General Pharmacology Question And Answers

General Pharmacology Definitions

Pharmacology: Pharmacology is the science that deals with the study of drugs.

Drug: A drug is a substance (Drogue—a dry herb in French) used in the diagnosis, prevention, or treatment of a disease. WHO definition, “A drug is any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.”

Pharmacokinetics: Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of drugs, i.e. what the body does to the drug (in Greek Kinesis = movement).

Pharmacodynamics: Pharmacodynamics is the study of the effects of drugs on the body and their mechanisms of action, i.e. what the drug does to the body Therapeutics deals with the use of drugs in the prevention and treatment of disease.

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Pharmacoeconomic: Pharmacoeconomics deals with the cost, i.e. economic aspects of drugs used therapeutically.

Pharmacogenetics: Pharmacogenetics is the science that deals with the study of the genetic basis for variations in drug responses.

Pharmacogenomics: Pharmacogenomics is a branch of pharmacogenetics and deals with the use of genetic information of a person to choose drugs for him/her. It helps to tailor the drug and the dose based on the genotype of a person.

Pharmacovigilance: Pharmacovigilance is the science and activities relating to the detection, assessment, understanding, and prevention of adverse drug effects.

Toxicology: Toxicology deals with the adverse effects of drugs and also the study of poisons, i.e. detection, prevention, and treatment of poisoning (Toxicon = poison in Greek).

Chemotherapy: Chemotherapy is the use of drugs and chemicals for the treatment of infections. The term now also includes the use of chemical compounds to treat malignancies.

Pharmacy: Pharmacy is the science of identification, compounding, and dispensing of drugs. It also includes the collection, isolation, purification, synthesis, and standardization of medicinal substances.

Chronopharmacology: Chronopharmacology is the science that involves the correlation of drug effects to the circadian rhythm to obtain optimum therapeutic effects and minimize the adverse effects, for example, bronchospasm usually occurs at night.

Blood pressure rises at dawn and dusk and is the lowest at midnight.

Acute MI is more common in the morning hours of the day. Chronotherapy is the administration of drugs to match the circadian rhythm. Chronobiotics are drugs that can be used to modify or reset the circadian rhythm—useful in conditions like sleep disorders and jet lag.

Pharmacopoeia:

Question 1. Write a short note on pharmacopeia.
Answer:

Pharmacopoeia (in Greek, Pharmacon = drug; poeia = to make) is the official publication containing a list of drugs and medicinal preparations approved for use, their formulae, and other information needed to prepare a drug.

• Pharmacopoeia also has information on the sources of drugs, their properties, doses, and tests for the identity, purity, and potency of drugs.
• Most countries follow their own pharmacopeia to guide their physicians and pharmacists.
• We thus have the Indian Pharmacopoeia (IP), the British Pharmacopoeia (BP), United States
• Pharmacopoeia (USP), Japanese Pharmacopoeia, and others brought out by different countries.
• The International Pharmacopoeia is published by WHO in many languages like English, French and Spanish.
• The list is revised at regular periods to delete obsolete drugs and to include newly introduced ones.

Sources Of Drugs:

Question 2. Write short notes on sources of drugs.
Answer:

Sources of drugs could be

1. Natural sources: Obtained from plants, animals, minerals, microbes, and human beings too.
2. Synthetic sources: Most drugs used now are synthesized for therapeutic use.
3. Biotechnology:
   • By cell cultures, for example, Urokinase from cultured human kidney cells.
   • Recombinant DNA technology, for example, Human insulin, tissue plasminogen activator, hematopoietic growth factors like erythropoietin
   • Hybridoma technique, monoclonal antibodies like rituximab

Routes Of Drug Administration

Question 3. Enlist the different routes of drug administration. What are the advantages and disadvantages of sublingual IV, and oral routes? Add a note on Novel routes of drug administration.
Answer:

Drugs may be given by different routes depending on the patient’s requirements and the properties of the drug.

1. Systemic Routes:

They are enteral and parenteral routes. Drugs given through these routes reach systemic circulation.

Enteral routes: Include oral, sublingual, and rectal routes.

1. Oral route: 

• The Oral route is the most commonly used, oldest and safest route of drug administration.
• The large surface area of the gastrointestinal tract, the mixing of its contents, and the differences in pH at different parts of the gut facilitate the effective absorption of the drugs given orally.
• However, the acid and enzymes secreted in the gut and the activity of the bacterial flora of the gut can destroy some drugs before they are absorbed.

Advantages of Oral route:

• Safest route
• Most convenient
• Most economical
• Noninvasive route
• Drugs can be self-administered

Disadvantages of the Oral route:

1. Slow action: As absorption needs time → not suitable for emergencies.
2. Irritant and unpalatable drugs → cannot be administered.
3. Poor absorption: Due to certain physical and chemical characteristics, e.g. streptomycin is not absorbed orally.
4. GI irritation → may lead to vomiting.
5. Unpredictable absorption: This may be irregular.
6. Metabolism: Some drugs may be destroyed by gastric juices, e.g. insulin.
7. Unsuitable situations: Cannot be given to unconscious and uncooperative patients.
8. First-pass effect: Some drugs may undergo extensive first-pass metabolism.

To overcome some of the disadvantages, irritants are given in capsules, and bitter drugs are given as sugar-coated tablets.

Enteric-coated tablets:

Question 4. Write briefly on enteric-coated tablets.
Answer:

Some tablets are coated with substances or polymers like cellulose-acetate, phthalates, gluten, shellac, etc. ‘ Which are not digested by the gastric acid but get disintegrated in the alkaline juices of the intestine. The polymer used and the thickness of the coating influence the dissolution of the coat in the intestines.

Enteric coating will:

• Prevent gastric irritation
• Avoid the destruction of the drug by the stomach
• Provide a higher concentration of the drug in the small intestine
• Retard the absorption, and thereby prolong the duration of action—controlled-release or sustained-release preparations.

However, if the coating is inappropriate, the tablet may be expelled without being absorbed at all.

2. Sublingual route:

• Here, the tablet is placed under the tongue. As the drug dissolves, it is absorbed across the sublingual mucosa, for example, Nitroglycerin, Nifedipine, and Buprenorphine.
• The tablet may also be crushed in the mouth but not swallowed and the contents are absorbed across the buccal mucosa.
• The formulation should be so designed that it quickly dissolves in the saliva.
• The buccal mucosa is rich in blood supply and this allows quick absorption of the drug.

Advantages of the Sublingual route:

• Absorption is rapid—within minutes the drug reaches the circulation.
• First-pass metabolism is avoided because the drug directly reaches the systemic circulation.
• After the desired effect is obtained, the drug can be spat out to avoid unwanted effects.

Disadvantages of the Sublingual route:

• Buccal ulceration can occur.
• Lipid-insoluble drugs, high molecular weight drugs, irritants and unpalatable drugs cannot be given by this route.

3. Rectal route:

• Rectum has a rich blood supply and drugs can cross the rectal mucosa to be absorbed for systemic effects.
• Drugs absorbed from the upper part of the rectum are carried by the superior hemorrhoidal vein to the portal circulation (can undergo first-pass metabolism).
• While that is absorbed from the lower part of the rectum is carried by the middle and inferior hemorrhoidal veins directly to the systemic circulation.
• Drugs like indomethacin, chlorpromazine, diazepam, and paraldehyde can be given rectally. Some irritant drugs are given rectally as suppositories.
• Drugs may also be given by rectal route as an enema.

Advantages of Rectal route:

• Gastric irritation is avoided.
• Can be administered by unskilled persons.
• Useful in geriatric patients; patients with vomiting, those unable to swallow, and after gastrointestinal surgery.
• Useful in unconscious patients.

Disadvantages of the Rectal route:

• Irritation of the rectum can occur.
• Absorption may be irregular and unpredictable.

Enema: Enema is the administration of a drug in a liquid form into the rectum. Enema may be evacuant or retention enema.

• Evacuant enema: In order to empty the bowel, about 600 mL of soap water is administered per rectum.
• Retention enema: The drug is administered with about 100 mL of fluids and is retained in the rectum for local action, for example, Prednisolone enema in ulcerative colitis.

4. Parenteral routes:

Systemic routes other than the enteral (intestinal) route like injections, inhalation, and transdermal routes. Here the drugs are directly delivered into the tissue fluids or blood.

Advantages of Parenteral routes:

• Action is more rapid and predictable → useful in emergencies.
• Can be employed in an unconscious or uncooperative patient.
• Gastric irritants can be given parenterally.
• Used in patients with vomiting or those unable to swallow.
• Digestion by the gastric and intestinal juices and the first-pass metabolism are avoided.

Disadvantages s of Parenteral routes:

• Asepsis must be maintained.
• Injections may be painful.
• More expensive.
• Less safe.
• Inconvenient.
• Injury to nerves and other tissues may occur.

Injections: Injections are given using a syringe and needle.

They are:

Intradermal: The drug is injected

• Into the layers of the skin raising a bleb, (for example, BCG vaccine, tests for allergy) or
• By multiple punctures of the epidermis through a drop of the drug, e.g. smallpox vaccine.

Only a small quantity can be administered by this route and it may be painful.

5. Subcutaneous route:

• The drug is deposited in the subcutaneous (SC) tissue,  (for example,  Insulin, Heparin.
• As this tissue is less vascular, absorption is slow and largely uniform, making the drug long-acting.
• It is reliable and patients can be trained for self-administration.
• Absorption can be enhanced by the addition of the enzyme hyaluronidase.

Disadvantages Subcutaneous route:

• Irritant drugs cannot be injected because they can cause severe pain as SC tissue is richly supplied by nerves.
• In shock, absorption is not dependable because of vasoconstriction.
• Repeated injections at the same site can cause lipoatrophy resulting in erratic absorption.
• Hypodermoclysis is the subcutaneous administration of large volumes of saline employed in pediatric practice.

Drugs can also be administered subcutaneously as:

• Dermojet: In this method, a high-velocity jet of drug solution is projected from a fine orifice using a ‘gun’. The solution gets deposited in the SC tissue from where it is absorbed. As a needle is not required, this method is painless. It is suitable for vaccines.
• Pellet implantation: Small pellets packed with drugs are implanted subcutaneously. The drug is slowly released for weeks or months to provide constant blood levels, e.g. testosterone, desoxycorticosterone acetate (DOCA).
• Sialistic implants: The drug is packed in sialistic tubes and implanted subcutaneously. The drug gets absorbed over months to provide constant blood levels, for example, Hormones and contraceptives. The empty nonbiodegradable implant has to be removed.

6. Intramuscular route:

• An aqueous solution of the drug is injected into one of the large skeletal muscles deltoid, triceps, gluteus or rectus femoris.
• The volume of injection should not exceed 10 mL.
• Absorption is by simple diffusion. Larger molecules enter through lymphatic channels.
• As the muscles are vascular, absorption is rapid and quite uniform.
• Drugs are absorbed faster from the deltoid region than gluteal region, especially in women.
• For infants, rectus femoris is used instead of gluteus because the gluteus is not well-developed
  till the child starts walking.
• If the drug is injected as an oily solution or suspension, absorption is slow and steady and can
  have prolonged effects.
• Soluble substances, mild irritants, depot preparations, suspensions, and colloids can be
  injected by this route.

Advantages of the Intramuscular route:

• Reliable.
• Absorption is rapid and uniform as muscles are vascular.

Disadvantages of the Intramuscular route:

• May be painful
• May result in an abscess.
• Irritant solutions injected near a nerve—can damage the nerve
• Local infection and tissue necrosis are possible.
• For some drugs, absorption by the IM route is slower than oral, e.g. diazepam, or phenytoin.
• For some drugs, the IM route should be avoided, e.g. heparin, calcium gluconate, and diazepam.

7. Intravenous route:

Here, the drug is injected into one of the superficial veins so that it directly reaches the circulation and is immediately available for action.

Drugs can be given IV as:

• A bolus, for example, Heparin.
• Slow injection—over 15–20 minutes, for example, Aminophylline.
• Slow infusion—when constant plasma concentrations are required, for example, Oxytocin in labor, or when large volumes have to be given for example, Dextrose, or Saline.

