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Health and Welfare Canada, several yearsago, listed many items accidentally swallowed by young children. what are some?
Among the ten most common itemslisted were: aspirin, bleach, diaper-pail deodorizer, chocolate flavoured laxatives, children’s fever drops,cough syrups, tranquillizers, birth control pills, and cigarette butts
Types of Adverse Effects to Drugs
- Extension of therapeutic effect: When a barbiturate is taken for its sedative effects, an overdose will produce over-sedation. Similarly, when an anticoagulant is used for its anticoagulant effect (prevention of clot formation), an overdose will cause bleeding. These adverse effects are anticipatedsince they are simply an extension of normal therapeutic effects. The logical step is to reduce thedose of the drug.
- Unrelated to main drug action: The digitalis group of drugs is used to strengthen heart muscle inpatients with congestive heart failure. However, in many cases, these drugs will produce nausea,vomiting, and abnormal colour vision, which is totally unrelated to their main action
- Idiosyncrasy: The drug succinylcholine is used to produce muscle relaxation. It is normallyinactivated by an enzyme present in the blood. Approximately one in 3,000 patients lack the enzymenormally present in blood and are unable to inactivate the drug. For this reason, in such patients, thedrug will act for excessively long periods. There are a variety of adverse effects of this type due to anunusual genetic makeup in an individual.
- Drug allergy: The basis of the allergic reaction to drugs in some patients is the following. The firsttime the drug is administered, it combines with a protein to form a complex known as an antigen. The antigen provokes the body to make a substance named an antibody. The next time the drug isadministered it will combine with the protein to produce an antigen and the antigen will combine withthe antibodies which were produced when the drug was first administered. The antigen-antibodycombination provokes an adverse reaction in the patient.
introduction of new drugs usually proceed through three stages
- Panacea: When the drug is first marketed with considerable advertising, it is thought that the drug is a major new advance.
- Poison: After the drug has been is use for a few months, additional adverse effects usually become apparent and sales of the drug drop precipitously. The drug is then thought to be a poison.
- Pedestrian: With the further passage of time, the benefit/risk ratio of the drug is easier to assess andit is realized that the drug is neither a panacea nor a poison, but rather an average (or pedestrian)drug.
A drug said to have little or no toxicity when first introduced later turns out to be significantly toxic. Let us consider the reasons for this:
- The toxic reaction may be a rare event: The antibiotic, chloramphenicol, was used for several yearsbefore it was realized that in one in 50,000 patients, it could cause death of the cells in the bonemarrow leading to death of the patient. Clearly this rare adverse effect could not be picked up in theinitial testing of the drug. Chloramphenicol is now used much less than when it was first introducedinto therapeutics. It remains an important drug for those indications where the benefit exceeds the risk.
- The toxic reaction may only appear after the drug has been in prolonged use: When streptomycinwas first introduced for the treatment of tuberculosis, it was not realized that it could cause deafnessif used for an extensive period. Therefore, a long period of time had to pass before the toxic potentialof the drug was appreciated. When lincomycin was first introduced as an antibiotic, several yearspassed before its propensity to cause inflammation of the colon (colitis) accompanied by diarrhea,abdominal pain and blood in the stools, was appreciated
- Toxic effect not detectable in animals: Clearly, headache, insomnia, nausea and mental disturbanceswill not be readily picked up in animal testing
- Toxic effect may be unique to a particular period: Thalidomide produced adverse effects on the fetus. However, its adverse effects are confined to the pregnant patient. Until it was demonstrated thatthalidomide produced abnormal limb growth (phocomelia) in the fetus, it was not realized that it wasnecessary to test drugs in pregnant animals.
Acommon measure of toxicity of drugs in animals is the median lethal dose (LD50). This is the dose that islethal to 50% of the population of animals
For any given effect of a drug, for example, sedation, thedose which is effective in 50% of the population is called the ‘median effective dose’ (ED50).
Thetherapeutic index is equal to LD50/ED50. The higher this figure, the greater the safety of the drug and thewider the safety margin. Drugs such as anticoagulants, anticancer agents, and digoxin have a lowtherapeutic index and require particular caution in use. Drugs such as diazepam (Valium) have a highertherapeutic index than barbiturates and are safer.
