Glycine conjugation Salicylates, nicotinic acid and other drugs having carboxylic acid group are conjugated with glycine, but this is not a major pathway of metabolism. 

(vi) Glutathione conjugation  This is carried out by glutathione-S-transferase (GST) forming a mercapturate. It is normally a minor pathway. However, it serves to inactivate highly reactive quinone or epoxide intermediates formed during metabolism of certain drugs, e.g. paracetamol. When large amount of such intermediates are formed (in poisoning or after enzyme induction), glutathione supply falls short—toxic adducts are formed with tissue constituents → tissue damage. 

(vii) Ribonucleoside/nucleotide synthesis This pathway is important for the activation of many purine and pyrimidine antimetabolites used in cancer chemotherapy.

ENZYMES FOR METABOLISM:

Microsomal enzymes: These are located on smooth endoplasmic reticulum (a system of microtubules inside the cell), primarily in liver, also in kidney, intestinal mucosa and lungs. The monooxygenases, cytochrome P450, UGTs, epoxide hydrolases, etc. are microsomal enzymes. 

They catalyse most of the oxidations, reductions, hydrolysis and glucuronide conjugation. Microsomal enzymes are inducible by drugs, diet and other agencies. 

Nonmicrosomal enzymes: These are present in the cytoplasm and mitochondria of hepatic cells as well as in other tissues including plasma. The esterases, amidases, some flavoprotein oxidases and most conjugases are nonmicrosomal. Reactions catalysed are: Some oxidations and reductions, many hydrolytic reactions and all conjugations except glucuronidation.

The nonmicrosomal enzymes are not inducible but many show genetic polymorphism (acetyl transferase, pseudocholinesterase). 

Both microsomal and nonmicrosomal enzymes are deficient in the newborn, especially premature, making them more susceptible to many drugs, e.g. chloramphenicol, opioids. This deficit is made up in the first few months, more quickly in case of oxidation and other phase I reactions than in case of glucuronide and other conjugations which take 3 or more months. 

FACTORS AFFECTING METABOLISM

1. Age: Neonates and infants donot have well developed complexes, i.e. phase II reaction is not well developed, whereas in adults phase II reaction is well developed. For example, in infants chloramphenicol results in grey baby syndrome. In old patients low hepatic enzyme activity due to lack of enzyme in liver or due to low hepatic blood flow results in improper kidney function and prevent drug excretion. 

2. Body temperature: increase in body temperature increases drug metabolism.

3. Chemical properties of the drug: certain drugs stimulates or inhibits the metabolism of other drugs. For example, phenobarbitone stimulates the metabolism of phenytoin.

4. Diet: Starvation can deplete enzymes (like glycine storage) and alter glycine conjugation reactions. For example, protein malnutrition prolongs the phenobarbitone (sleeping time).

5. Dose: Toxic dose can deplete enzymes necessary for detoxification reactions.

6. Enzyme induction: Certain drugs on chronic administration increases the activity of microsomal enzymes by an increased enzyme synthesis.

7. Enzyme inhibition: Azole antifungal drugs, macrolide antibiotics and some other drugs binds to heme iron in CYP450 and inhibits the metabolism of many drugs, as well as some endogenous substances like steroids, bilirubin. One drug can competitively inhibit the metabolism of another if it utilizes the same enzyme or cofactors. However, such interactions are not as common as one would expect, because often different drugs are substrates for different CYP-450 isoenzymes. It is thus important to know the CYP isoenzyme(s) that carry out the metabolism of a particular drug. A drug may inhibit one isoenzyme while being itself a substrate of another isoenzyme.

8. Genetic disorder: Abnormal development of enzymes responsible for metabolism give genetic disorder. For example, a typical choline esterase deficiency, metabolism of succcinyl choline becomes slow and respiratory muscle paralysis develops. 

9. Routes of drug administration: Oral route of administration can result in effective hepatic metabolism of some drugs i.e. first pass metabolism. 

