Basic background concepts

Revise basic background concepts of pharmacology in a Q&A format, with helpful tables, lists, and tags for SAQ, LAQ, and Viva questions.

The concepts are also reviewed in the following video sessions

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SAQ, Viva

Define “Drug” with examples

Drug is a chemical substance which is used or intended to be used for –

1. Diagnosis of a disease: (Phentolamine for diagnosis of pheochromocytoma, barium sulphate / iodine /gadolinium – radioopaque contrast media used for radiologic procedures, Anti-Acetylcholine Receptor Antibody test [Anti-AchR-Ab test] for diagnosis of myasthenia gravis) 
2. Prevention of a disease: (Diphtheria, pertusis, tetanus vaccine for prevention of these 3 diseases, low-dose aspirin for prevention of platelet aggregation and myocardial infarction)
3. Cure or treatment of disease: (Norfloxacin – a fluoroquinolone antibiotic for treating a susceptible urinary tract infection, antituberculosis drugs for treatment of tuberculosis)
4. Symptomatic relief: (Paracetamol for symptomatic relief of fever, diclofenac for relief of pain)
5. Prevention of pregnancy: (Estrogen-progestin combination oral contraceptives for prevention of pregnancy)

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SAQ,Viva

What do you mean by pharmacokinetics?

Pharmacokinetics: (Kinetic means movement) (drug movement in the body) Drug moves inside the body, undergoes absorption, distribution, biotransformation, and excretion. So Pharmacokinetics is the study of absorption, distribution, biotransformation, excretion of a drug.

Includes half life, duration of action, onset of action, bioavailability.

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Viva

What is the difference between “pharmacological action/effect” or “mechanism of action”?

“Pharmacological actions or effects” means the changes that the drug produces on various body systems or cells.

“Mechanism of action” means how the drug produces those actions, or what is the way by which the drug produces those actions.

Actions may be many because they are the effects on different body systems

For example: Pharmacological action of salbutamol is to produce bronchodilation, and the mechanism of this action is by stimulating the beta-2 receptors in the bronchial smooth muscles and increasing the cyclic AMP.

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SAQ

Mention the various sources of drugs with relevant examples

1. Plants / vegetable source (alkaloids): Morphine, atropine, vincristine, vinblastine, quinine, quinidine, d-tubocurarine, cocaine, caffeine, nicotine, papaverine, chloroquine. They are called alkaloids. 

(Spellings of most of them end with “ine”) [So also there are some alkaloids whose spellings do not end with “ine” ! Examples: Digoxin, Aspirin]

[Examples of those end with “ine” but they are not alkaloids: epinephrine, procaine, doxycycline, ranitidine].

(Overdose: Universal antidote is useful for gastric lavage in alkaloidal poisoning)  

2. Animal source: Thyroxine, Insulin, most of the hormones

3. Mineral source: Iron, liquid paraffin, magnesium sulfate 

4. Micro-organisms: Penicillin G (benzyl penicillin), cephalosporins, aminoglycosides (streptomycin, kanamycin, gentamicin) = ANTIBIOTICS: Prepared mostly from the fungi, actinomycetes, and also inhibit other microorganisms. Also substances obtained from microorganisms may have other actions e.g. streptokinase obtained from microorganisms is a thrombolytic agent.

5. Synthetic source (From chemicals, in a laboratory): Ibuprofen, sulfonamides, trimethoprim, cotrimoxazole, metronidazole, newer synthetic tetracyclines (doxycycline, minocycline), newer synthetic penicillins 

6. Genetic engineering (Recombinant DNA technology): Genetic sequence responsible for synthesis of a substance (e.g. insulin) is transferred to a microorganism (E.coli), and the bacteria are trained to synthesize substances !! e.g. Insulin, recombinant tissue plasminogen activator (r-tPA)

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Viva

What is the difference between route of administration for systemic action and route of administration for local action?

After giving a drug by a particular route, if the drug remains restricted to only some area or site, then that route is considered as “route for local action”.

The route by which the drug enters systemic circulation and produces systemic effect on all or many body systems is called a “route for systemic action”.

Never call a route of administration as systemic route or local route.

A route is not systemic route or local route.

The effect which is produced can be local or systemic.