Advantages of the Intravenous route:

• The most useful route in emergencies drugs immediately available for action
• Provides predictable blood concentrations with 100% bioavailability.
• Large volumes of solutions can be given.
• Irritants can be given get quickly diluted in blood.
• Rapid dose adjustments are possible  If unwanted effects occur, the infusion can be stopped; if higher levels are required, the infusion rate can be increased especially for short-acting drugs.

Disadvantages of the Intravenous route:

• Once injected, the drug cannot be withdrawn.
• Irritation of the veins may cause thrombophlebitis.
• Extravasation of some drugs may cause severe irritation and sloughing.
• Only aqueous solutions can be given IV but not suspensions, oily solutions, and depot
  preparations.
• Self-medication is difficult.
• Risk of embolism — Though rare.

Intraperitoneal:  Peritoneum has a large surface area for absorption. Fluids are injected intraperitoneally in infants. Also used for peritoneal dialysis.

• Intrathecal: Strict aseptic precautions are a must. Drugs may be injected:
  • Into subarachnoid space for action on the CNS, for example, Spinal anesthetics, some antibiotics, and corticosteroids.
  • Extradurally, for example, Morphine is given epidurally to produce analgesia.
  • Direct intraventricular administration—in brain tumors.
• Intra-articular:
  • Drugs are injected directly into a joint for the treatment of diseases of the joints, for example, Rheumatoid arthritis, hydrocortisone is injected into the affected joint. Strict aseptic precautions are required.
• Intra-arterial: Drug injected directly into the arteries. Used only in the treatment of:
  • Peripheral vascular diseases
  • Local malignancies
  • Diagnostic studies like angiogram.
• Intramedullary: Injection into bone marrow—now rarely used.

Inhalation: Lungs have a large surface area for absorption of drugs. Volatile liquids and
gases are given by inhalation, for example, General anesthetics.

• Drugs can also be administered as solid particles in solutions and the fine droplets inhaled as aerosol, for example, Salbutamol.
• Inhaled drugs may act locally on the respiratory tract or may be absorbed through these membranes.
• Drugs (other than anesthetics) for inhalation are available as metered dose inhalers, dry powder inhalers, and nebulizers.

Advantages of Inhalation:

• Almost immediate absorption of the drug (due to large surface area and high vascularity)
• In pulmonary diseases, inhalation is a local route, hence, more effective and less harmful.
• Because the drug is directly delivered, a smaller dose is needed and toxicity is less.
• Hepatic first-pass metabolism is avoided.
• Blood levels of volatile anesthetics can be controlled because their absorption and excretion through the lungs are governed by the laws of gases.

Disadvantages of Inhalation:

• Irritant gases may increase pulmonary secretion—should be avoided.
• Drug particles may induce cough, for example, Cromolyn sodium.

Transdermal drug delivery:

Question 5. Write a short note on transdermal drug delivery.
Answer:

Highly lipid-soluble drugs can be applied over the skin for slow and prolonged absorption, for example, Nitroglycerine ointment in angina pectoris.

Some forms of transdermal drug delivery are:

Adhesive units:

• Transdermal adhesive units (transdermal therapeutic systems) are adhesive patches of different sizes and shapes made to suit the area of application.
• The drug is held in a reservoir between an outer polymer layer and a porous membrane. The undersurface of the membrane is smeared with an adhesive to hold onto the area of application.
• The drug slowly diffuses through the membrane and percutaneous absorption takes place. The rate of absorption is constant and predictable.
• Highly potent drugs (because a small quantity is sufficient) and short-acting drugs (because the effect terminates quickly after the system is removed) are suitable for use in such systems.
•  Sites of application depend on the indication— they may be applied over the chest, abdomen, upper arm, back, or mastoid region; a testosterone patch is applied over the scrotum.
• Examples: Hyoscine, nitroglycerin, testosterone, estrogen, nicotine, and fentanyl transdermal patches.

Examples of transdermal therapeutic systems:

Advantages of transdermal drug delivery:

• Duration of action is prolonged
• Provides constant plasma drug levels
• Patient compliance is good.

Disadvantages of transdermal drug delivery:

• Large doses of the drug cannot be loaded into the system
• Can cause irritation to the skin
• Expensive.

1. Inunction: Here, a drug is rubbed into the skin and it gets absorbed to produce systemic effects.

2. Iontophoresis: Since the flow of electricity increases the permeability of the skin, in this procedure, galvanic current is used for bringing about the penetration of lipid-insoluble drugs into the deeper tissues where their action is required, for example, Salicylates.

3. Jet injection: As absorption of the drug occurs across the layers of the skin, dermojet may also be considered a form of transdermal drug administration

Transmucosal drug administration includes:

• Sublingual
• Nasal
• Rectal routes

2. Local Routes:

Drugs may be applied on the skin or mucous membrane for local action as ointment, cream, gel, powder, paste, etc. Drugs may also be applied locally in the eyes, ears, and nose as ointment, drops, and sprays. Drugs are absorbed across the mucous membranes.

Nasal route:

• Drugs are administered through the nasal route either for systemic absorption or for local effects, for example, Systemic absorption—oxytocin spray.
• For local effect—decongestant nasal drops, for example, Oxymetazoline, and Budesonide nasal spray for allergic rhinitis.
• Drugs may be administered as suppositories for the rectum, bougie for the urethra, and pessary and douche for the vagina.
• Pessaries are oval-shaped tablets to be placed in the vagina to provide high local concentrations of the drug at the site, for example,  Antifungal pessaries in vaginal candidiasis.
• Douche is an aqueous solution used for rinsing a body cavity. Though the word ‘douche’ is generally used for vaginal solutions, it can be used for solutions meant for the bladder or the rectum.

Prodrug:

Prodrug is an inactive form of a drug that gets metabolized to the active form in the body.

Advantages of Prodrug: 

• Increase availability: Increase availability at the site, for example, Dopamine does not cross the BBB; levodopa, a prodrug, crosses the BBB and is then converted to dopamine in the CNS.
• Prolong duration of action: Prolong duration of action for example, Bacampicillin, a prodrug of ampicillin is longer-acting than ampicillin.
• Improve tolerability: Improve tolerability, for example, Cyclophosphamide, an anticancer drug, gets converted to its active metabolite aldophosphamide in the liver. y
• Drug targeting: Zidovudine is taken up by the virus-infected cells and gets activated in these cells resulting in selective toxicity to infected cells.
• Improve stability: A prodrug may be more stable at gastric pH, for example, Aspirin the prodrug of salicylic acid is more stable than salicylic acid.
• Reduced side effects: For example, bacampicillin, a prodrug of ampicillin is better absorbed and therefore, causes less diarrhea than ampicillin.

Disadvantages of Prodrug: 

• Not suitable in emergencies due to slower action
• In liver diseases, prodrugs may not be activated.

Special Drug Delivery Systems

Question 6. Write short notes on special drug delivery systems.
Answer:

Special drug delivery systems are introduced:

• In order to improve drug delivery
• To prolong the duration of action
• Improve patient compliance.

Drug targeting is also tried, particularly for anticancer drugs. Some such systems are:

1. Ocusert:
   • Ocuserts are thin elliptical units that contain the drug in a reservoir which slowly releases the drug through a membrane.
   • By diffusion at a steady rate, for example, Pilocarpine focused used in glaucoma is placed under the lid and can deliver pilocarpine for 7 days.
2. Progestasert is inserted into the uterus where it delivers progesterone constantly for over 1 year.
3. Transdermal patch
4. Prodrugs
5. Osmotic pumps:
   • These are small tablet-shaped units containing the drug and an osmotic substance in two different chambers.
   • The tablet is coated with a semipermeable membrane in which a minute laser-drilled hole is made.
   • When the tablet is swallowed and reaches the gut, water enters the tablet through the semipermeable membrane.
   • The osmotic layer swells and pushes the drug slowly out of the laser-drilled orifice. This allows slow and constant delivery of the drug over a long period of time.
   • It is also called the gastrointestinal therapeutic system (GITS).
   • Some drugs available as GITS are iron, prazosin, and nifedipine.
6. Computerized miniature pump: These are programmed to release drugs at a definite rate either continuously as in the case of insulin or intermittently in pulses as with GnRH.

Targeted Drug Delivery Systems:

Drug targeting is delivering drugs to the site of action. This largely reduces the adverse drug reactions because the drug will be delivered at the required site of action.

Some such systems are:

1. Liposomes: Liposomes are phospholipids suspended in aqueous vehicles to form minute vesicles. Drugs are entrapped in the aqueous spaces or within the lipid layer itself.

• Though liposomes can be given both orally and parenterally, the IV route is the most common.
• Small liposomes are taken up by the reticuloendothelial cells while larger ones are deposited in the lungs and are also concentrated in malignant tumors.
• Liposomes are used in the treatment of cancers, systemic fungal infections, diabetes mellitus, and in heavy metal poisoning.

2. Monoclonal antibodies: Monoclonal antibodies against the tumor-specific antigens are used to deliver anticancer drugs to specific tumor cells.

3. Nanoparticles: The drug is dissolved in the nanoparticle matrix to get nanoparticles.

• The size of the nanoparticles varies from 10 to 1,000 nm and is biodegradable.
• They can be used to deliver anticancer drugs to the cancer tissue in order to improve efficacy and reduce toxicity.

4. Polymer-based drug delivery:

• Polymers have been used in transdermal drug delivery systems and for coating as in enteric-coated capsules and drug-eluting stents.
• Drugs are also designed for delivery to the colon in ulcerative colitis and inflammatory bowel disease.

5. Drug-eluting stents:

• Drug-eluting stents are devices consisting of a tubular mesh-like metallic stent coated with a drug on a polymer coating.
• The drug may be sirolimus or paclitaxel which is gradually released over 4–6 weeks and prevents the proliferation of vascular smooth muscles and endothelial cells over the stent placed.

Pharmacokinetics

1. Transport Of Drugs:

• Once the drug is administered, the processes of absorption, distribution, metabolism, and excretion involve the passage of the drug molecules across various barriers like intestinal epithelium, cell membrane, renal filtering membrane, capillary barrier, etc.
• The cell membrane/biological membrane is made up of two layers of phospholipids with intermingled protein molecules.
• The junctions between adjacent epithelial or endothelial cells have pores through which small water-soluble molecules can pass.
• The movement of some specific substances is regulated by special carrier proteins.
• The passage of drugs across biological membranes or drug permeation involves different processes.

Transport Of Drugs Across Biological Membranes:

1. Passive transfer:
   • Simple diffusion
   • Filtration
2. Carrier-mediated transport:
   • Active transport
   • Facilitated diffusion
3. Endocytosis and exocytosis:

2. Passive Transfer:

The drug moves across a membrane without any need for energy.

• Simple diffusion: Simple diffusion is the transfer of a drug across the membrane in the direction of its concentration gradient.
  • The speed of diffusion depends on the degree of concentration gradient, lipid solubility, and ionization.
  • The higher the concentration gradient, the faster is the diffusion across the membrane.
  • Lipid-soluble, unionized drugs are rapidly transferred across membranes by simple diffusion.
  • Most drugs follow simple diffusion.
• Filtration: Filtration is the passage of drugs through aqueous pores in the membrane.
  • Water-soluble drugs with molecular size (mol wt <100) smaller than the diameter of the pores (7A°) cross the biological membranes by filtration.
  • The movement is along the concentration gradient, e.g. urea.

3. Carrier-Mediated Transport:

Transport of some substances is aided by specific carriers.

• Active transport:  Active transport is the transfer of drugs against a concentration gradient and needs energy. It is carried by a specific carrier protein.
  • Only drugs related to natural metabolites are transported by this process, for example, Levodopa, Iron, sugars, and amino acids.
  • The compound binds to a specific carrier and carried.
  • Substances competing for the same mechanism for transport may interfere with drug movement because this process is saturable.
• Facilitated diffusion: Facilitated diffusion is a form of transport that uses a carrier but is not energy dependent and movement occurs in the direction of the concentration gradient. It is highly specific for the substance, for example, the Uptake of glucose by cells, vitamin B₁₂ from the intestines.

 Endocytosis And Exocytosis:

• In endocytosis, small droplets are engulfed by the cell membrane and carried into the cell as a vesicle which is then broken down to release the substances.
• Some proteins and vitamin B₁₂ with the help of intrinsic factors are taken up by this process (like pinocytosis in amoeba).
• The reverse process—exocytosis is responsible for the secretion of many substances from cells, for example, Neurotransmitters stored in nerve endings.