FIRST PASS (PRESYSTEMIC) METABOLISM

 This refers to metabolism of a drug during its passage from the site of absorption into the systemic circulation. All orally administered drugs are exposed to drug metabolizing enzymes in the intestinal wall and liver (where they first reach through the portal vein). Presystemic metabolism in the gut and liver can be avoided by administering the drug through sublingual, transdermal or parenteral routes. However, limited presystemic metabolism can occur in the skin (transdermally administered drug) and in lungs (for drug reaching venous blood through any route). The extent of first pass metabolism differs for different drugs and is an important determinant of oral bioavailability. 

A drug can be excreted as such into bile. The hepatic extraction ratio (ERLiver) of a drug Is fraction of the absorbed drug prevented by the liver from reaching systemic circulation. Both presystemic metabolism as well as direct excretion into bile determine ERLiver, which is given by equation 

Accordingly the systemic bioavailability (F) of an orally administered drug will be:

F = fractional absorption x (1-ER)

Attributes of drugs with high first pass metabolism: 

(a) Oral dose is considerably higher than sublingual or parenteral dose. 

(b) There is marked individual variation in the oral dose due to differences in the extent of first pass metabolism. 

(c) Oral bioavailability is apparently increased in patients with severe liver disease. 

(d) Oral bioavailability of a drug is increased if another drug competing with it in first pass metabolism is given concurrently, e.g. chlorpromazine and propranolol.

distribution of drugs

Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and then the cells of the tissues. For a drug administered IV, when absorption is not a factor, the initial phase (that is, from immediately after administration through the rapid fall in concentration) represents the distribution phase, during which a drug rapidly disappears from the circulation and enters the tissues. This is followed by the elimination phase, when drug in the plasma is in equilibrium with drug in the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on cardiac output and regional blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity of the drug.  

The extent and pattern of distribution of a drug depends on its: 

• lipid solubility 

• ionization at physiological pH (a function of its pKa) 

• extent of binding to plasma and tissue proteins 

• presence of tissue-specific transporters 

• differences in regional blood flow.

Plasma protein binding

 Most drugs possess physicochemical affinity for plasma proteins and get reversibly bound to these. Acidic drugs generally bind to plasma albumin and basic drugs to α1 acid glycoprotein. Binding to albumin is quantitatively more important. Extent of binding depends on the individual compound; no generalization for a pharmacological or chemical class can be made.

Increasing concentrations of the drug can progressively saturate the binding sites: fractional binding may be lower when large amounts of the drug are given. The generally expressed percentage binding refers to the usual therapeutic plasma concentrations of a drug. The clinically significant implications of plasma protein binding are: 

(i) Highly plasma protein bound drugs are largely restricted to the vascular compartment because protein bound drug does not cross membranes (except through large paracellular spaces, such as in capillaries). They tend to have smaller volumes of distribution.

(ii) The bound fraction is not available for action. However, it is in equilibrium with the free drug in plasma and dissociates when the concentration of the latter is reduced due to elimination. Plasma protein binding thus tantamounts to temporary storage of the drug.

(iii) High degree of protein binding generally makes the drug long acting, because bound fraction is not available for metabolism or excretion, unless it is actively extracted by liver or by kidney tubules. Glomerular filtration does not reduce the concentration of the free form in the efferent vessels, because water is also filtered. Active tubular secretion, however, removes the drug without the attendant solvent → concentration of free drug falls → bound drug dissociates and is eliminated resulting in a higher renal clearance value of the drug than the total renal blood flow. Highly protein bound drugs are not removed by haemodialysis and need special techniques for treatment of poisoning. 

(iv) The generally expressed plasma concentrations of the drug refer to bound as well as free drug. Degree of protein binding should be taken into account while relating these to concentrations of the drug that are active in vitro, e.g. MIC of an antimicrobial. 

(v) One drug can bind to many sites on the albumin molecule. Conversely, more than one drug can bind to the same site. This can give rise to displacement interactions among drugs bound to the same site(s). The drug bound with higher affinity will displace that bound with lower affinity. If just 1% of a drug that is 99% bound is displaced, the concentration of free form will be doubled. This, however, is often transient because the displaced drug will diffuse into the tissues as well as get metabolized or excreted.

