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Learning objectives

• Important pharmacokinetic aspects
• Important pharmacodynamic aspects
• Important questions for university examinations
• Multiple choice questions (MCQs)

Important pharmacokinetic aspects

Parenteral routes of drug administration
Parenteral refers to administration by injection which takes the drug directly into the tissue fluid or blood without having to cross the enteral mucosa. Gastric irritation and vomiting are not provoked. Parenteral routes can be employed even in unconscious, uncooperative or vomiting patient.
Important parenteral routes include
a. Subcutaneous (s.c.)
The drug is injected in the loose subcutaneous tissue which is richly supplied by nerves but has poor vascular access.
Advantages – Self ­injection is possible (e.g. insulin by diabetics). Depot preparations containing hormones and contraceptives can be injected for prolonged action.
Disadvantages – Only small volumes can be injected. Irritant drugs cannot be injectedAbsorption is slower than intramuscular. This route should be avoided in shock patients who are vasoconstricted—absorption will be delayed.
b. Intramuscular (i.m.)
The drug is injected into large skeletal muscles such as deltoid, triceps, gluteus maximus, rectus femoris, etc. which are highly vascular but has limited sensory nerve supply.
Advantages – Mild irritants can be injected, less painful. Absorption of drugs in aqueous solution is faster.
Disadvantages – Self injection is not possible as deep penetration is needed. Depot preparations (oily solutions, aqueous suspensions) can be injected by this route. I.M injections should be avoided in anticoagulant treated patients, because it can produce local haematoma.
c. Intravenous (i.v.)
The drug is injected into one of the superficial veins. The drug reaches directly into the blood stream and effects are produced immediately.
Advantages – Extremely helpful in emergency situations as drugs can be given as a bolus or infused slowly over hours. Bioavailability is 100%. Titration of the dose with the response is possible. Highly irritant drugs can be injected but if extravasation occurs, they can cause thrombophlebitis of the injected vein and necrosis of adjoining tissues.
Disadvantages – Only aqueous solutions are to be injected i.v. Aqueous suspensions or depot preparations can cause embolism. Can result in air embolism.
d. Intradermal injection
The drug is injected into the skin raising a bleb.
Examples – Administration of BCG vaccine, Penicillin sensitivity testing
General disadvantages of all parenteral routes
• Drug preparations have to be sterilized
• Injectables are costlier than oral drugs.
• Injection technique is invasive and often painful
• Assistance of another person is mostly needed.

Plasma protein binding and its clinical significance
After administration, many drugs at therapeutic concentrations exist mainly in bound form in our body. The fraction of drug that is unbound and pharmacologically active in plasma can be less than 1%, the remainder being associated with plasma protein. Even the small differences in protein binding can have significant effects on free drug concentration and drug effect.
The most important plasma protein in relation to drug binding is albumin, which binds many acidic drugs such as warfarin, NSAIDs, sulfonamides etc and a smaller number of basic drugs such as atropine. Other plasma proteins include β-globulin and an acid glycoprotein. They bind to basic drugs such as quinidine, lidocaine, and propranolol.
The amount of a drug that is bound to protein depends on three factors:
• the concentration of free drug
• its affinity for the binding sites
• the concentration of protein
Plasma albumin binds many different drugs, so competition can occur between them. If two drugs (A and B) compete this way, administration of drug B can reduce the protein binding, and hence increase the free plasma concentration, of drug A. To do this, drug B needs to occupy a significant fraction of the binding sites.
At therapeutic plasma concentrations, most drugs occupy only a small fraction of the available sites on plasma proteins. However, drugs such as NSAIDs, antiepileptics, warfarin, sulfonamides occupy about 50% of the binding sites at therapeutic concentrations. This can cause harmful effects by displacing other drugs.
Example – Displacement of bilirubin from albumin by highly plasma protein binding drugs in jaundiced premature neonates results in crossing of unbound bilirubin through immature blood–brain barrier and cause kernicterus (staining of the basal ganglia by bilirubin). This causes a distressing and permanent disturbance of movement known as choreoathetosis, characterised by involuntary writhing and twisting movements in the child.
However in adults, it should be remembered that when the amount of unbound drug in plasma increases, the metabolism and rate of elimination also increases, and after four half-lives the unbound concentration will return to its previous steady-state value.

Important pharmacodynamic aspects

Pharmacovigilance program of India
Adverse Drug Reaction is one of the leading causes of morbidity and mortality worldwide. In developing countries, the cost of management of adverse reactions in the general population is very high and under-recognized. It is, therefore necessary to evaluate the safety of medicines.
Pharmacovigilance is the ‘science and activities relating to the detection, assessment, under-standing and prevention of adverse effects or any other drug related problems.’ Pharmaco-vigilance generates evidence-based information on safety of medicines. It also promotes rational use of medicines.
In India, pharmacovigilance programme was launched in July 2010 by Ministry of Health & Family Welfare. Indian Pharmacopoeia Commission, Ghaziabad is the National Coordination Centre for Pharmacovigilance Programme of India. The mission of PvPI is to safeguard the health of Indian population by ensuring that the benefits of use of medicine outweigh the risks associated with its use.
Healthcare Professionals or Patients or Consumers may report ADRs (known/unknown, serious/non-serious, frequent/rare) using ADR Reporting Form and submit to ADR monitoring centers or directly to National Coordination Centre, PvPI via e-mail or mobile app. These reports are processed for causality assessment and communicated to WHO Uppsala Monitoring Center, Sweden through a software called VigiFlow. The information generated by pharmacovigilance is communicated to central drug regulatory agency CDSCO, India for appropriate regulatory actions.
The regulatory actions include ‘drug alerts’, or changes in the labelling of medicines indicating restrictions in use or statuary warnings, precautions, or even withdrawal of the drug from the market.