Absorption

Question 7. What are the mechanisms of drug absorption? What is first-pass metabolism? Explain enterohepatic circulation.
Answer:

Definition of absorption:

Absorption is the passage of the drug from the site of administration into the circulation. Absorption occurs by passive diffusion or carrier-mediated transport. Except for the intravenous route, the drug needs to be absorbed from all other routes of administration. The rate and extent of absorption varies with the route of administration.

Absorption From The Gut:

• Drugs taken orally may be absorbed from any part of the gut. Highly lipid-soluble drugs may be absorbed from the buccal cavity from where they directly enter the systemic circulation.
• Acidic drugs are absorbed from the stomach, while basic drugs get ionized in the stomach and are not absorbed.
• Intestines have a large surface area and most drugs are absorbed from the proximal part of the jejunum. Basic drugs are absorbed from the intestines because of the favorable pH.
• Absorption from the large intestine is negligible.
• Certain drugs may be transported out from the cells of the intestinal wall back into the gut lumen.
• This is done with a reverse transporter or efflux transporter P-glycoprotein.

Factors influencing the absorption of a drug given orally:

1. Pharmaceutical Factors:

• Disintegration and dissolution time:
  • The drug taken orally should break up into particles and then dissolve in the gastrointestinal fluids. In the case of drugs given SC or IM, the drug molecules have to dissolve in the tissue fluids.
  • Liquids are absorbed faster than solids.
  • Delay in disintegration and dissolution as with poorly water-soluble drugs like aspirin results in delayed absorption.
• Formulation: Drugs are formulated to produce the desired absorption. Inert substances used with drugs as diluents like starch and lactose may sometimes interfere with absorption.
• Particle size: Small particle size is important for better absorption of drugs.
  • Drugs like corticosteroids, griseofulvin, digoxin, aspirin, and tolbutamide are better absorbed when given as small particles.
  • On the other hand, when a drug has to act on the gut and its absorption is not desired, then particle size should be kept large, for example, Anthelmintics like bephenium.

2. Drug Factors:

• Lipid solubility: Lipid-soluble drugs are absorbed faster and better by dissolving in the phospholipids of the cell membrane.
• pH and ionization: Ionized drugs are poorly absorbed while unionized drugs are lipid soluble and are well absorbed.
  • The degree of ionization depends on the pH of the medium.
  • Acidic drugs remain unionized in the acidic medium of the stomach and are rapidly absorbed from the stomach, for example, Aspirin, and barbiturates.
  • Basic drugs are unionized when they reach the alkaline medium of the intestine from where they are rapidly absorbed, for example, Pethidine, and ephedrine.
  • Basic drugs given IV may diffuse from the blood into the stomach because of acidic pH and may ionize quickly.
  • This is known as ‘ion trapping’.
  • Strong acids and bases are highly ionized and therefore, poorly absorbed, for example, Heparin, and Streptomycin.

3. Biological Factors:

• Area and vascularity of the absorbing surface: If the area of the absorbing surface is large and more vascular absorption is better. Thus most drugs are absorbed from the small intestine.
• Gastrointestinal motility:
  • Gastric emptying time if gastric emptying is faster, the passage of the drug to the intestines is quicker, and hence absorption is faster.
  • Intestinal motility when highly increased as in diarrheas, drug absorption is reduced.
• Presence of food: The presence of food delays gastric emptying, dilutes the drug, and delays absorption.
  • Drugs may form complexes with food constituents and such complexes are poorly absorbed
  • For example, tetracyclines chelate calcium is present in the food hence their bioavailability is decreased.
• Diseases: Malabsorption and achlorhydria result in reduced absorption of drugs. Acidic drugs are poorly absorbed in achlorhydria. In the absence of intrinsic factors, vitamin B₁₂ is not absorbed in pernicious anemia.
• First-pass metabolism: Some drugs may be degraded in the gut by first-pass metabolism, for example, Nitroglycerine, and insulin. Such drugs should be given in higher doses or by alternative routes.

First Pass Metabolism

Question 8. Write a short note on first-pass metabolism.
Answer:

Definition of first-pass metabolism: It is the metabolism of a drug during its passage from the site of absorption to the systemic circulation

• Also called presystemic metabolism or first-pass effect and is an important feature of the oral route of administration.
• Drugs given orally may be metabolized in the gut wall and liver before reaching systemic circulation.
• The extent of first-pass metabolism differs from drug to drug and among individuals from partial to total inactivation.
• When it is partial, it can be compensated by giving a higher dose of the particular drug, for example, Nitroglycerine, propranolol, or salbutamol.
• For drugs that undergo complete first-pass metabolism, the route of administration has to be changed, for example, Isoprenaline, hydrocortisone, and insulin.
• The bioavailability of many drugs is increased in liver disease due to a reduction in hepatic metabolism.
• First-pass metabolism reduces bioavailability.

Bioavailability

Question 9. What is bioavailability? Explain the factors affecting the bioavailability of a drug.
Answer:

Definition of Bioavailability: Bioavailability is the fraction of the administered drug that reaches the systemic circulation in unchanged form following administration by any route:

• Intravenously, the bioavailability is 100%.
• On IM/SC injection and sublingual administration, drugs are almost completely absorbed (bioavailability >75%)
• By oral route, bioavailability may be low due to incomplete absorption and first-pass metabolism, for example, the Bioavailability of chlortetracycline is 30%, carbamazepine — 70%, chloroquine — 80%, minocycline and diazepam almost 100%.
• Transdermal preparations have 80–100% bioavailability; for rectal route—30–100%.
• Large bioavailability variations can result in toxicity or therapeutic failure, for example, Halofantrine.

Determining Bioavailability

• The drug is injected IV and its plasma concentration is measured at one-hourly intervals. The plasma concentration is plotted against time on graph paper.
• The same dose of the drug is given orally and a plasma concentration—time graph is also obtained.

Bioavailability is calculated by the formula:

Factors that influence bioavailability:

• Unionized drugs with good lipid solubility and of small particle size have good bioavailability since they are well absorbed.
• All the ten factors which influence the absorption of a drug also alter bioavailability—they include pharmaceutical factors, drug factors, and biological factors.

Bioequivalence:

• If two formulations of a drug have the same bioavailability and rate of absorption, they are bioequivalent.
• Comparison of bioavailability of different formulations of the same drug is the study of bioequivalence.
• Oral formulations containing the same amount of a drug from different manufacturers may result in different plasma concentrations or may differ in the rate of absorption, i.e. there is no bioequivalence among them.
• Such differences occur with poorly soluble, slowly absorbed drugs, mainly due to differences in the rate of disintegration and dissolution.

Significance:

• Variation in bioavailability (nonequivalence) can result in toxicity or therapeutic failure of drugs that have low safety margins like digoxin and drugs that need precise dose adjustments like anticoagulants and corticosteroids.
• For such drugs, in a given patient, preparations from a single manufacturer should be used.

Plasma Protein Binding

Question 10. Write a short note on plasma protein binding.
Answer:

• On reaching circulation, most drugs bind to plasma proteins; acidic drugs bind mainly to albumin, and basic drugs to alpha-1 acid glycoprotein.
• The free or unbound fraction of the drug is the only form available for action, metabolism, and excretion while the protein-bound form serves as a reservoir.
• The extent of protein binding varies with each drug, for example, Warfarin is 99% and morphine is 35% protein bound while binding of ethosuximide and lithium is 0%, i.e. they are totally free.
• Some drugs also bind to tissue proteins and specific carrier proteins (for example, Corticosteroids to transcortin, iron to ferritin).

 Plasma Protein Binding Clinical Significance :

1. Only a free fraction is available for action, metabolism, and excretion.
2. When the free drug levels in the plasma fall, the bound drug is released. Thus protein binding may delay the drug from reaching the site of action.
3. Protein binding serves as a store (reservoir) of the drug.
4. Protein binding prolongs the half-life and thereby the duration of action. Highly protein-bound drugs are generally long-acting.
5. Drugs may compete for the same binding sites and one drug may displace another from the binding sites resulting in displacement interactions.
6. Protein binding sites may get saturated.
7. Chronic renal failure and chronic liver disease result in hypoalbuminemia with reduced protein binding of drugs leading to raised levels of free drugs and particularly highly protein-bound drugs may require dose reduction.
8. In acute inflammatory states, higher doses may be needed.

 Plasma Protein Binding Redistribution

Question 11. Write a short note on redistribution.
Answer:

• When some highly lipid-soluble drugs are given intravenously or by inhalation, they get rapidly distributed into highly perfused tissues like the brain, heart and kidney.
• But soon they get redistributed into less vascular tissues like the muscle and fat resulting in termination of the action of these drugs.
• The best example is the intravenous anesthetic thiopental sodium which induces anesthesia in 10–20 seconds but the effect ceases in 5–15 minutes due to redistribution.

Volume Of Distribution (V)

Question 12. Write a short note on the volume of distribution.
Answer:

The volume of Distribution Definition: It is the volume necessary to accommodate the entire amount of the drug administered if the concentration throughout the body is equal to that in plasma. It relates the amount of the drug in the body to the concentration of the drug in plasma.

It is calculated as:

• Since the ‘volume’ can be more than the total body water, it is also called the apparent volume of distribution.
• For example, if the dose of a drug given is 500 mg and it attains a uniform concentration of 10 mg/L of plasma in the body, its V = 50 L.

Important facts about V are:

1. If a drug is retained mostly in the plasma, its V is small (for example, Aspirin, aminoglycosides) while if it is distributed widely in tissues, then its V is large (e.g. pethidine).
2. Highly lipid-soluble drugs that remain in the adipocytes have a large V (for example,Chloroquine ~ 1,000 L).
3. Drugs extensively bound to plasma proteins have a low V (~3L), for example,Phenylbutazone.
4. The knowledge of V of drugs is clinically important in the treatment of poisoning.
5. Drugs with large V like pethidine are not easily removed by hemodialysis because such drugs are widely distributed in the body.
6. V may vary with changes in tissue permeability and protein binding as seen in some diseases.
7. Low V drugs like aminoglycosides may have a larger V in presence of edema or ascites due to increased ECF volume.
8. In CCF and uremia, reduced perfusion of tissues would lead to reduced V.

Biotransformation

Question 13. What is biotransformation? Explain the different biotransformation reactions with examples.
Or
Write short notes on conjugation reactions.
Answer:

• Biotransformation (metabolism) is the process of biochemical alteration of the drug in the body.
• Body treats most drugs as foreign substances and tries to inactivate and eliminate them by various biochemical reactions.
• These processes convert the drugs into more polar, water-soluble compounds so that they are easily excreted through the kidneys.
• Some drugs may be excreted largely unchanged in the urine, for example, Frusemide, and atenolol.

Site: Most important organ → liver. Drugs are also metabolized to a small extent by → kidney, gut mucosa, lungs, blood, and skin.

• Consequences of Biotransformation
• Biotransformation generally inactivates the drug
• Some drugs may be converted to active metabolites—longer action.
• Biotransformation may also activate an inactive drug—prodrug.
• The active metabolite may sometimes be toxic, for example, Paracetamol converted to N-acetyl-benzoquinone imine which causes hepatotoxicity.

Enzymes in biotransformation: Biotransformation reactions are catalyzed by:

• Microsomal-mixed function oxidase system: Present in liver cells—CYP P450 enzymes— CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP3A4. CYP3A4 alone metabolizes nearly 50% of drugs.
• Nonmicrosomal enzymes: Present in plasma and other tissues, for example, Xanthine oxidase.

Biotransformation takes place in 2 phases:

• There are many families of cytochrome enzymes.
• They are numbered (1, 2, 3, and 4..) to denote family and A, B, C, D. to denote subfamily.
• The last digit denotes a form naming cytochrome enzymes.
• For example, CYP 2 C 9
• Family Subfamily Isoforms

Phase 1 reactions (nonsynthetic reactions): Convert the drug to a more polar metabolite by oxidation, reduction, or hydrolysis.