(vi) In hypoalbuminemia, binding may be reduced and high concentrations of free drug may be attained, e.g. phenytoin and furosemide. 

Barriers

Penetration into brain

Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies widely in terms of the fraction of the basement membrane that is exposed by slit junctions between endothelial cells. In the liver and spleen, a large part of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. This is in contrast to the brain, where the capillary structure is continuous, and there are no slit junctions. To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported. For example, a specific transporter for the large neutral amino acid transporter carries levo dopa into the brain. By contrast, lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells. Ionized, or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS, which have no slit junctions. These tightly juxtaposed cells form tight junctions that constitute the so-called blood-brain barrier.

   

Passage across placenta   

Placental membranes are lipoidal and allow free passage of lipophilic drugs, while restricting hydrophilic drugs. The placental efflux P-gp and other transporters like BCRP, MRP3 also serve to limit foetal exposure to maternally administered drugs. Placenta is a site for drug metabolism as well, which may lower/modify exposure of the foetus to the administered drug. However, restricted amounts of nonlipid-soluble drugs, when present in high concentration or for long periods in maternal circulation, gain access to the foetus. Some influx transporters also operate at the placenta. Thus, it is an incomplete barrier and almost any drug taken by the mother can affect the foetus or the newborn (drug taken just before delivery, e.g. morphine).

Redistribution 

Highly lipid-soluble drugs get initially distributed to organs with high blood flow, i.e. brain, heart, kidney, etc. Later, less vascular but more bulky tissues (muscle, fat) take up the drug—plasma concentration falls and the drug is withdrawn from the highly perfused sites.  If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of drug action. Greater the lipid solubility of the drug, faster is its redistribution. Anaesthetic action of thiopentone sod. injected i.v. is terminated in few minutes due to redistribution. A relatively short hypnotic action lasting 6–8 hours is exerted by oral diazepam or nitrazepam due to redistribution despite their elimination t ½ of > 30 hr. However, when the same drug is given repeatedly or continuously over long periods, the low perfusion high capacity sites get progressively filled up and the drug becomes longer acting.

Volume of distribution 

Usually drugs donot get remain in only one water compartment of the body. It gets distributed in several compartments where binding cellular components are more. For example, Components like lipids that are abundantly present in adipose tissue and cell membranes, proteins abundant in plasma and within the cells or components like nucleic acids present in nuclei of cells are the storage sites of drugs getting distributed. Therefore to what extend drug is getting distributed to different compartment according to the component of body ‘Apparent volume of distribution (Vd)” will give idea of distribution of drugs. Therefore Vd is the volume into which the drugs get distributed and calculated as 

  Vd = Amount of drug in the body        

Concentration of drug in plasma

The apparent volume of distribution, Vd, can be thought of as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0). 

Significance:

(i) High Vd indicated high lipophilicity or many receptors are present for the drug.

(ii) In overdose the drug has low Vd, are easily removed by hemodialysis, but drugs having high Vd are less available for dialysis because they get distributed in total body fluid.

(iii) It helps to calculate the loading dose.

ROUTES OF DRUG ADMINISTRATION

The route of administration is determined primarily by the properties of the drug (for example, water or lipid solubility, ionization) and by the therapeutic objectives (for example, the desirability of a rapid onset of action, the need for long-term treatment, or restriction of delivery to a local site). Major routes of drug administration include enteral, parenteral, and topical among others. 

 

1. LOCAL ROUTES 

 It is the simplest mode of administration of a drug at the site where the desired action is required. Systemic side effects are minimal. 

i. Topical: 

Drug is applied to the skin or mucous membrane at various sites for local action.  

a) Oral cavity: As a suspension, e.g. nystatin; as a troche, e.g. clotrimazole (for oral candidiasis); as a cream, e.g. acyclovir (for herpes labialis); as ointment and jelly, e.g. 5% lignocaine hydrochloride (for topical anaesthesia); as a spray, e.g. 10% lignocaine hydrochloride (for topical anaesthesia). 

b) GI tablet tract: As that is not absorbed, e.g. neomycin (for sterilization of gut before surgery). 

c) Rectum, Vaginal and anal canal:  

• As an enema (administration of drug into the rectum in liquid form):  

- Evacuant enema (for evacuation of bowel): For example, soap water enema—soap acts as a lubricant and water stimulates the rectum. 