So, always say as – “Routes for local action” or “Routes for systemic action”

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LAQ, SAQ, Viva

Classify routes of administration with examples

Routes of administration

A. Routes for systemic action

a. Enteral (Enteron=Intestine)(means through part of gastrointestinal tract)

1. Oral: Paracetamol tablets for headache, Ramipril capsule for hypertension
2. Sublingual: Sublingual tablet – Isosorbide dinitrate (5 mg) (Sorbitrate) or Nitroglycerine (0.4 mg) (Nitrostat) for acute angina 
3. Buccal: Prochlorperazine (stemetil) buccal tablet for vertigo
4. Rectal: Diazepam rectal suppository for sedation

b. Parenteral (Par-Enteral / Beyond GIT)

1. Cutaneous / Transdermal: Diclofenac transdermal patch for pain relief, Buprenorphine transdermal patch for relief of pain in terminal stages of cancer
2. Inhalational route for systemic action: When an inhaled drug is absorbed into systemic circulation, enters all the body systems and produces systemic effect. E.g. General anesthetic drugs – Halothane, enflurance, sevoflurane etc are given by inhalation, but they enter the systemic circulation and produce general anesthesia
3. Nasal route for systemic action: Oxytocin used as a nasal spray enters systemic circulation and activates letdown of milk. Zolmitriptan / dihydroergotamine nasal spray – the drugs get absorbed systemically and relieve migraine symptoms
4. Injections
   Subcutaneous (S/C): Subcutaneous injection of granulocyte colony stimulating factor (G-CSF), Subcutaneous insulin injection
   Intramuscular (I/M): Intramuscular vitamin B12 injection, intramuscular injection of hyoscine for acute abdominal pain
   Intradermal (I/D): Tuberculin test, hypersensitivity testing for various injections
   Intravenous (I/V): Intravenous lorazepam to stop convulsions, intravenous fluids in treatment of dehydration

B. Routes for local action

1. Local application (topical) to Skin, wounds, burns (Formulations – Ointment,cream,lotion,powder) Examples: Antibiotics (neomycin, gentamicin, kanamycin, bacitracin), Soothening agents (calamine lotion), Steroids (betamethasone), Antifungals (nystatin,clotrimazole)

2. Local application to mucous membranes

-Oral cavity (Astringents,local anesthetics) 

-Pharynx (Gargles) 

-Eye, Ear (Drops, ointments)

-Nose (Drops)

-Urethra, Anal canal (jelly, ointment)

-Vagina (suppositories, pessaries)

-Rectum (suppositories – laxatives – bisacodyl)

3. Oral route for local effect (!!!) on gastrointestinal tract 

– Neomycin tablet (an aminoglycoside antibiotic) ingested orally is poorly absorbed but remains active in GIT and produces local antimicrobial effect on intestinal microorganisms !! 

– Aluminium hydroxide / magnesium hydroxide (Gellusil/digene) ingested by oral route as tablets or suspensions are unabsorbable (nonsystemic antacids) and produce local effect of neutralizing gastric hydrochloric acid in the stomach 

4. Inhalation for local effect !!! 

-When an inhaled drug is not absorbed to systemic circulation, produces local effect on the bronchus e.g. Salbutamol – selective beta-2 stimulant produces local effect of bronchodilation

5. Injections for local action

-Intraarticular injection (injection of steroids or anti-inflammatory drugs in the joint space)

Note: Compare, understand, & Enjoy the difference between – Inhalational route for systemic effect and inhalation for local effect

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LAQ,SAQ,Viva

Mention advantages and disadvantages of oral route of administration

Oral route: Advantages

1. It is safe
2. Convenient
3. Noninvasive route
4. Painless
5. Self administration is easy
6. The formulation need not be sterile
7. Less expensive as compared to other routes
8. No sudden hazardous effect is expected as the absorption is going to be slow

Oral route: Disadvantages

1. Slow onset of action, so takes time to produce effect
2. Non-palatability (Taste of certain formulations may be bad)
3. Gastro Intestinal  intolerance (Nausea, vomiting)
4. Absorption may not be complete or may be poor: Some drugs may have a very poor absorption by oral route, they can’t be given by oral route for systemic effect (Gentamicin – an aminoglycoside is very poorly absorbed by oral route, so practically can’t be used in the form of tablets or capsules) 
5. Acid lability of a drug: If major amount of the drug is destroyed by gastric hydrochloric acid, then oral route is not useful. e.g. Penicillin G is not useful by oral route
6. High first pass metabolism: Drugs which have high first pass metabolism cannot be used by oral route. E.g. Insulin
7. Cannot be used in uncooperative or unconscious patients
8. Cannot be used in patients who are constantly vomiting or those who have severe dysphagia (cannot swallow) 

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LAQ,SAQ,Viva

Explain what is sublingual route of administration. Mention its advantages and disadvantages.

Sublingual route of administration is a route of administration for systemic action. By this route, certain drugs are absorbed through the sublingual blood vessels directly into systemic circulation within shortest time to produce immediate action.