1. Oxidation is the addition of oxygen or the removal of hydrogen from a drug molecule.
   • Mostly catalyzed by mono-oxygenases present in the liver.
   • Carried on by cytochrome P450, NADPH, and molecular oxygen.
   • There are several types of oxidation reactions including microsomal and nonmicrosomal
   • For example:

Ethyl alcohol → CO₂ + H₂O

1. Reduction may be catalyzed by microsomal or nonmicrosomal enzymes.
   • Nitro reduction, for example, Chloramphenicol → Arylamine
   • Keto reduction, for example, Cortisone → Hydrocortisone
   • Disulfiram and nitrites are reduced by nonmicrosomal enzymes.
2. Hydrolysis is the process where a drug molecule is ‘split’ by the addition of a molecule of water.
3. Esterases, amidases, and peptidases catalyze hydrolytic reactions.

Acetylcholine + H₂O → choline + acetic acid

If the metabolite of the phase 1 reaction is not sufficiently polar to be excreted, it undergoes phase 2 reactions.

Types of biotransformation reactions with examples:

Phase 2 reactions are synthetic reactions where endogenous water-soluble substances like glucuronic acid, sulfuric acid, glutathione, or an amino acid combine with the drug to form a highly polar conjugate which gets readily excreted by the kidneys.

Large molecules are excreted through the bile.

• Conjugation: Conjugation results invariably in the inactivation of the drug. Some products of conjugation are glucuronides and amino acid conjugates.
  • Glucuronide conjugation:  A most common type of metabolic reaction.
    • Bilirubin and steroid hormones also undergo conjugation. Glucuronide conjugate formed is polar, inactive, and readily excreted through the kidneys.
    • For example, Morphine + Glucuronic acid → Morphine Glucuronide
  • Neonatal jaundice: The enzyme glucuronyl transferase is not adequately formed in the neonate. Hence bilirubin levels increase → neonatal jaundice.
  • Gray baby syndrome: An adverse effect of chloramphenicol seen in neonates is also because of the lack of UDP glucuronyl transferase.
• Acetylation: Drugs are conjugated with acetyl coenzyme A and the reaction is catalyzed by N-acetyltransferase, for example, Sulfonamides and isoniazid.
• Methylation: Methyl conjugation is catalyzed by the enzyme trans methylase, for example, Catecholamines like adrenaline and dopamine.
• Glutathione conjugation:  By the enzyme glutathione-S-transferase—inactivates highly reactive intermediates formed during the metabolism of drugs like paracetamol. Other conjugation reactions are amino acid conjugation, sulfate conjugation, and glycine conjugation.

1. Enzyme Induction:

Question 14. Write a short note on enzyme induction.
Answer:

• Microsomal enzymes are present in the microsomes lining the smooth endoplasmic reticulum of the liver cells.
• Some drugs and environmental pollutants can increase the synthesis of these microsomal enzymes mainly cytochrome P450.
• This is called enzyme induction and this process speeds up the metabolism of the inducing drug itself and other drugs metabolized by the same microsomal enzymes.
• For example, phenobarbitone, rifampicin, alcohol, cigarette smoke, DDT (environmental pollutants), griseofulvin, carbamazepine, and phenytoin are some enzyme inducers.
• Drugs can selectively induce some particular enzymes (DDT) or maybe nonselective as with phenobarbitone which can induce most microsomal enzymes.
• Enzyme induction may be blocked by drugs that inhibit protein synthesis. Enzymes are induced gradually and take about 1–2 weeks For the peak effect to increase drug metabolism by 2–4 times.

Clinical Relevance Of Microsomal Enzyme Induction:

• Drug interactions:
  • Therapeutic failure: By speeding up metabolism, enzyme induction may reduce the duration of action of some other drugs which can result in therapeutic failure, for example, Failure of oral contraceptives in patients taking rifampicin.
  • Toxicity: Enzyme induction may result in toxicity due to the production of higher amounts of the toxic intermediate metabolites, for example, A patient undergoing treatment with rifampicin is likely to develop
• Tolerance: Tolerance to drugs may develop as in the case of carbamazepine since it induces its own metabolism called autoinduction.
• Result in disease: Antiepileptics increase the breakdown of vitamin D resulting in osteomalacia on long-term administration.
• Variable response: In chronic smokers and alcoholics, enzyme induction may result in failure to achieve the expected response to some drugs metabolized by the same enzymes.
• Therapeutic application of enzyme induction: Neonates are deficient in both microsomal and nonmicrosomal enzymes. Hence their capacity to conjugate bilirubin is low which results in jaundice.

2. Enzyme Inhibition:

Question 15. Write a short note on enzyme inhibition.
Answer:

• Drugs can inhibit the activity of both microsomal and nonmicrosomal enzymes. Drugs like cimetidine and ketoconazole bind to cytochrome P450 and competitively inhibit the metabolism of endogenous substances like testosterone and other drugs given concurrently.
• Enzyme inhibition by drugs results in several drug interactions. Chloramphenicol, erythromycin, ketoconazole, cimetidine, ciprofloxacin, and verapamil are some enzyme inhibitors.
• With some drugs, the binding of enzymes may be irreversible—leading to inactivation of the enzyme—called suicide inhibitors, for example, Selegiline, ticlopidine, clopidogrel, and propylthiouracil.

Drugs could also inhibit other enzymes (nonmicrosomal enzymes) which may be competitive or noncompetitive inhibition:

1. Competitive enzyme inhibitors:

Competitive enzyme inhibitors are structurally similar to the natural substrates and thereby compete for binding to the enzyme.

• This type of enzyme inhibition may be reversed by higher substrate concentration.
• However, if the binding takes place by covalent bonds, then it could be irreversible like organophosphates inhibiting acetylcholinesterase.

2. Noncompetitive enzyme inhibition:

Here there is no structural similarity and the inhibition is generally irreversible because such drugs alter the structure of the enzyme. New enzymes need to be synthesized to resume activity.

Factors That Influence Biotransformation:

1. Genetic variation results in altered metabolism of drugs, for example, Succinylcholine is metabolized very slowly in people with defective pseudocholinesterase resulting in prolonged apnea.
2. Environmental pollutants like cigarette smoke cause enzyme induction.
3. Age: At extremes of age, the activity of metabolic enzymes in the liver is low and hence there is an increased risk of toxicity with drugs.
4. Diseases of the liver: Markedly affect the metabolism of drugs.

Consequences of enzyme induction:

Drug Excretion

Drugs are excreted from the body after being converted to water-soluble metabolites while some are directly eliminated without metabolism. The major organs of excretion are the kidneys, intestine, biliary system, and lungs. Drugs are also excreted in small amounts in the saliva, sweat, and milk.

Renal excretion: The kidney is the most important organ of drug excretion.

The three processes involved are:

1. Glomerular filtration: The rate of filtration through the glomerulus depends on GFR, the concentration of free drug in the plasma, and its molecular weight. Ionized drugs of low molecular weight (<10,000) are easily filtered through the glomerular membrane.

2. Active tubular secretion: Cells of the proximal tubules actively secrete acids and bases by two transport systems.

• Thus acids like penicillin, salicylic acid, probenecid, frusemide; bases like amphetamine and histamine are so excreted.
• Drugs may compete for the same transport system resulting in prolongation of action of each other, for example, Penicillin and probenecid.

3. Passive tubular reabsorption: Passive diffusion of drug molecules can occur in either direction in the renal tubules depending on the drug concentration, lipid solubility, and pH. As highly lipid-soluble drugs are largely reabsorbed, their excretion is slow.

• Acidic drugs get ionized in alkaline urine and are easily excreted while bases are excreted faster in acidic urine.
• This property is useful in the treatment of poisoning. In poisoning with acidic drugs like salicylates and barbiturates, forced alkaline diuresis (diuretic + sodium bicarbonate + IV fluids) is employed to has inline, and amphetamine is enhanced by forced acid diuresis

Fecal and biliary excretion:

• An unabsorbed portion of the orally administered drugs is eliminated through the feces.
• Liver transfers acids, bases, and unionized molecules into bile by specific acid transport processes.
• Large water-soluble conjugates are excreted in the bile.

Pulmonary excretion: Gases and volatile liquids are excreted through the lung, viz. general anesthetics and alcohol. The drug is eliminated with the expired air and is dependent on the rate of respiration and the blood flow to the lungs.

Other routes of excretion: Small amounts of some drugs are eliminated through sweat (iodide, rifampicin, heavy metals), saliva (phenytoin, clarithromycin), and milk. For the suckling infant, it may be sometimes important especially because of the infant’s immature metabolic and excretory mechanisms.

1. Clearance: 

Question 16. Write a short note on the kinetics of elimination.
Answer:

Clearance is the volume of plasma freed completely of the drug in unit of time.

Kinetics Of Elimination:

Drugs are metabolized/eliminated (kinetics of elimination) from the body by:

First-order kinetics:

• In first-order kinetics (linear kinetics), a constant fraction of the drug is metabolized/eliminated per unit time.
• Most drugs follow first-order kinetics and the rate of metabolism/excretion is dependent on their concentration in the body, i.e. it is exponential
• It also holds good for the absorption of drugs

Comparison between first-order and zero-order kinetics:

Zero-order kinetics (saturation kinetics):

• Here a constant amount of the drug present in the body is metabolized/eliminated per unit of time.
• The metabolic enzymes get saturated and hence with an increase in dose, the plasma drug level increases disproportionately resulting in toxicity.
• Such elimination is known as zero order kinetics, for example, Alcohol, heparin, phenytoin, phenylbutazone, and aspirin.

Some drugs like phenytoin and warfarin are eliminated by both processes, i.e. by first order initially and by zero-order at higher concentrations (mixed order kinetics or Michaelis Menten kinetics). Hence, at higher doses, there is an accumulation of the drug.

Plasma Half-Life (T½):

Plasma half-life  Definition:

• Plasma half-life is the time taken for the plasma concentration of a drug to be reduced to half its initial value.
• Four to five half-lives are required for the complete elimination of a drug.
• Each drug has its own t½ and is an important pharmacokinetic parameter that guides the dosing regimen, for example, Eesmolol has a t½ of 10 minutes, zolpidem 2 hours, aspirin 4 hours and chloroquine 10–24 days.

Significance of Plasma t½: Plasma t½ is necessary to know the:

• Duration of action of the drug
• Frequency of administration
• Time needed for the attainment of SSC—longer the t½, the longer is the time needed to attain SSC
• To calculate the loading and maintenance doses of the drug.

Factors Influencing Plasma t½:

• Plasma protein binding highly protein-bound drugs have a longer t½.
• Enterohepatic circulation ↑ ↑ t½ of the drug.
• Metabolism — Faster the metabolism of a drug, the shorter is its plasma t½.
• Tissue storage —Stored drugs have longer t½.
• Clearance — Drugs cleared faster have a shorter t½.
• Biological half-life is the time required for the total amount of drug in the body to be reduced to half.

The biological effect half-life is the time required for the biological effect of the drug to reduce to half. With some drugs like propranolol, the pharmacological effect of the drug may last much longer, i.e. even after its plasma levels fall. In such drugs, the biological effect of half-life gives an idea of the duration of action of the drug.

Mnemonic:

2. Steady State Concentration:

If a drug is administered repeatedly at short intervals before complete elimination, the drug accumulates in the body and reaches a ‘state’ at which the rate of elimination equals the rate of administration.

• This is known as the ‘steady-state’ or plateau level. After attaining this level, the plasma concentration fluctuates around an average steady level.
• It takes 4–5 half-lives for the plasma concentration to reach the plateau level.
• A drug with t½ >24 hours, if given daily, accumulates on prolonged use and could lead to toxicity.
• Hence for such drugs, once the steady-state concentration (SSC) is attained, the dose given should be equal to the dose eliminated daily.

3. Administration Of Drugs In Renal Diseases:

Question 17. What precautions are to be taken in using drugs for renal diseases?
Answer:

The kidney is the primary excretory and is itself exposed to large concentrations of drugs. Absolute caution is required in the administration of drugs. In patients undergoing dialysis, some drugs are easily dialysable and should be administered after dialysis.