– Retention enema: For example, methylprednisolone in ulcerative colitis. 

• As a suppository (administration of the drug in a solid form into the rectum), e.g. bisacodyl— for evacuation of bowels. 

 Advantages  

- Used in children.  

- Little first pass effect.  

- Can be given in vomiting.  

- Can be given in unconscious patient.  

- Higher therapeutic concentrations of drug are achieved rapidly in rectum.  

- For rapid evacuation of bowel, usually during gut sterilization before any surgical or radiological procedure.  

 Disadvantages  

 - Inconvenient.  

 - Drug absorption is slow and erratic. 

 - Irritation or inflammation of rectal mucosa can occur.  

d) Eye, ear and nose: As drops, ointments and sprays (for infection, allergic conditions, etc.), e.g. gentamicin eye/ear drops. 

e) Bronchi: As inhalation, e.g. salbutamol (for bronchial asthma and chronic obstructive pulmonary disease). Gases, volatile liquids and solids (in the form of finely divided powders) are inhaled for systemic and local effects. Inhalation of solids is called insufflation.

 Advantages  

- Rapid absorption of the drug due to large surface area.  

- First pass effect is avoided.  

- Rapid local effects.   

 Disadvantages  

- Only few drugs can be administered.  

- May produce irritation of pulmonary mucosa.  

- Inconvenient procedure.  

- Chances of cardiotoxicity.  

f) Skin: As ointment, cream, lotion or powder, e.g. clotrimazole (antifungal) for cutaneous candidiasis. 

g) Transdermal: Transdermal patches can provide prolonged or controlled (iontophoresis) drug delivery. Systemic absorption (Transdermal) is better with low dose, low MWt, lipid soluble drugs 

ii. Intra-arterial route: This route is rarely employed. It is mainly used during diagnostic studies such as coronary angiography and for the administration of some anticancer drugs, e.g. for treatment of malignancy involving limbs. 

iii. Administration of the drug into some deep tissues by injection, e.g. administration of triamcinolone directly into the joint space in rheumatoid arthritis.

Systemic Routes

A. Enteral 

Enteral administration, or administering a drug by mouth, is the safest and most common, convenient, and economical method of drug administration. When the drug is given in the mouth, it may be swallowed, allowing oral delivery, or it may be placed under the tongue (sublingual), facilitating direct absorption into the bloodstream.

1. Oral: Giving a drug by mouth provides many advantages to the patient. Oral drugs are easily self-administered and, compared to drugs given parenterally, have a low risk of systemic infections that could complicate treatment. Moreover, toxicities and overdose by the oral route may be overcome with antidotes, such as activated charcoal. On the other hand, the pathways involved in oral drug absorption are the most complicated, and the low pH of the stomach may inactivate some drugs. A wide range of oral preparations is available including enteric-coated and extended-release preparations.

a. Enteric-coated preparations: An enteric coating is a chemical envelope that resists the action of the fluids and enzymes in the stomach but dissolves readily in the upper intestine. Such coating is useful for certain groups of drugs (for example, omeprazole) that are acid unstable. Enteric coatings protect the drug from stomach acid, delivering them instead to the less acidic intestine, where the coating dissolves and allows the drug to be released. Similarly, drugs that have an irritant effect on the stomach, such as aspirin, can be coated with a substance that will dissolve only in the small intestine, thereby protecting the stomach.

b. Extended-release preparations: Extended-release medications have special coatings or ingredients that control how fast the drug is released from the pill into the body. Having a longer duration of action may improve patient compliance, because the medication does not have to be taken as often. Additionally, extended-release dosage forms may maintain concentrations within an acceptable therapeutic range over a long period of time, as opposed to immediate-release dosage forms, which may result in larger peaks and troughs in plasma concentrations. These extended-release formulations are advantageous for drugs with short half-lives. For example, the half-life of morphine is 2 to 4 hours in adults. Oral morphine must be administered six times in 24 hours to obtain a continuous analgesic effect. However, only two doses are needed when controlled-release tablets are used. Unfortunately, many of the extended release formulations may have been developed to create a marketing advantage over conventional-release products, rather than because of documented clinical advantage.