Examples: 

1. Isosorbide dinitrate 5 mg (Sorbitrate) or glyceryl trinitrate (NTG or GTN) (Nitrostat 0.4 mg) for acute attack of angina.
2. Zolmitriptan tablets 1.25 mg/2.5 mg  for migraine
3. Buprenorphine 2 mg / 8 mg – for pain, and for morphine dependence 
4. Ergotamine tartarate – 2 mg – migraine
5. Hyoscyamine (Hyoscine butyl bromide) – 0.125 mg – for abdominal cramps

Method of Sublingual administration

• Place the tablet below the tongue.
• It is absorbed through the sublingual mucous membrane, directly in to the systemic circulation.
• You can spit out the tablet and – stop/terminate the drug action !

Advantages: Sublingual route

1. Rapid, instantaneous onset of action
2. Bypasses the liver and GIT; avoids first pass metabolism
3. So, Almost 100% bioavailability
4. Termination of action possible
5. Useful in emergency
6. Non-invasive route

Disadvantages: Sublingual route

• Short duration of action
• Sudden hazardous effect is possible due to rapid, instant absorption 

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LAQ,SAQ,Viva

Describe intravenous route of administration. Mention its advantages and disadvantages.

Intravenous route: A drug is injected into a vein.

A single dose of a drug may be injected into a vein (single dose) or a single larger dose may be injected (bolus dose) or a drug may be added into a diluting fluid and may be continuously sent over a long time into the patient’s vein through an intravenous line (continuous intravenous infusion/drip) by monitoring the rate of infusion. This intravenous catheter may be kept intact in a place and used to inject the drugs or to re-start an intravenous continuous drip whenever needed.

Thus, Intravenous route of administration is an absolute virtue in patient management, when –

– the patient is hospitalized / unconscious 

– having difficulties in having the drugs orally or intramuscularly or 

– needing too many drugs or 

– too much quantity of a drug or

– requiring a drug too frequently or

– as an emergency or

– needing continued action,

Advantages: Intravenous route

1. Rapid onset of action
2. Immediate absorption to systemic circulation
3. 100% bioavailability
4. Absolutely useful in emergency
5. Metabolism in the liver and GIT is bypassed
6. No gastric irritation
7. Useful in Unconscious /uncooperative patients
8. Continuous drug administration is possible

Disadvantages: Intravenous route

1. Sudden hazardous effects are likely
2. Self administration difficult
3. Sterile precautions are needed
4. Expertise is required
5. Supervision is needed
6. Expensive
7. Irritation and pain is likely
8. Extravasation of the drug is likely (the drug coming out of a vein)
9. Thrombophlebitis and pain are likely on continuous administration 

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LAQ,SAQ,Viva

Write a note on transdermal therapeutic system (TTS)/ Mention briefly about transdermal therapeutic system (TTS). Mention its advantages and disadvantages./Mention about transdermal route of administration.

Transdermal route is a route of administration for systemic effect.

By this route, the drug enters into the systemic circulation slowly over a long period of time, and provides a long, sustained action. 

Obviously, not all drugs can do this. Some of the highly lipid soluble drugs can get absorbed in this way. The drug bypasses the liver and the gastrointestinal tract to enter directly into the systemic circulation, but the entry is slow. So, it leads to a slow, prolonged aborption, and a slow, long, and sustained action over a long period of time.

The drugs can be administered in the form of ointment (example: nitroglycerin ointment in the management of angina) or as a patch (Example: Fentanyl patch or Buprenorphine patch for sustained pain relief in the pain due to terminal stages of cancer). A patch is usually meant for a sustained action of 48 to 72 hours after which the patch may be removed and a new patch applied.

The patch or the transdermal therapeutic system contains –

-drug reservoir

-a drug release membrane

-a clear backing film to hold the drug reservoir, and –

-a contact adhesive to hold the formulation

Please note – Transdermal therapeutic systems shall provide long and sustained action and shall avoid repeated drug administration by oral or injectable methods. (Transdermal therapeutic systems are NOT meant for acute effect)

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LAQ,SAQ,Viva

Mention some newer drug delivery systems and their imporance with examples.

“Newer drug delivery systems” are the comparatively newer routes or methods or ways or techniques employed for drug administration, in which the traditional routes are modified for the improved bioavailability of drugs at the site of action as well as to serve some other purposes.

The purposes served by the newer drug delivery systems vary according to the system, the drug, and the route of administration.