The following guidelines may be followed:

1. Use only drugs that are absolutely needed.
2. Avoid nephrotoxic drugs.
3. In a group of drugs, select a drug that is not nephrotoxic, if possible.
4. Dose of some drugs needs to be reduced while many drugs may have to be avoided in p in renal dysfunction. The dose should be adjusted with the help of a nomogram.
5. Duration of treatment should be restricted as far as possible.
6. Therapeutic drug monitoring may be done wherever required.
7. Serum creatinine may be used to know the extent of renal impairment

4. Drug Dosage:

Depending on the patient’s requirements and the characteristics of the drug, drug dosage can be of the following kinds:

• Fixed dose: In case of reasonably safe drugs, a fixed dose of the drug is suitable for most patients, for example, Analgesics like paracetamol—500–1,000 mg 6 hourly is the usual adult dose.
• Individual dose: For some drugs especially the ones with low safety margins, the dose has to be ‘tailored’ to the needs of each patient, for example, Anticonvulsants, Antiarrhythmic drugs.
• Loading dose: Loading dose is a single large dose or quickly repeated doses given to rapidly attain or reach target concentration, for example, Heparin is given as a 5,000 IU bolus dose.
  • Drugs with a large V (for example, Chloroquine) and drugs with long t½ (for example, Digitoxin) need a long time to attain SSC and therefore, need a loading dose.
  • In emergencies, to rapidly attain SSC, particularly for short t½ ones.
  • The disadvantage of the loading dose is that the patient is rapidly exposed to high concentrations of the drug which may result in toxicity.

5. Fixed Dose Combinations (FDC):

• When two or more drugs are combined to be given as a single preparation, it is called a fixed dose combination (FDC).
• In these, both the drugs and the doses are fixed.
• There are hundreds of such
• FDCs are available in the market.

Advantages of Fixed Dose Combinations:

• Better patient compliance, the convenience of the single pill for example, Antitubercular drugs/antiretroviral drugs in a single tablet
• Synergistic effect, for example, Cotrimoxazole, levodopa + carbidopa
• To reduce adverse effects thiazides with potassium-sparing diuretics
• Prevent the development of resistance antitubercular drugs.

Disadvantages of Fixed Dose Combinations:

• Dose adjustment is difficult
• Difficulty to assess side effects
• Increased risk of toxic effects due to both drugs especially if there are overlapping side effects, for example, Hepatotoxicity due to INH, rifampicin, and pyrazinamide.

Several rational and approved FDCs are available and may be used in suitable patients. However, hundreds of such FDCs are being marketed which are irrational, wasteful, and often harmful. The use of such irrational FDCs should be avoided.

Examples:

• Amoxicillin + cloxacillin for staphylococcal infection
• Norfloxacin + metronidazole for diarrhea Irrational
• Enalapril + losartan for hypertension.

6. Therapeutic Drug Monitoring:

The response to a drug depends on the plasma concentration attained in the patient. This in turn depends on the bioavailability, volume of distribution, and clearance. As these parameters vary among individuals, there is a wide variation in the plasma concentration attained from patient to patient.

Hence, in some situations, it may be necessary to monitor treatment by measuring plasma drug concentrations.

Therapeutic drug monitoring (TDM) is required for:

1. Low safety margin drugs to avoid therapeutic failure, for example, Digoxin, theophylline, and lithium.
2. To reduce the risk of toxicity particularly when nephrotoxic drugs are used in renal failure,
   for example, Aminoglycosides.
3. When there are no reliable methods to assess benefits, for example, Antidepressants.
4. To treat poisoning
5. When there is unexplainable therapeutic failure
6. To check patient compliance.

TDM is not required for:

• Drugs whose response can be easily measured, for example, Blood pressure for antihypertensives
• For ‘hit and run’ drugs its effects persist for a long time even after the drug is eliminated.

Methods Of Prolonging Drug Action

Question 18. Write short notes on methods of prolonging the actions of drugs.
Answer:

The duration of action of drugs can be prolonged by interfering with the pharmacokinetic processes given in Table i.e. by:

• Slowing absorption
• Using a more plasma protein-bound derivative
• Inhibiting metabolism
• Delaying excretion.

Methods of prolonging the duration of action of drugs:

Pharmacodynamics

Definition of  Pharmacodynamics:  Pharmacodynamics is the study of the actions of the drugs on the body and their mechanisms of action, i.e. to know what drugs do and how they do it.

• Drugs produce their effects by interacting with the physiological systems of the organisms and altering the rate of functions of various systems.
• However, drugs cannot change the basic functions of any physiological system.

Drugs may act by:

1. Stimulation or increase in activity of specialized cells, for example, Adrenaline stimulates the heart.
2. Depression or a decrease in the activity of the specialized cells,  for example, Quinidine depresses the heart. Some drugs may stimulate one system and depress another, for example, Morphine depresses the CNS but stimulates the vagus.
3. Irritation—may result in inflammation, corrosion, and necrosis of cells.
4. Replacement: When there is a deficiency of natural substances like hormones, metabolites, or nutrients, for example, Insulin in diabetes mellitus, iron in anemia, and vitamin C in scurvy.
5. Anti-infective: Destroying infective organisms, e.g. penicillins.
6. Cytotoxic action: Anticancer drugs on cancer cells.
7. Modification of immune status: Vaccines and sera improve our immunity while immunosuppressants act by depressing immunity, for example, Glucocorticoids.

Mechanisms of drug action: Drugs may act by one or more mechanisms of action and some of them are yet to be understood.

The mechanisms of drug action may be:

1. Through receptors: By interacting with specific receptors in the body (see receptor).
2. Through enzymes and pumps Inhibition of various enzymes—for example,
   • Allopurinol inhibits the enzyme xanthine oxidase
   • Acetazolamide inhibits carbonic anhydrase
   • Membrane pumps, for example, Proton pump—inhibited by omeprazole sodium pump—inhibited by digoxin.
3. Through ion channels: Drugs modify the movement of ions across specific channels either by opening or closing them, e.g. calcium channel blockers, and potassium channel openers.
4. By physical action: From its physical properties like:
   1. Adsorption Activated charcoal in poisoning
   2. Mass of the drug Bulk laxatives like psyllium, bran
   3. Osmotic property Osmotic purgatives like magnesium sulfate, and osmotic diuretics like mannitol.
   4. Radioactivity – ¹³¹I
   5. Radio-opacity: Barium sulfate, Contrast media.
5. By chemical interaction: Drugs may act by chemical reaction—
   • Antacids—neutralize gastric acids
   • Oxidizing agents—potassium permanganate as germicidal
   • Chelating agents—bind heavy metals making them nontoxic.
6. By altering metabolic processes: Drugs like antimicrobials and anticancer drugs by altering the metabolic pathway, for example, Sulfonamides interfere with bacterial folic acid synthesis.

Dose-Response Relationship

• The clinical response to the increasing dose of the drug is plotted on a graph to get the dose-response curve (DRC).
• Initially, the extent of response increases with an increase in dose till the maximum response is reached. Dose-response relationships are of 2 types, viz. graded dose-response relationship, and quantal dose-response relationship.
• The graded dose-response curve has the shape of a rectangular hyperbola. After the maximum effect has been obtained, a further increase in doses does not increase the response. If the dose is plotted on a logarithmic scale, the curve becomes sigmoid

The advantages of plotting log DRC are:

1. Wide range of doses can be displayed on the graph.

2. Easy to compare agonists and study antagonists.

• The slope of DRC has clinical significance. A steep slope indicates that a small increase in dose produces a large increase in response, for example, Loop diuretics.
• Such drugs are more likely to cause toxicity and therefore, individualization of the dose is required.
• A relatively flat DRC indicates that with an increase in dose, there is little increase in the response, for example, Thiazide diuretics. For such drugs, standard doses can be given to most patients.

Quantal DRC:

Certain responses can only be all or none (for example, vomiting) and when represented on the DRC, the curve appears bell-shaped, and it indicates the percentage of responders

Drug potency:

• The amount of drug required to produce a response indicates the potency. For example, 1 mg of bumetanide produces the same diuresis as 50 mg of frusemide.
• Thus bumetanide is more potent than frusemide. In, drugs A and B are more potent than drugs C and D, drug A being the most potent and drug D the least potent.
• Hence higher doses of drugs C and D are needed as compared to drugs A and B.
• Generally, potency is not of much clinical significance unless very large doses of the drug need to be given due to low potency.

Maximal efficacy:

• Efficacy indicates the maximum response that can be produced by a drug, for example, Frusemide produces powerful diuresis, not produced by any dose of amiloride.
• In , drugs B and C are more efficacious than drugs A and D.
• Drug A is more potent but less efficacious than drugs B and C. Such differences in efficacy are of great clinical importance.

Receptor

Question 19. What is a receptor? Explain briefly the different receptor families.
Or
Write a short note on GPCR.
Answer:

Definition of Receptor: A receptor is a site on the cell with which an agonist binds to bring about a response.

1. Affinity: Affinity is the ability of a drug to bind to a receptor, e.g. morphine has a high affinity for opioid receptors.
2. Intrinsic activity or efficacy: Intrinsic activity or efficacy is the ability of a drug to elicit a response after binding to the receptor.
3. Agonist: Agonist is a substance that binds to the receptor and produces a response. It has both affinity and intrinsic activity, for example, Adrenaline is an agonist at a- and b adrenergic receptors; morphine is an agonist at mu(μ) opioid receptors.
4. Antagonist: An antagonist is a substance that binds to the receptor and prevents the action of an agonist on the receptor. It has affinity but no intrinsic activity. An antagonist is structurally similar to the agonists, for example, Naloxone is an antagonist at μ opioid receptors
5. Partial agonist: Partial agonist binds to the receptor but has low intrinsic activity and brings about weak effects. It also blocks the binding of the full agonists. Pentazocine is a partial agonist at μ opioid receptors, pindolol is a partial agonist at b-adrenergic receptors.
6. Inverse agonist: Some drugs, bind to the receptors and produce actions opposite to those produced by a pure agonist. They are known as inverse agonists, for example, Diazepam acts on benzodiazepine receptors produces sedation, anxiolysis, muscle relaxation, and controls convulsions.
7. Spare receptors: Some experiments showed that a high concentration of an agonist can still produce a maximal response in the presence of an irreversible antagonist and this was because of the presence of ‘spare’ or reserve receptors.
8. Silent receptors: These are receptors to which an agonist binds but does not produce a response. The presence of such silent receptors may explain the phenomenon of tolerance.

Plasma proteins that bind drugs are considered to act as silent receptors as they just bind the drug and the drug is not available for action.

• Site: Receptors may be present on the cell membrane, in the cytoplasm or on the nucleus.
• Nature of receptors: Receptors are proteins.
• Synthesis: Receptor proteins are synthesized by the cells.
• Functions of receptors: The two functions of receptors are:
  • Recognition and binding of the ligand.
  • Propagation of the message.
• For the above functions, the receptor has two functional domains (areas).
• Receptor families: Five types or superfamilies of the cell surface receptors are identified

Receptor Families And Their Transduction Mechanisms:

1. Ion channel receptors or receptor channels are proteins present on the cell surface.

• The binding of the agonist opens the channel allowing ions to cross the membrane.
• Depending on the ion and the channel, depolarization/hyperpolarization occurs, for example, in the Nicotinic cholinergic receptor channel.

2. G-protein-coupled receptors (GPCRs) are proteins spread across the plasma membrane.

• They are called G-proteins because of their interaction with GTP and GDP.
• The G-proteins are bound to the inner face of the plasma membrane and consist of three subunits, with GDP bound to the a-subunit.
• When a ligand binds to the GPCR, the associated G protein gets activated.
• This in turn activates adenylyl cyclase or phospholipase C to generate the respective second messengers (cAMP, IP3, DAG, Ca++ or cGMP) which bring about a chain of intracellular changes.
• Thus G-proteins act as links or mediators between the receptors and the effector systems.
• G-proteins are of different classes like Gs, Gi, Gq, Go, and G. Gs is stimulatory and Gi is inhibitory. Adrenergic receptors and muscarinic cholinergic receptors are examples of GPCRs.

Effector pathways through which the G-protein-coupled receptors work are:

• Adenylyl cyclase pathway: Stimulation of adenylyl cyclase results in the formation and accumulation of cAMP within the cell. This cAMP acts through protein kinases which phosphorylate various proteins to regulate the cell function.
• Phospholipase C/IP3-DAG pathway: Activation of phospholipase C results in the formation of second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) from the membrane phospholipids PIP2.
  • IP3 mobilizes Ca⁺⁺ from intracellular depots and this Ca⁺⁺ mediates responses like secretion, contraction, metabolism, and hyperpolarization.
  • DAG activates protein kinase C which regulates cell function.
• Ion channel regulation: The activated G-proteins can also directly (without the help of second messengers) convey the signal to some ion channels causing the opening or closing of the channels. The resulting responses include depolarization/hyperpolarization.