Relation of Dose of Drug, Concentration in Blood, and Pharmacological Effect
When the same dose of a drug is given to different individuals, the concentration of the drugin the blood can vary by a factor of as much as 10 between different people. Why is this so? The reasonis that there are wide differences in the rate at which a drug is absorbed and eliminated in differentpatients. These differences are due to: (1) genetic factors, (2) environmental factors, (3) disease, and (4) presence of other drugs. It is becoming increasingly realized that if we are to use certain classes of drugs in the most effective way possible, we should be monitoring the blood concentration of these drugs inpatients. This applies particularly to drugs which have a low therapeutic index and where a change inblood concentration can be of major significance. It also applies where drugs are given for long periods of time; for example, the use of phenytoin (Dilantin) for the prevention of epileptic attacks. Another good example where measurement of the concentration in the blood will add greatly to the safety of druguse is in the use of lithium to treat manic-depressive illness. For optimal efficacy and safety, the lithium blood levels must be maintained within specific limits.
Enteral Routes of Administration
- When we say that a drug enters bythe enteral route, it means that the drug is placed directly into the gastrointestinal tract.
- Drug taken by mouth.
- Rectal administration.
- Under the tongue.
Parenteral Routes of Administration
- when we say that a drug is given by the parenteral route, it means it is given by a route such thatthe gastrointestinal tract is bypassed.
- The most common forms of parenteral administration of drugs are (1) intramuscular, (2) subcutaneous,and (3) intravenous.
- Less common methods are (4) by inhalation; and (5) into the spinal canal. Finally,chemicals may penetrate the skin and get into the circulation.
The hypodermic syringe
The hypodermic syringe was invented in 1853 in order to inject morphine subcutaneously to relievethe pain of neuritis (inflammation of the nerve). It was introduced by a Scottish physician, AlexanderWood.
Intravenous Administration Advantages:
The drug is placed directly into the circulation with a minimum of delay. The rate of drug infusionc an be held constant for long periods using a constant infusion apparatus. Some drugs such as nitrogen mustard, which are used in certain types of cancer, are intolerably painful when given by subcutaneous or intramuscular routes. For this reason, giving the drugs by the intravenous route is advantageous.
Intravenous Administration Disadvantages:
- A drug injected into a vein cannot be retrieved. When a drug is given by mouth, one can alwaysremove a part of the drug by causing the patient to vomit.
- If the drug is given too rapidly into a vein, it can lead to disaster. If a drug is injected over a period of one second, a very high concentration of the drug reaches the heart. This may lead to a disorder in the rhythm of the heart and possibly to death. Injections by the intravenous route are usually done slowly.
- There is an ever present danger of infection if a sterile technique is not used. This is particularly prevalent in narcotic-dependent individuals who fail to take sterile precautions.This is a particular problem with regard to the spread of AIDS. In third world countries, there may bea shortage of sterilized needles and the traveller is advised to carry supplies of his/her own whenspending time in such areas of the world. Spread of infection has also been noted in weight liftingclubs where steroids have been injected with shared needles. Moreover, water has to be speciallypurified before drugs can be dissolved in it. If the water is not purified, the pyrogens which arepresent in water will provoke fever in the patient.
After injection of a drug into skeletal muscle, the drugs are generally rapidly absorbed into the blood supply of the muscle and will usually act after a period of 10 to 30 minutes. Sometimes,drugs are deliberately injected into skeletal muscle in a form in which they can only slowly dissolve and pass into the blood stream. The reason for this is that it is sometimes desirable to have a drug act over a period of many hours. Several penicillin preparations are available of this type. They can be injected into a muscle and then be absorbed very slowly into the blood so that the patient receives protection from the penicillin for a period of days to weeks.Hormones and antipsychotic drugs can also be given in this manner.
The absorption of drugs into the blood following a subcutaneous injection is slightly slower than that following intramuscular injection. The reason for this is that the blood flow is some what poorer in the subcutaneous tissues than in skeletal muscle.
Absorption Through Skin
several poisonous materials can be readily absorbed through the skin and numerous fatalities have occurred by failure of farmers and house holders to realize this. Thus, people have been poisoned by the insecticides, parathion and malathion, and by nicotine which is also frequently used as an insecticide. Parathion and malathion are inhibitors of the enzyme, acetylcholinesterase, and this leads to the build-upat nerve terminals of the neurotransmitter, acetylcholine. Antidotes are atropine to block acetylcholinereceptors, and pralidoxime to regenerate the enzyme, acetylcholinesterase. Chemicals related toparathion and malathion are manufactured for potential use as nerve gases in gas warfare. Atropine andpralidoxime are also intended for use as antidotes should nerve gases be used in gas warfare. In the Gulfand Iraq wars, these antidotes were distributed to soldiers.