Purposes of using newer drug delivery systems:

1. Higher concentration of drug at the site of action
2. Sustained drug delivery over a long period of time
3. Avoiding the breakdown or wastage of a drug by concentrating the drug at a particular site of action
4. Bypassing the transmucosal or transcutaneous barriers for drug entry
5. Bypassing the drug metabolism
6. Avoiding repeated oral or injectable administrations
7. Reaching deeper tissue sites which may not be achievable by usual routes of administration
8. Rapid entry / action of drugs (in some cases)

Examples of Newer Drug Delivery Systems:

1. Dermojets (useful for mass inoculations)

2. Dermal implants, pellets, sialistic/biodegradable implants providing long duration of action of upto years and avoiding repeated administrations (medroxyprogesterone acetate, testosterone, levonorgestrel)

3. Transdermal Therapeutic Systems (TTS) or patches-  Fentanyl, clonidine, nitroglycerin, nicotine, transdermal patches of scopolamine for motion sickness

4. Ocusert – Pilocarpine for glaucoma

5. Targetted drug delivery systems: monoclonal antibodies

6. Liposomes incorporated with drugs (I.V.) (daunorubicin,doxorubicin,gentamicin, amphotericin B)

7. Computerized, miniature syringe pumps (insulin,GnRH,NTG)

8. Pen devices

9. Jet injections

10. Programmed pumps: Insulin, patient controlled analgesia

9. Nebulizer with Microprocessor-controlled vibrating mesh (Amikacin for pneumonia – local action)

10. Drug eluting stents

11. Antibiotic-impregnated polymethyl-methacrylate cement beads for antibiotic delivery to bones (Gentamicin)

12. Sonophoresis: Use of ultrasonic waves (1-3 MHz) for enhancement of migration of drug molecule through skin. Eg. Hydrocortisone in arthritis 

13. Vitraserts, retiserts or duraserts allowing drug delivery in the eye for very long periods of upto some years

14. Inhaled insulin: (Under research, and not yet established for routine use)

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SAQ,Viva

Define “Pharmacogenetics”. Give examples of genetic factors modifying drug effect.

Pharmacogenetics is the study of genetic factors modifying drug effects. Genetic factors may alter the effect of the drug at a pharmacodynamic or pharmacokinetic level or both.

Pharmacogenetic factors modifying drug effect:

1. Atypical plasma pseudocholinesterase leading to succcinylcholine apnea. The enzyme butyrylcholinesterase is genetically atypical or ineffective in certain individuals, so it modifies the breakdown of succinylcholine (a skeletal muscle relaxant). This leads to slow breakdown of succinylcholine  🡪 Neuromuscular paralysis and apnea. Since the enzyme responsible for succinylcholine breakdown is in fault, the treatment of this condition is going to be cholinesterase enzyme, which will be supplied through fresh blood transfusion. Hence treatment of succinylcholine apnea is fresh blood transfusion and artificial respiration.

2. N-Acetylation (slow acetylators) (AR): (INH, procainamide, hydralazine): This is called genetic polymorphism. Certain individuals have an autosomal recessive trait of slowly acetylating certain substances. The defect is in N-acetylation. In such individuals, certain drugs like INH, procainamide, hydralazine are metabolized slowly over a long period of time. This leads to their prolonged effects or toxic responses e.g. Lupus erythematosus like symptoms with joint swelling and joint pains. This is exhibited in about 5-% of white and African-Americans in US.

3. Hemolysis in G6PD deficiency: The enzyme glucose-6-phosphate dehydrogenase (G6PD) is essential for generation of NADPH and reduced glutathione, which are necessary for survival of RBCs. Absence of this enzyme is an X-linked disorder, and predisposes an individual to hemolysis on exposure to certain oxidant drugs such as Primaquine, sulfa drugs, fluoroquinolones, aspirin in large doses, nitrofurantoin, NSAIDs, cephalosporins. Thus G6PD deficiency is a genetic factor that modifies the effect of oxidant drugs, hence this is a pharmacogenetic factor that modifies the drug effect.

4. Malignant hyperthermia – e.g. halothane. Repeated exposure to halothane may make certain individuals susceptible to severe rise in body temperature. The condition is called malignant hyperthermia. Certain individuals have abnormal Rynodine receptor (Ryr) associated with skeletal muscles, due to which there is excessive entry of calcium into the skeletal muscles, which leads to heat production and rise in body temperature.

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SAQ,Viva

Define “Pharmacogenomics”. Give examples

Pharmacogenomics is the science that is concerned with determining the likely response of an individual to therapeutic drugs. It is an applied branch of genomics (Study of genes and their functions) and pharmacology. Based on the knowledge obtained from Pharmacogenetics, it will be possible to find out which drugs would suite which human being. This will help to develop effective and safe medications, and their appropriate doses that will be based on a particular person’s genetic makeup.