 Advantages: 

- Convenient 

- Portable, safe, no pain, can be self-administered.

 - Cheap 

- No need to sterilize (but must be hygienic of course) 

- Variety of dosage forms available - fast release tablets, capsules, enteric coated, layered tablets, slow release, suspensions, mixtures 

- Convenient for repeated and prolonged use. 

 Disadvantages: 

- Sometimes inefficient: high dose or low solubility drugs may suffer poor availability, only part of the dose may be absorbed. Griseofulvin was reformulated to include the drug as a micronized powder. The recommended dose at that time was decreased by a factor of two because of the improved bioavailability. 

- First-pass effect: - drugs absorbed orally are transported to the general circulation via the liver. Thus drugs which are extensively metabolized will be metabolized in the liver during absorption. E.g. the propranolol oral dose is somewhat higher than the IV, the same is true for morphine. Both these drugs and many others are extensively metabolized in the liver.

 

- Food: - Food and G-I motility can effect drug absorption. Often patient instructions include a direction to take with food or take on an empty stomach. Absorption is slower with food for tetracyclines and penicillins, etc. However, for propranolol bioavailability is higher after food, and for griseofulvin absorption is higher after a fatty meal. 

- Local effect: - Antibiotics may kill normal gut flora and allow overgrowth of fungal varieties. Thus, antifungal agent may be included with an antibiotic. 

- Unconscious patient: - Patient must be able to swallow solid dosage forms. Liquids may be given by tube.

2. RECTAL ROUTE 

Drugs can be given in the form of solid or liquid. –

 Suppository: It can be used for local (topical) effect as well as systemic effect, e.g. indomethacin for rheumatoid arthritis. 

Enema: Retention enema can be used for local effect as well as systemic effect. The drug is absorbed through rectal mucous membrane and produces systemic effect, e.g. diazepam for status epilepticus in children. 

 Advantages 

- Used in children

- Little first pass effect. 

- Can be given in vomiting. 

- Can be given in unconscious patient. 

- Higher therapeutic concentrations of drug are achieved rapidly in rectum. 

- For rapid evacuation of bowel, usually during gut sterilization before any surgical or radiological procedure. 

 Disadvantages 

- Inconvenient, not well accepted. May be some discomfort 

-Drug absorption is slow and erratic. 

- Irritation or inflammation of rectal mucosa can occur

B. Parenteral 

Routes of administration other than enteral route are called parenteral routes. 

 Advantages of parenteral routes 

- Onset of action of drugs is faster; hence it is suitable for emergency. 

- Useful in: 

- Unconscious patient. 

- Uncooperative and unreliable patients. 

- Patients with vomiting and diarrhoea. 

- It is suitable for: 

- Irritant drugs. 

- Drugs with high first-pass metabolism.

- Drugs not absorbed orally. 

- Drugs destroyed by digestive juices. 

 Disadvantages of parenteral routes 

- Require aseptic conditions. 

- Preparations should be sterile and is expensive. 

- Requires invasive techniques that are painful. 

- Cannot be usually self-administered. 

- Can cause local tissue injury to nerves, vessels, etc. 

1. Sublingual:

 Placement under the tongue allows a drug to diffuse into the capillary network and, therefore, to enter the systemic circulation directly. Sublingual administration of an agent has  several advantages, including rapid absorption, convenience of administration, low incidence of infection, bypass of the harsh gastrointestinal (GI) environment, and avoidance of first-pass metabolism (the drug is absorbed into the superior vena cava). The buccal route (between cheek and gum) is similar to the sublingual route.

 

 Advantages: 

- Quick onset of action. 

- Action can be terminated by spitting out the tablet. 

- Bypasses first-pass metabolism. 

- Self-administration is possible.  

 Disadvantages 

- It is not suitable for bitter tasting and unpalatable drug. 