3. Enzymatic receptors or kinase-linked receptors are transmembrane proteins with an extracellular site for ligand binding and intracellular domain to carry out the catalytic activity and the two domains are linked by a single peptide chain.

• The binding of the agonist to the outer site activates the intracellular site and triggers the phosphorylation of various intracellular proteins resulting in the characteristic response.
• For example, RTeceptors of insulin and growth factors.

4. JAK-STAT kinase binding receptor: When an agonist binds to the extracellular domain, it activates the intracellular domain and mobile JAK (Janus kinase) molecules are activated.

• These molecules in turn activate STAT molecules (STAT—signal transducers and activation of transcription).
• Which move to the nucleus and regulate transcription, for example, Growth hormones, and interferons.

5. Nuclear receptors (receptors that regulate gene transcription) are intracellular proteins that get activated by agonists.

• The agonist–receptor complex moves to the nucleus where it interacts with DNA, regulates gene transcription and thereby directs the synthesis of specific proteins to regulate the activity of target cells.
• For example, receptors for steroidal hormones, thyroid hormones, vitamin D, and retinoids.

Receptor Regulation:

• The number of receptors (density) and their sensitivity can be altered in many situations.
• Denervation or prolonged deprivation of the agonist or constant action of the antagonist, all result in an increase in the number and sensitivity of the receptors.
• This phenomenon is called upregulation Prolonged use of a b-adrenergic antagonist like propranolol results in upregulation of b-adrenergic receptors.
• On the other hand, continued stimulation of the receptors causes desensitization and a decrease in the number of receptors known as downregulation of the receptors.

Clinical consequences: After prolonged administration, a receptor antagonist should always be tapered.

• For example, if propranolol, a b-adrenoceptor blocker is suddenly withdrawn after long-term use, it precipitates angina.
• Constant use of b-adrenergic agonists in bronchial asthma results in reduced therapeutic response due to downregulation of a₂-Recep

Receptor regulation:

Therapeutic Index (IT):

Question 20. What is a therapeutic index? Write briefly the significance of TI.
Answer:

Definition of Therapeutic Index: Therapeutic index (TI) is the ratio of the median lethal dose to the median effective dose.

• The dose-response curves for different actions of a drug could be different.
• Thus salbutamol may have one DRC for bronchodilation and another for tachycardia.
• The distance between the beneficial effect of DRC and the unwanted effect of DRC indicates the safety margin of the drug.

TI = LD50/ED50

1. Median lethal dose (LD50): A dose which is lethal to 50% of the population.
2. Median effective dose (ED50): A dose that produces a desired effect in 50% of the test population.

Significance Of Therapeutic Index:

1. It gives an idea about the safety of the drug.
2. The higher the therapeutic index, the safer is the drug.
3. TI varies from species to species.
4. For a drug to be considered reasonably safe, its TI must be >1.
5. Penicillin has a high TI, while lithium and digoxin have low TI.
6. TI may be different for each action of a drug.
7. For example, TI of aspirin used for headaches is different from its TI for inflammation.

Receptor families (with examples) and their transduction mechanisms:

Limitations Of the Therapeutic Index:

1. The therapeutic index does not consider idiosyncratic responses that result in toxicity.
2. The data is based on animal studies which may be difficult to apply on human beings.

In human population, LD50 cannot be obtained and therefore, TD50 is considered.

Drug Synergism And Antagonism:

Question 21. Write a short note on drug synergism and antagonism.
Answer:

1. Synergism: When the action of one drug is enhanced or facilitated by another drug, the combination is synergistic. In Greek, ergon = work; syn = with.

• Here, the total effect of the combination is greater than the sum of their independent effects.
• It is often called potentiation’ or ‘supra-additive’ effect.

For example:

1. Acetylcholine + Physostigmine
2. Levodopa + Carbidopa.

2. Antagonism: One drug opposing or inhibiting the action of another is antagonism. Types of antagonism are listed in below.

Types of antagonism with examples:

 Chemical antagonism:

• Two substances interact chemically to result in the inactivation of the effect.
• For example, Chelating agents bind heavy metals like lead and mercury to form inactive complexes antacids like aluminum hydroxide neutralize gastric acid.

Physiological antagonism:

• Two drugs act at different sites to produce opposing effects.
• For example, in anaphylaxis, histamine acts on H1 receptors to produce bronchospasm and hypotension, while adrenaline reverses these effects by acting on adrenergic receptors.
• Insulin and glucagon have opposite effects on the blood sugar level.

Antagonism at the receptor level (pharmacological):

• The antagonist binds to the receptor and inhibits the binding of the agonist to the receptor.
• Such antagonism may be reversible or irreversible.

Reversible or competitive antagonism:

The agonist and antagonist compete for the same receptor but by increasing the concentration of the agonist, the antagonism can be overcome.

• It is thus reversible antagonism. It is also called surmountable or equilibrium type of antagonism.
• This is the most common type of antagonism.
• For example, acetylcholine and atropine at muscarinic receptors.
• Tubocurarine and acetylcholine compete for nicotinic receptors at the NMJ

Irreversible antagonism:

• The antagonist binds firmly by covalent bonds to the receptor and it dissociates very slowly or not at all.
• The blockade cannot be overcome by increasing the dose of the agonist (nonequilibrium type) and hence it is irreversible antagonism.
• In this type of antagonism, the duration of action is usually long since the effect remains till the new receptors are synthesized.
• For example, Phenoxybenzamine at alpha-adrenergic receptors. There is a progressive flattening of the dose-response curve.

Compare and Contrast: Irreversible and Noncompetitive Antagonism:

Noncompetitive antagonism:

• The antagonist blocks at the level of the receptor–effector linkage, i.e. at a different site beyond the receptor and not on the receptor.
• There is flattening as well as some rightward shift of the dose-response curve.
• For example, verapamil blocks the cardiac calcium channels and inhibits the entry of Ca++ during depolarization.

Factors That Modify The Effects Of Drugs

Question 22. Describe briefly the factors modifying drug action.
Or
Write a short note on pharmacogenetics.
Answer:

The same dose of a drug can produce different degrees of response in different patients and even in the same patient under different situations. Various factors modify the response to a drug.

They are:

1. Body weight: The recommended dose is calculated for medium-built persons. For obese and underweight persons, the dose has to be calculated individually. Though body surface area is a better parameter for a more accurate calculation of the dose, it is inconvenient and hence not generally used.

2. Age: The pharmacokinetics of many drugs change with age resulting in altered responses in extremes of age.

Newborn and infants

• Liver and kidneys: Immature to handle drugs
• Blood-brain barrier: Not well-formed
• Gastric acidity: Low
• Intestinal motility: Slow
• Skin: Delicate and permeable to drugs applied topically

Hence, the child’s dose should be calculated to avoid toxicity.

Also, pharmacodynamic differences can exist, for example, Barbiturates which produce sedation in adults may produce excitation in children. The formula for calculation of dose for children:

• In the elderly, the capacity of the liver and kidney to handle the drug is reduced and they are more susceptible to adverse effects. Hence, lower doses are recommended.
• For example, the Elderly are at a higher risk of ototoxicity and nephrotoxicity by streptomycin.

3. Sex: No gross gender differences in response to drugs but hormonal effects and smaller body size may influence the drug response in women.

• Special care is necessary while prescribing for pregnant and lactating women and during menstruation.
• For example, if purgatives are given during menstruation they may increase the menstrual blood loss as they may cause pelvic congestion.
• Adult male rats metabolize drugs at a much faster rate than female rats.

4. Species and race: Response to drugs may vary with species and race.

• Blacks need higher doses of atropine to produce mydriasis.
• Rabbits are resistant to atropine.

Such variations make it difficult to extrapolate the results of animal experiments.

Antipsychotic clozapine may cause a higher incidence of agranulocytosis in people of Finland. Hence most countries now approve a drug only after it has undergone trials on its own population.

5. Diet and environment: Food interferes with the absorption of many drugs. For example, tetracyclines form complexes with calcium present in the food and are poorly absorbed.

Polycyclic hydrocarbons present in cigarette smoke may induce microsomal enzymes resulting in enhanced metabolism of some drugs, examples of drug-food interactions:

• Absorption increased by food— chloroquine, riboflavin, lithium, albendazole
• Absorption reduced by food—ampicillin, rifampicin, tetracycline, INH.

6. Route and time of administration: Route of administration may modify the pharmacodynamic response, for example, Magnesium sulfate given orally is a purgative; given 4  it causes CNS depression and has anticonvulsant effects for which it is used in eclampsia of pregnancy.

Applied topically (poultice), it reduces local edema. Hypertonic magnesium sulfate retention enema reduces intracranial tension.

Time of administration:

• There are several diurnal variations in the body. For example, the secretion of glucocorticoids is highest in the morning.
• Hence, if exogenous glucocorticoids are administered in the morning, the HPA axis suppression is much less chronopharmacology.

7. Genetic factors: Variations in an individual’s response to drugs could be genetically mediated.

• Pharmacogenetics is the study of genetically mediated variations in drug responses.
• Genetic variations (polymorphisms) can result in changes in pharmacokinetics or pharmacodynamics.
• Pharmacokinetic variations: Production of drug-metabolizing enzymes is genetically controlled and variations are common.

Examples:

• Oxidation of drugs: Genetic variation in cytochrome P450 enzymes results in an altered rate of metabolism (oxidation, hydroxylation) of drugs metabolized by these enzymes, for example, SSRIs, phenytoin, and warfarin.
• Acetylation of drugs: The rate of drug acetylation may differ among individuals—people may be fast or slow acetylators, for example, INH, sulfonamides, hydralazine, procainamide, and dapsone are metabolized by acetylation. Slow acetylators treated with hydralazine are more likely to develop lupus erythematosus.
• Atypical pseudocholinesterase: Succinylcholine a skeletal muscle relaxant is metabolized by the enzyme pseudocholinesterase.
• Some people inherit an atypical pseudocholinesterase which cannot quickly metabolize succinylcholine (SCh) and they develop a prolonged apnea due to persistent action of succinylcholine.

Pharmacodynamic variations: Variations in receptors, enzymes, susceptibility to adverse effects and diseases:

• G6PD deficiency: Deficiency of G6PD in RBCs leads to the accumulation of glutathione.
• Exposure of such RBCs to drugs like primaquine, sulfones, and quinolones leads to hemolysis.
• Malignant hyperthermia: Halothane and succinylcholine can trigger malignant hyperthermia in some genetically predisposed individuals.
• Hepatic porphyrias: Some people lack an enzyme required for heme synthesis, and this results in the accumulation of porphyrin-containing heme precursors. Some drugs like barbiturates, griseofulvin, and carbamazepine, induce the enzyme required for porphyrin synthesis resulting in the accumulation of porphyrins.

In both the above cases, neurological, gastrointestinal, and behavioral abnormalities can occur due to excess porphyrins.

8. Dose: It is fascinating that the response to a drug may be modified by the dose administered.

• Generally, as the dose is increased, the magnitude of the response also increases proportionately till the ‘maximum’ is reached.
• Further increases in doses may with some drugs produce effects opposite to their lower-dose effect.
• For example, In myasthenia gravis, neostigmine enhances muscle power in therapeutic doses, but in high doses, it causes muscle paralysis.
• Physiological doses of vitamin D promote calcification, while hypervitaminosis D leads to decalcification.

9. Diseases: The presence of certain diseases can influence drug responses, for example,

• Gastrointestinal diseases: Drugs are poorly absorbed in malabsorption syndrome.
• Liver diseases: The rate of drug metabolism including first-pass metabolism is reduced.
• Protein binding is reduced due to low serum albumin because albumin is synthesized in the liver.
• Cardiac diseases: In CCF, there is edema of the gut mucosa and decreased perfusion of the liver and kidneys → cumulation, and toxicity of drugs like propranolol, and lignocaine.
• Renal dysfunction: Drugs mainly excreted through the kidneys may accumulate and cause toxicity, for example, Streptomycin, and amphotericin B. Doses of such drugs should be reduced.
• Also, diseased kidneys are more susceptible to the toxic effects of nephrotoxic drugs like gold, penicillamine, and aminoglycosides.
• Endocrine diseases: Hypothyroid patients are more sensitive to the effects of certain drugs like CNS depressants. Patients with Benign prostatic hypertrophy are more susceptible to urinary retention with anticholinergics and tricyclic antidepressants.