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SAQ/Viva

What is “Disulfiram-like effect?”(Antabuse-like effect). Give examples of drugs producing such effect and its clinical application

Disulfiram (Antabuse) is an acetaldehyde dehydrogenase inhibitor used in the management of alcohol addiction.

Ethyl alcohol (by alcohol dehydrogenase) gets converted to acetaldehyde, and acetaldehyde (by acetaldehyde dehydrogenase) gets converted to acetic acid and water. Disulfiram inhibits the second step, leading to accumulation of acetaldehyde, and thus the patient gets severe symptoms of alcohol intolerance. This phenomenon is used as aversive therapy to discourage the patient from consuming alcohol. This is the action of disulfiram or antabuse. 

There are certain drugs capable of producing the same effect, when a patient consumes alcohol. Then this effect produced by those drugs is called “disulfiram or antabuse like effect”.

Such drugs include-

Metronidazole, Cephalosporins, Chlorpropamide, Macrolids, H2 blockers, Trimethoprim, Sulfa drugs, Fluoroquinolones.

Hence when the patient shall take any of the above drugs and consume alcohol, it will lead to a severe reaction of alcohol intolerance.

When the patient is prescribed any of the above drugs, the patient should be warned not to consume alcohol.

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LAQ, SAQ, Viva

Define “Teratogenicity” with examples.

Teratogenicity is the capacity of a drug to produce structural defects or deformities in the fetus, when a drug is administered to a pregnant mother.

“Terat” means a monster or a structurally strange object, hence the word “teratogenicity” should be used specifically to describe the structural defects or deformities or abnormalities, and not in general to every abnormality produced in a fetus.

In general, the process of organogenesis takes place during the early pregnancy (upto first 8 weeks or 55 days). Hence the term “teratogenicity” applies to the drug administration during this period. Naturally, teratogenicity is the manifestation of the drug administration during the first trimester of pregnancy.

Teratogenic effects: Examples

1. Thalidomide – Phocomelia – seal limbs – short limbs  

2. Phenytoin – Neural tube defects including spina bifida, anencephaly

3. Warfarin – Depressed nose; Eye, hand defects

4. Tetracyclines – Teeth abnormalities including discoloured, weak, fragile, and ill-developed or carious teeth.

Other complications are known to occur due to drug administration during the 2^nd and 3^rd trimester of pregnancy. Examples:

1. Warfarin – fetal hemorrhage

2. Morphine – respiratory depression

3. Oral antidiabetics – hypoglycemia

4. Lithium – fetal goiter

5. ACE inhibitors – hypoplasia of organs

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SAQ, Viva

Enumerate the Pregnancy risk categories with examples, and write their interpretation.

Pregnancy risk categories describe the severity of risk of the drugs to the fetus, if the drug is administered during pregnancy.

The categories are based on the evidence from observations and experiences in pasat from clinical set-up and from the observations in the experimental animals.

From A to X, the risk goes on increasing. Drugs in category A are supposed to be the most safe, and as you go further down until the category X, the risk is highest.

For example – Penicillins and other beta lactam antibiotics are comparatively safer whereas tetracyclines, chloramphenicol, and most of the aminoglycosides and antiepileptics are toxic to the fetus.

Risk Category	Examples
A	Injection Mgso4, thyroxine
B	Beta lactams (Penicillin V, amoxicillin, cefaclor), clindamycin, erythromycin, azithromycin, metronidazole, sulfa drugs, paracetamol, lignocaine
C	Chloramphenicol, fluoroquinolones, clarithromycin, trimethoprim, vancomycin, gentamicin, cotrimoxazole, morphine, codeine, atropine, steroids, thiopentone, bupivacaine, adrenaline, gabapentin
D	Tetracyclines, all aminoglycosides (except gentamicin), aspirin, phenytoin, carbamazepine, valproate, lorazepam
X	Estrogens, isotretionin,ergometrine

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LAQ

Enumerate and elaborate the factors modifying drug effect/drug action.

Factors modifying drug action

A. Patient- related factors

1. Age
2. Body weight/body size
3. Sex
4. Diet / food
5. Species / Race
6. Environmental factors/occupation
7. Genetic factors
8. Presence of disease
9. Psychological factors – Placebo
10. Psychological factors – Patient compliance

B. Drug- related factors

1. Route of administration
2. Environment
3. Time of administration
4. Cumulation
5. Tolerance
6. Tachyphylaxis
7. Drug dependence
8. Drug interactions