Human Pharmacology I: Adverse Drug Reactions

And now we're onto our last topic! This is a fairly relatable topic- the possibility of adverse drug interactions. Nasty stuff, but necessary to know.

Be able to provide a working definition of adverse drug reactions (ADRs) and demonstrate basic appreciation of the contribution ADRs make to the burden of human disease

Adverse drug reactions are nasty, unwanted reactions to drugs. In contrast to toxicity responses, which occur when too much of a drug is taken, adverse drug reactions occur when the normal dose of a drug is taken. Of course, this is bad for two reasons: firstly, the patient (who is probably already sick to be taking a drug) is made even sicker by the adverse reaction, and secondly it might make it harder to treat the patient's original condition as it limits the number of drugs that you can use.

Show awareness of the main categories of patients that are at most risk of ADRs, including the elderly, children and pregnant women

As the heading says, the elderly, children and pregnant women are most at risk of adverse drug reactions. Let's have a brief look at why.

• Elderly: More likely to receive multiple drugs for various chronic conditions. Also there are other physical changes that might affect pharmacokinetics, including reduced drug metabolism, reduced drug protein binding and reduced renal excretion.
• Children: Different capacities for renal excretion and hepatic metabolism as compared to adults. There is also limited information on the safety of many drugs in children.
• Pregnant women: Altered activity of drug metabolising enzymes. A whole bunch of physiologic changes, such as increased fat and decreased protein binding, which might affect pharmacokinetic parameters such as volume of distribution. There is also a risk of teratogenicity with regards to the woman's baby.

Identify basic features of Type A adverse drug reactions, identifying insulin hypoglycaemia as a classic example of these syndromes

The A in "Type A" stands for "augmented." Basically, Type A reactions are simply exaggerated effects of what the drug is normally meant to do. Hence, these are kind of predictable and can usually be worked around by switching to a different drug or different dosing regimen.

An example of a Type A drug reaction is insulin hypoglycaemia. Insulin is a hormone that lowers glucose levels in the blood. As you're likely well aware, patients with diabetes have to take insulin because their bodies either don't produce it or don't respond to it, leaving them at risk for hyperglycaemia. If they take too much insulin though, their glucose levels can drop considerably, leaving them hypoglycaemic, which is also pretty undesirable.

Identify 2 subcategories of immune-mediated Type B ADRs, namely immediate (IgE-mediated) and non-immediate (T-cell mediated) responses

Type B drug reactions are "bizarre" drug reactions. These tend to be unpredictable, though there may be certain genetic sensitivities to drugs (e.g. differences in HLA alleles). Allergic reactions to drugs are also classified as Type B drug reactions. Usually these involve some sort of priming, or prior exposure to the drug.

Type B reactions can also be further classified into "immediate" and "non-immediate" reactions. Let's take a look at them one at a time.

Immediate drug reactions occur within one hour of exposure. These tend to be mediated by specific IgE antibodies. IgE is produced by antigen-specific B-lymphocytes. It can then bind to Fc receptors on mast cells and basophils, which are both involved in mediating immune responses (or at least that's my basic understanding). Initially, this occurs during a period of sensitisation in which no symptoms occur. Later on, when the patient is re-exposed to the drug, IgE cross-links, which stimulates the release of histamine and a bunch of other stuff involved in allergic reactions. (I've never done any immunology, so I can't really go into more detail.)

Non-immediate drug reactions occur over an hour after the time of exposure (though within a few days). These tend to be mediated by T-cells. Firstly, dendritic cells process the drug antigen before internalising it and sending it to lymph nodes. Here, naïve T-cells get excited, and antigen-specific T-cells eventually begin making their way around the body. (Once again, this occurs during a period of sensitisation where no symptoms occur.) Upon re-exposure, those primed T-cells go nuts and the patient gets sick.

The last two paragraphs were really just skimming the surface of what happens. Once again, I've never done immunology, so I can't go into much more detail. Maybe we'll learn about this next semester!