- It is not suitable for Irritant and lipid-insoluble drugs. 

- cannot give to unconscious patient. 

- Large quantities cannot be given. 

- Cannot be given in severe vomiting.  

2. INJECTABLES 

 

i. INTRAVENOUS (IV) 

• Drugs may be given into a peripheral vein over 1 to 2 minutes or longer by infusion, or Drugs are injected directly into the blood stream through a vein.

• Drugs are administered as: 

a) Bolus: Single, relatively large dose of a drug injected rapidly or slowly as a single unit into a vein. For example, i.v. ranitidine in bleeding peptic ulcer.  

b) Slow intravenous injection: For example, i.v. morphine in myocardial infarction. 

c) Intravenous infusion: For example, dopamine infusion in cardiogenic shock; mannitol infusion in cerebral oedema; fluids infused intravenously in dehydration. 

 Advantages 

- Bioavailability is 100%. 

- Quick onset of action; therefore, it is the route of choice in emergency, e.g. intravenous diazepam to control convulsions in status epilepticus. 

- Large volume of fluid can be administered, e.g. intravenous fluids in patients with severe dehydration. 

- Highly irritant drugs, e.g. anticancer drugs can be given because they get diluted in blood. - Hypertonic solution can be infused by intravenous route, e.g. 20% mannitol in cerebral oedema. 

- By i.v. infusion, a constant plasma level of the drug can be maintained, e.g. dopamine infusion in cardiogenic shock. 

 Disadvantages 

- Once the drug is injected, its action cannot be halted. 

- Local irritation may cause phlebitis. 

- Self-medication is not possible. 

- Strict aseptic conditions are needed. 

- Extravasation of some drugs can cause injury, necrosis and sloughing of tissues. 

- Depot preparations cannot be given by i.v. route. 

 Precautions 

- Drug should usually be injected slowly. 

- Before injecting, make sure that the tip of the needle is in the vein.

i. SUBCUTANEOUS (s.c.) ROUTE

• The drug is injected into the subcutaneous tissues of the thigh, abdomen and arm, e.g. adrenaline, insulin, etc. 

 Advantages:  

- Actions of the drugs are sustained and uniform.  

- Drugs can be given in presence of vomiting and diarrhea.  

- Drugs can be given to unconscious patients. 

- First pass effect is avoided.  

- Drugs that are not absorbed from G.I.T can be given. 

- Self-administration is possible (e.g. insulin). 

- Depot preparations can be inserted into the subcutaneous tissue, e.g. norplant for contraception.  

 Disadvantages  

- Only non-irritant drugs can be given otherwise severe irritation, pain and necrosis of subcutaneous tissues can occur.  

- Absorption of the drugs is slow than I/M injection.  

- Expensive.  - Danger of infection, if proper sterilization techniques are not used.  

- Large volumes of drug cannot be given.

ii. INTRAMUSCULAR (i.m) ROUTE 

• The drug is injected deep in the belly of a large skeletal muscle. The muscles that are usually used are detoid, triceps, Gluteus,. Maximus, rectus, femurs depending on the specie of animal. 

• The muscle is less richly supplied with sensory nerves, hence injecting a drug 1m is less painful. 

• Absorption of drug from gluteal region is slow especially in females due to high fat deposition.  

• Deep intramuscular injections are given at upper outer quadrant of buttock to prevent the injury to major nerves.  

• Deep I/M injections are less painful than I/M injections on arm due to high fat content. 

• Intramuscular injections are given at an angle of 90 degrees.

 Advantages 

- Rate of absorption is uniform. 

- Rapid onset of action. 

- Irritant substances can be given. 

- Drugs can be given to unconscious patients. 

- Accuracy of dosage is ensured. 

- Useful in emergency situations. 

- First pass effect is avoided. 

- Drugs producing gastric irritation can be given. - Drugs that are not absorbed from G.I.T can be given. 

 Disadvantages 

- Small quantities up to 10 ml of the drug can be given at a time. 

- Local pain and abscess formation. 

- Technical person is needed, self-administration is difficult. 

- Expensive. 

- Danger of infection, if proper sterilization techniques are not used. 

- Chances of nerve damage.

iii. INTRATHECAL ROUTE 

 Drug is injected into the subarachnoid space (spinal anaesthetics, e.g. lignocaine; antibiotics, e.g. amphotericin B, etc.). 

 

iv. INTRA-ARTICULAR ROUTE 

 Drug is injected directly into the joint space, e.g. hydrocortisone injection for rheumatoid arthritis. Strict aseptic precautions should be taken. Repeated administration may cause damage to the articular cartilage.

2. TRANSDERMAL ROUTE 

The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect. For example, scopolamine patch for sialorrhoea and motion sickness, nitroglycerin patch/ointment for angina, oestrogen patch for hormone replacement therapy (HRT).

 Advantages

- Self-administration is possible.

- Patient compliance is better.

- Duration of action is prolonged.

- Systemic side effects are reduced.

- Provides a constant plasma concentration of the drug.

 Disadvantages 

- Expensive.

- Local irritation may cause dermatitis and itching.

- Patch may fall-off unnoticed.

 

4 Nasal inhalation: 

This route involves administration of drugs directly into the nose. Agents include nasal decongestants, such as oxymetazoline, and anti-inflammatory corticosteroids such as mometasone furoate. Desmopressin is administered intranasally in the treatment of diabetes insipidus. Salmon calcitonin, a peptide hormone used in the treatment of osteoporosis, is also available as a nasal spray. 

PHARMACOKINETICS: ABSORPTION

ABSORPTION 

Absorption is the transfer of a drug from its site of administration to the bloodstream via one of several mechanisms. The rate and efficiency of absorption depend on both factors in the environment where the drug is absorbed and the drug’s chemical characteristics and route of administration (which influence its bioavailability). For IV delivery, absorption is complete. That is, the total dose of drug administered reaches the systemic circulation (100% bioavailability). Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. 

A. Mechanisms of absorption of drugs from the GI tract 

Depending on their chemical properties, drugs may be absorbed from the GI tract by passive diffusion, facilitated diffusion, active transport, or endocytosis. 

1. Passive diffusion: The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body compartments. In other words, the drug moves from a region of high concentration to one of lower concentration. Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs gain access to the body by this mechanism. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores, whereas lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane lipid bilayers. 

2. Facilitated diffusion: Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules into the interior of cells and moving them from an area of high concentration to an area of low concentration. This process is known as facilitated diffusion. It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier.

3. Active transport: This mode of drug entry also involves specific carrier proteins that span the membrane. A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using these specific carrier proteins. Energy-dependent active transport is driven by the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher drug concentration. The process shows saturation kinetics for the carrier, much in the same way that an enzyme-catalyzed reaction shows a maximal velocity at high substrate levels where all the active sites are filled with substrate.Active transport systems are selective and may be competitively inhibited by other cotransported substances.

4. Endocytosis and exocytosis: These types of drug delivery systems transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug filled vesicle. Exocytosis is the reverse of endocytosis and is used by cells to secrete many substances by a similar vesicle formation process. Vitamin B12 is transported across the gut wall by endocytosis, whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular membrane-bound vesicles in the nerve terminal and are released by exocytosis.

    

Factors influencing absorption 

1. Aqueous solubility: Drugs given in solid form must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) rate of dissolution governs rate of absorption. Ketoconazole dissolves at low pH: gastric acid is needed for its absorption. Obviously, a drug given as watery solution is absorbed faster than when the same is given in solid form or as oily solution.

2. Blood flow: Blood circulation removes the drug from the site of absorption and maintains the concentration gradient across the absorbing surface. Increased blood flow hastens drug absorption just as wind hastens drying of clothes.

3. Concentration: Passive diffusion depends on concentration gradient; drug given as concentrated solution is absorbed faster than from dilute solution.

4. Total surface area available for absorption: With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient.

5. Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. 

6. Dosageform: This affects drug absorption, because each route has its own peculiarities. 

Oral: Nonionized lipid soluble drugs, e.g. ethanol are readily absorbed from stomach as well as intestine at rates proportional to their lipid : water partition coefficient. Acidic drugs, e.g. salicylates, barbiturates, etc. are predominantly unionized in the acid gastric juice and are absorbed from stomach, while basic drugs, e.g. morphine, quinine, etc. are largely ionized and are absorbed only on reaching the duodenum.

Presence of food dilutes the drug and retards absorption. Further, certain drugs form poorly absorbed complexes with food constituents, e.g. tetracyclines with calcium present in milk; moreover food delays gastric emptying. Thus, most drugs are absorbed better if taken in empty stomach. However, there are some exceptions, e.g. fatty food greatly enhances lumefantrine absorption. Highly ionized drugs, e.g. gentamicin, neostigmine are poorly absorbed when given orally.

Subcutaneous and Intramuscular: By these routes the drug is deposited directly in the vicinity of the capillaries. Lipid soluble drugs pass readily across the whole surface of the capillary endothelium. Capillaries having large paracellular spaces do not obstruct absorption of even large lipid insoluble molecules or ions. Thus, many drugs not absorbed orally are absorbed parenterally. Absorption from s.c. site is slower than that from i.m. site, but both are generally faster and more consistent/ predictable than oral absorption. Application of heat and muscular exercise accelerate drug absorption by increasing blood flow, while vasoconstrictors.

Topical sites: Systemic absorption after topical application depends primarily on lipid solubility of drugs. However, only few drugs significantly penetrate intact skin.

7. Effect of pH on drug absorption: Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a proton (H+), causing a charged anion (A–) to form.

 

Weak bases (RNH3+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (RNH2):

 

A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A– cannot. For a weak base, the uncharged form, RNH2, penetrates through the cell membrane, but RNH3+, the protonated form, does not. Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa. [Note: The pKa is a measure of the strength of the interaction of a compound with a proton. The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug.] Distribution equilibrium is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces. [Note: Highly lipid-soluble drugs rapidly cross membranes and often enter tissues at a rate determined by blood flow.]

  

5. Expression of P-glycoprotein: P-glycoprotein is a multidrug transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed throughout the body, and its functions include:  

• In the liver: transporting drugs into bile for elimination 

• In kidneys: pumping drugs into urine for excretion 

• In the placenta: transporting drugs back into maternal blood, thereby reducing fetal exposure to drugs 

• In the intestines: transporting drugs into the intestinal lumen and reducing drug absorption into the blood 

• In the brain capillaries: pumping drugs back into blood, limiting drug access to the brain Thus, in areas of high expression, P-glycoprotein reduces drug absorption. In addition to transporting many drugs out of cells, it is also associated with multi drug resistance.

Bioavailability

Bioavailability is the fraction of administered drug that reaches the systemic circulation. For example, if 100 mg of a drug are administered orally, and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7, or 70 percent. Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration. The route by which a drug is administered, as well as the chemical and physical properties of the agent, affects its bioavailability.  

Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection, in which the total agent rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured. This curve reflects the extent of absorption of the drug. [Note: By definition, this is 100 percent for drugs delivered intravenously.] Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection if doses are equivalent.

 

 Factors that influence bioavailability: In contrast to IV administration, which confers 100% bioavailability, oral administration of a drug often involves first-pass metabolism. This biotransformation, in addition to the drug’s chemical and physical characteristics, determines the amount of the agent that reaches the circulation and at what rate.  

a. First-pass hepatic metabolism: When a drug is absorbed across the GI tract, it first enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug that gains access to the systemic circulation is decreased. [Note: First-pass metabolism by the intestine or liver limits the efficacy of many drugs when taken orally. For example, more than 90 percent of nitroglycerin is cleared during a single passage through the liver, which is the primary reason why this agent is administered via the sublingual route]. Drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target concentration. 

 

b. Solubility of the drug: Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases.

Bioequivalence: 

Oral formulations of a drug from different manufacturers or different batches from the same manufacturer may have the same amount of the drug (chemically equivalent) but may not yield the same blood levels—biologically inequivalent.  Two preparations of a drug are considered bioequivalent when the rate and extent of bioavailability of the active drug from them is not significantly different under suitable test conditions.