10. Tolerance: Tolerance is the requirement of higher doses of a drug to produce a given response.

Tolerance may be:

1. Natural tolerance: The species/race shows less sensitivity to the drug, for example, Rabbits show tolerance to atropine; the black race is tolerant to mydriatics.
2. Acquired tolerance develops on repeated administration of a drug: The patient who was initially responsive becomes tolerant, for example, Tolerance develops to barbiturates, opioids, and nitrites.

Tolerance may develop to some actions of the drug and not to others

For example:

1. Morphine  — Tolerance develops to the analgesic and euphoric effects of morphine but not to its constipating and miotic effects.
2. Barbiturates — Tolerance develops to sedative but not antiepileptic effects of barbiturates.

Mechanisms of Tolerance :

• Pharmacokinetic: Changes in absorption, distribution, metabolism and excretion of drugs may result in a reduced concentration of the drug at the site of action and is also known as dispositional tolerance, for example, Barbiturates induce microsomal enzymes and enhance their own metabolism.
• Pharmacodynamic: Changes in the target tissue, may make it less responsive to the drug. It is also called functional tolerance.

Cross tolerance:

Cross tolerance is the development of tolerance to pharmacologically related drugs, i.e. to drugs belonging to a particular group. Thus chronic alcoholics also show tolerance to other CNS depressants like barbiturates and general anesthetics.

Tolerance: 

When some drugs are administered repeatedly at short intervals, tolerance develops rapidly and is known as tachyphylaxis or acute tolerance, for example, Ephedrine, Amphetamine, tyramine, and 5-hydroxytryptamine.

• This is thought to be due to the depletion of noradrenaline stores as the above drugs act by displacing noradrenaline from the sympathetic nerve endings.
• Other mechanisms involved may be slow dissociation of the drug from the receptor thereby blocking the receptor.
• Thus ephedrine given repeatedly in bronchial asthma may not give the desired response.

11. Psychological factor:

• The doctor–patient relationship influences the response to a drug often to a large extent by acting on the patient’s psychology.
• The patient’s confidence in the doctor may itself be sufficient to relieve suffering particularly the psychosomatic disorders.
• Hence a large number of patients respond to placebo.

12. Presence of other drugs: Use of two or more drugs together may result in drug interactions

Placebo:

Question 23. Write a short note on the placebo.
Answer:

Definition of Placebo: Placebo is the inert dosage form with no specific biological activity but only resembles the actual preparation in appearance (dummy medication).

Placebo = ‘I shall be pleasing’ (in Latin).

Placebo medicines are used in:

• Clinical trials as a control to compare and assess whether the new compound is significantly better than the placebo.
• To please a patient psychologically—when he does not actually require an active drug as in mild psychosomatic disorders and in chronic incurable diseases.

In fact, all forms of treatment including physiotherapy and surgery have some placebo effect.

• The effect of a placebo is influenced by the personality of the treating doctor, the personality of the patient, and the formulation of the placebo used.
• The ability of the doctor to boost confidence in the patient is important and the skill should be developed right from the student’s days as part of medical education.
• Some people are more likely to respond to a placebo and are called placebo reactors. The formulation given as placebo should appear ‘impressive’. Injections seem to have a more powerful ‘placebo effect’ than oral preparations.
• Substances used as a placebo include lactose, some vitamins, minerals, and distilled water injections.
• Placebo can release endorphins in the brain to produce analgesia. However, the effect of a placebo may be temporary.

Nocebo: When an established drug fails to produce its known therapeutic effect, it is often referred to as the ‘nocebo’ effect which means it is opposite to that of ‘placebo’. It could be because the patient lacks faith in the drug or doctor. Psychological factor thus plays an important role in therapeutics

Evidence-Based Medicine:

• With the development of scientific methods of research, the treatment of diseases now depends on scientific evidence from research.
• Well-designed clinical trials involving a fair number of participants are now required to prove the safety and benefits of a new drug before using it in clinical practice.
• Hence the modern system of medicine is ‘Evidence-based medicine’.

Over-The-Counter Drugs:

• Drugs that are considered safe for use by the general public without a prescription are called over-the-counter (OTC) drugs.
• Drugs that can be available as OTC are chosen by the regulatory agency and include drugs for common conditions like cough, diarrhea, vomiting, allergy, influenza and gastritis.
• History of OTC drug intake should be taken to avoid drug interactions and note the adverse effects.

Patient Compliance:

• For the success of any treatment, good patient compliance is essential.
• Patient compliance is considered ‘good’ when the patient strictly follows the treatment-related instructions given by the doctor. It may vary from partial compliance to total non-compliance.

Compliance is an important factor that influences treatment. Various factors which influence patient compliance are:

• Poor education unable to understand the instructions, particularly complex regimen
• Adverse effects particularly disturbing adverse drug reactions (ADRs)
• Polypharmacy (multiple drugs) some drugs may be missed
• Lack of confidence in doctors
• Cost may be unable to afford
• Disease Psychiatric illness or false belief.

Directly observed treatment short course (DOTS) is a strategy to ensure good patient compliance to antitubercular drugs where a health worker supervises the tablet being swallowed.

Orphan drugs:

• Orphan drugs are to be used for the prevention and treatment of rare diseases. Such drugs are not readily developed and marketed because they are not profitable to the manufacturer.
• For example, acetylcysteine used for paracetamol overdosage, 4-methyl pyrazole in poisoning due to methanol or ethylene glycol, and 4-aminosalicylic acid in the treatment of ulcerative colitis.
• Such rare diseases are also called orphan diseases.
• The Orphan Drugs Act provides incentives to drug manufacturers for the development of orphan drugs.

Adverse Drug Reactions

Question 24. Write a short note on adverse drug reactions.
Answer:

Definition of adverse drug reactions: Adverse drug reaction is any response to a drug that is noxious and unintended and that occurs at doses used in man for prophylaxis, diagnosis or therapy.

All drugs can cause adverse effects. ADRs are classified as follows:

Type A (augmented) reactions:

• Type A (augmented) reactions are related to the known pharmacological effects of the drug and are predictable, dose-related, quantitative adverse effects and are mostly reversible.
• For example, insulin-induced hypoglycemia, and bleeding following anticoagulants.

Type A reactions include:

1. Side effects are an extension of the pharmacological effects and are seen with the therapeutic dose of the drug.
2. They are predictable, common, and can occur in all people
   • For example, Hypokalemia following frusemide.
3. Secondary effects are the indirect result of primary drug action.
   • For example, superinfection following broadspectrum antibiotics.
4. Toxic effects are seen with higher doses of the drug and can be serious.
   • For example, Morphine causes respiratory depression in overdosage which can be fatal.

Type B (bizarre) reactions:

Type B (bizarre) reactions are unrelated to the primary pharmacological effects of the drug and are, therefore, not predictable. They are less common, not tolerated, and are an abnormal reaction to the drug. Type B reactions could be:

• Idiosyncrasy a genetically determined abnormal reaction to a drug, For example, Primaquine induces hemolysis in patients with G6PD deficiency; some patients show excitement with barbiturates.
• Allergic reactions are immunologically mediated reactions that are not related to the therapeutic effects of the drug.
  • The drug acts as an antigen to induce antibody formation.
  • Next exposure to the drug may result in allergic reactions.
  • The manifestations of allergy are seen mainly on the target organs, viz. skin, respiratory tract, gastrointestinal tract, blood, and blood vessels.

Type C (chronic) reactions: Occur on chronic use of drugs, for example, Chloroquine retinopathy, Cushing’s syndrome, and analgesic nephropathy.

Type D (delayed) reactions: Occur long after stopping treatment, sometimes after years, For example, Leukemia following treatment of Hodgkin’s lymphoma; teratogenic effects.

Type E (end of use): These effects are due to the sudden stopping of a drug after prolonged use. For example, acute adrenal insufficiency after the sudden stopping of glucocorticoids, and angina after the sudden withdrawal of atenolol.

Drug Allergy:

Drugs can induce allergic reactions which could range from mild itching to anaphylaxis. They can induce both types of allergic reactions, viz. humoral and cell-mediated immunity.

Mechanisms involved in Types 1, 2, and 3 reactions are humoral immunity, while Type 4 reactions are due to cell-mediated immunity

Types Of Allergic Reactions And Their Mechanisms:

Type 1 (anaphylactic) reactions:

The drug induces the synthesis of IgE antibodies which are fixed to the mast cells.

• On subsequent exposure, the antigen-antibody complexes cause degranulation of mast cells releasing the mediators of inflammation like histamine, leukotrienes, prostaglandins, and platelet-activating factor.
• These are responsible for the characteristic signs and symptoms of anaphylaxis like bronchospasm, laryngeal edema, and hypotension which could be fatal.
• Allergy develops within minutes and is called an immediate hypersensitivity reaction, for example, Penicillins.
• Skin tests may predict this type of reaction, for example, Penicillins, Cephalosporins, lignocaine, procaine, iron dextran, and streptomycin.

Type 2 (cytolytic) reactions:

The drug binds to a protein and together they act as antigens and induce the formation of antibodies.

• The antigen-antibody complexes activate the complement system resulting in cytolysis causing thrombocytopenia, agranulocytosis, and aplastic anemia, for example, Carbamazepine, Phenytoin, Sulfonamides, and Phenylbutazone.
• Mismatched blood transfusion reactions are also cytolytic reactions.

Type 3 (arthus) reactions:

The antigen binds to circulating antibodies and the complexes are deposited on the vessel wall where it initiates the inflammatory response resulting in vasculitis.

Rashes, fever, arthralgia, lymphadenopathy, serum sickness, and Stevens-Johnson syndrome are some of the manifestations of Arthus-type reaction.

• Serum sickness is characterized by fever, arthritis, nephritis, edema, and skin rashes. Penicillins, sulfonamides, phenytoin, streptomycin, and heparin can cause serum sickness.
• Stevens-Johnson syndrome (SJS) is characterized by severe bullous erythema multiforme, particularly in the mucous membranes with fever and malaise.
• Toxic epidermal necrolysis (TEN) is the most serious form of drug allergy with mucocutaneous reactions that can be fatal.
• Aminopenicillins, sulfonamides, sulfones, phenytoin, barbiturates, carbamazepine, phenylbutazone, and quinolones are the drugs associated with SJS and TEN.

Type 4 (delayed hypersensitivity) reactions:

• Mediated by T lymphocytes and macrophages.
• The antigen reacts with receptors on T lymphocytes which produce lymphokines leading to a local allergic reaction
• For example, Contact dermatitis in nurses and doctors handling penicillins and local anesthetics.

Prevention of allergic reactions:

• To prevent allergic reactions, it is important to take a history of drug allergies. If such a history is present, the drug as well as its chemically related drugs should be avoided.
• For drugs that are known to cause allergies like penicillins and cephalosporins, sensitivity skin tests should be done.

Drugs Likely to Cause Allergy:

• Penicillins Salicylates
• Sulfonamides Quinolones
• Cephalosporins
• Local anesthetics
• Antisera
• Radio contrast media (with iodine)

Desensitization:

• Hyposensitization or desensitization is required for some drugs like penicillin
• G when there are not many alternatives available.
• To start with, very small doses of the drug is given repeatedly at short intervals to desensitize and the dose is then gradually increased as the patient gets desensitized.

Other forms of adverse drug reactions:

• Drug intolerance is the inability of a person to tolerate a drug even in therapeutic doses and is unpredictable. It could be quantitative or qualitative.
• Quantitative intolerance is when patients show exaggerated responses to even small doses of the drug.
• For example, Vestibular dysfunction after a single dose of streptomycin may be seen in some patients.
• Intolerance could also be qualitative, for example, Idiosyncrasy and allergic reactions.

Iatrogenic diseases:

• These are drug-induced or so-called physician-induced diseases. Even after the drug is withdrawn, its toxic effects can persist.
• For example, Isoniazid-induced hepatitis; chloroquine-induced retinopathy, and drug-induced parkinsonism due to chlorpromazine, haloperidol, and metoclopramide.

Examples of drugs affecting various organ systems:

Drug dependence:

Question 25. Write a short note on drug dependence.
Answer:

Drug dependence:

• Drugs that influence behavior and mood are misused to obtain pleasurable effects and repeated use of such drugs results in dependence.
• Drug dependence is a state of compulsive use of drugs in spite of the knowledge of the risks associated with their use.
• It is also referred to as drug addiction.
• Dependence could be ‘psychologic’ or ‘physical’ dependence.
• Psychologic dependence is compulsive drug-seeking behavior to obtain its pleasurable effects, for example , Cigarette smoking.
• Physical dependence is said to be present when withdrawal of the drug produces adverse symptoms.
• The body undergoes physiological changes to adapt itself to the continued presence of the drug in the body.
• Stopping the drug results in ‘withdrawal syndrome.’ The symptoms of withdrawal syndrome are disturbing and the person then craves for the drug, for example, Alcohol, opioids, and barbiturates.

Teratogenicity:

Question 26. Write a short note on teratogenicity.
Answer:

Teratogenicity: ‘

Teratogenicity is the ability of a drug to cause fetal abnormalities when administered to a pregnant woman. Teratos in Greek means a monster.

• The sedative thalidomide taken during early pregnancy for relief from morning sickness resulted in thousands of babies being born with phocomelia (seal limbs).’
• After this disaster (1958–61) it is made mandatory to conduct strict teratogenicity tests before a new drug is approved for use.

Depending on the stage of pregnancy the teratogen is administered and the effects may be:

• Conception to 16 days—usually resistant to teratogenic effects. If affected, abortion occurs.
• Period of organogenesis (17–55 days of gestation)—most vulnerable period; major physical abnormalities occur.
• Fetal period (56 days onwards)—period of growth and development—hence developmental and functional abnormalities result.
• Therefore, drugs should be avoided during pregnancy especially in the first trimester.
• The type of malformation also depends on the drug, for example, Thalidomide causes phocomelia; tetracyclines cause deformed teeth; sodium valproate causes spina bifida.

Drugs are categorized based on their teratogenic potential as given in Table.

Teratogenicity risk categories (general interpretation in brackets for simplification);

Drug Interactions

Definition of Drug interaction:

Drug interaction is the alteration in the duration or magnitude of the pharmacological effects of one drug by another drug. When two or more drugs are given concurrently, the responses may be beneficial or harmful. Harmful interactions can be avoided by judicious use of drugs.

Site: Drug interactions (DI) can occur:

• In vitro mixing of drugs in syringes can cause chemical or physical interactions and such combinations are incompatible in solution, for example, Penicillin and gentamicin should never be mixed in the same syringe.
• In vivo i.e. in the body after administration

The pharmacological basis of drug interactions is:

Pharmacokinetic mechanisms:

Change in response may be produced by influencing the absorption, distribution, metabolism, or excretion of one drug by another.

• Absorption:
  • Binding: Tetracyclines chelate iron and antacids → reduced absorption.
  • Altering gastric pH: Antacids ↑ ↑ gastric pH → ↓ ↓ absorption of iron, anticoagulants.
  • Altering GI motility: Atropine and morphine slow gastric emptying and delay the absorption of drugs. Purgatives reduce the absorption of riboflavin.
• Distribution: Competition for plasma proteins or tissue binding results in displacement interactions, for example, Warfarin displaced by phenylbutazone → ↑ warfarin levels
• Metabolism: Microsomal enzyme induction and inhibition can both result in DI.
  • For example, enzyme inducers: Phenytoin, phenobarbitone, and rifampicin.
  • Enzyme inhibitors chloramphenicol and cimetidine.
• Excretion: When drugs compete for the same renal tubular transport system, they prolong each other’s duration of action, for example, Penicillin and probenecid.

Pharmacodynamic mechanisms:

Drugs acting on the same receptors or physiological systems result in additive, synergistic or antagonistic effects, for example,

• Antagonism: Atropine opposes the effects of physostigmine; naloxone antagonizes
  morphine.
• Synergism: Organic nitrates increase cGMP levels and sildenafil prevents cGMP degradation by inhibiting phosphodiesterase and thereby potentiates the effects of nitrates. The combination can cause severe hypotension and sudden death.
• Additive: Sedation by antihistamines may be worsened by alcohol.

Drug-Food Interactions:

Food and drug interactions need to be kept in mind while prescribing drugs. The presence of food may interfere with the absorption of several drugs like rifampicin, and roxithromycin which should be given on an empty stomach.

• Drugs also interact with constituents of food like milk (tetracycline, iron) and their bioavailability gets reduced.
• Tender coconut water and fruits (like sweet lime) rich in potassium can add up to hyperkalemia caused by ACE inhibitors.
• Cheese reaction consumption of tyramine-containing foods like cheese, beer, wines, yeast, buttermilk, and fish by patients receiving MAO inhibitors results in hypertension termed as cheese reaction.
• Inhibition of MAO by drugs leads to raised tyramine levels which displace NA from the adrenergic nerve terminals resulting in hypertension.
• Grapefruit is an enzyme inhibitor and thereby raises the levels of phenytoin

Tyramine containing + MAO inhibitors → ↑ tyramine → displaces NA from → hypertension food  Nerve terminals

Drug Development

• The development of hundreds of new drugs in the last few decades has revolutionized the practice of medicine.
• The discovery and development of a new drug is a time-consuming and expensive procedure.
• After identification, the structure of the new compound and its purity are determined.
• The compound is screened for the presence of any useful biologic activity by a series of tests like bioassays, molecular and cellular studies.
• If the compound is found to be promising, then it is subjected to preclinical evaluation in animals and clinical trials in humans.

Preclinical evaluation: The compound is evaluated in animals for the following:

1. Toxicity—includes acute, subacute, and chronic toxicity studies.
2. Safety and efficacy evaluation; determination of therapeutic index.
3. Pharmacokinetic studies.

Clinical Trials of  Drug Development:

• When the drug is found to be reasonably safe in animals, it is subjected to clinical trials in human beings after obtaining permission from the regulatory agency.
• Clinical trials are conducted to know the therapeutic efficacy of a new drug and compare it with an existing drug or a placebo.

Good clinical practice:

• The guidelines for good clinical practice and ethics are formulated by the regulatory bodies. For the conduct of clinical trials in India, the guidelines by
• International Conference on Harmonization (ICH), WHO
• United States Food and Drug Administration (USFDA), Schedule ‘Y’ of India and ICMR are followed. These aim to ensure the safety of the subjects and the credibility of the clinical trial data generated.

Ethical clearance:

• After obtaining permission from the concerned regulatory authorities to conduct the trial in a given setting, permission should be obtained from the local institutional ethics committee (IEC) or institutional review board (IRB).
• The IEC looks into the ethical aspects of the trial and ensures that the trial is conducted ethically and the rights of the study participants are protected.

Informed consent:

• For enrolling a subject into a clinical trial, he/she should be informed in detail about the trial including the risks involved and the subject should willingly consent to participate in the study.
• He should sign the informed consent form and should also be made aware that he is free to withdraw from the study whenever he wants to.
• This is to ensure that participation in the study is purely voluntary and not by force.

Phases of clinical trials: Clinical trials are generally conducted in 4 phases though phase 0 is also included in some situations.

Phases of clinical trials:

Clinical trials registry:

• In order to make drug development transparent, accountable and data accessible, the Clinical Trial Registry of India (CTRI) has been set up by the joint efforts of ICMR, the Department of Science and Technology (DST), and WHO. All clinical trials conducted in
• India should be registered in CTRI.
• Though registration is voluntary and free of cost, it is required for the publication of data from clinical trials.
• The details registered are freely accessible to all including the general public.

Drug Nomenclature

The drug can have four names:

1. Code name
2. Chemical name
3. Generic/nonproprietary name
4. Brand/proprietary name/trade name

Essential Drugs:

WHO has introduced the concept of essential drugs.

Definition of Essential Drugs: Essential drugs are those that satisfy the healthcare needs of the majority of the population and should, therefore, be available at all times in adequate amounts and in the appropriate dosage forms.

• The list should be revised and updated from time to time to meet the changing requirements.
• Based on the WHO guidelines each country has its own national list of essential drugs.

Advantages of Essential drugs:

• Greater coordination in healthcare development.
• The list serves as a guideline for indenting and stocking essential drugs.
• Has also helped in the development of national formularies.
• A short list is compiled for community health workers to aid in providing primary health care.
• The use of essential drug lists has also emphasized the need for drug research and development.
• For example, the Safety and efficacy of a new drug should be established for it to be included in the essential drugs list.
• India’s first National Essential Drugs List consisting of about 300 drugs was formulated in 1996. The revised nineteenth model list was brought out by India in 2015.

Rational Drug Use:

Once a patient is diagnosed to have a particular disease and needs to be treated with drugs, the specific therapeutic objective and therapeutic endpoint should be defined. For example, in hypertension, the objective is to bring down the BP to a particular level in order to prevent complications of prolonged hypertension.

• Once the objective is clear, the right choice of drugs should be carefully made. For example, hyperacidity and mild gastritis may be managed with antacids.
• When not controlled, an H2 receptor blocker like ranitidine helps. Only more severe cases require to be treated with omeprazole.
• Patient factors like age, presence of other diseases, renal and liver function, other drugs being administered and cost of therapy should be considered. Newer drugs are all expensive.
• The dose and duration of treatment should be determined. When long-term treatment is required, regular review and monitoring of treatment should be planned.
• When a combination of drugs is to be administered, appropriate combinations should be used, and avoid irrational combinations of drugs.
• Many marketed combinations serve no useful purpose, are more expensive and unnecessary, but are vigorously promoted and unfortunately often prescribed by doctors.

Some such examples are:

• Amoxicillin (250 mg) with cloxacillin (250 mg): Combined with the view that cloxacillin can destroy the penicillinase-producing Staphylococcus aureus (PPSA), while amoxicillin can help if the infection is with other bacteria. But, in fact, if the infecting organism is
• PPSA, 250 mg cloxacillin is inadequate: If it is not PPSA, for others—250 mg of amoxicillin is inadequate. It should be noted that cloxacillin is not an efficient antibiotic in infections other than PPSA, while amoxicillin is of no use in PPSA. Therefore, the combination is totally irrational.
• Ibuprofen with paracetamol: One of them can be given based on the requirement. The combination serves no useful purpose
• Diclofenac + nimesulide: One of them can be given based on the requirement. The combination serves no useful purpose. Nimesulide is now banned in most of countries.
• Ciprofloxacin + tinidazole: The combination is used in diarrhea. It is claimed that it helps in diarrhea due to both gram-negative bacteria and ameba. In reality, the diarrhea is due to either of the organisms and not both.
  • Using the combination only exposes the patient to the risk of toxicity from the other antimicrobial agent and also adds to the cost of therapy.
  • Hence, every doctor needs to do his best for his patients with the right drug, the right dose, and the right duration of treatment based on his judgment and guided by his experience.
  • He has to update his knowledge regularly and revise from time to time rather than blindly following the directions of the seniors in his field.

 P Drugs:

• Pharmacology has grown to the extent that it is difficult to remember all the drugs described in the books. In daily practice, however, a physician needs to be good in using fewer drugs (40–60).
• For any illness, if there are many drugs in a group, the physician may choose some primary drugs which need to be used routinely and be thorough with their pharmacology. Such a choice of drugs called P  or personal drugs is used to prescribe regularly.
• The doctor also needs to know the dose, formulations, duration of treatment, drug interactions, and precautions in using such P-drugs.

P-treatment: For any given illness, the treatment of the first choice is the P-treatment. It depends on the therapeutic objective, safety, efficacy, and cost of treatment.

Drug Regulations:

• In 1940, The Drugs Act was passed to control the manufacture, sale, and distribution of allopathic drugs. Later the Act was amended several times and it now also includes
• Ayurvedic, Unani,
• Siddha and homeopathic drugs. An amendment was made in 1962 to include cosmetics and the title changed to the Drugs and Cosmetics Act.
• Under the Act, clear rules have been framed for the import, manufacture, sale, labeling, and packing of drugs.
• Drug schedules: Some important schedules controlling the manufacture, distribution, and sale of drugs in India are given in the table.

Important drug schedule: