Adverse drug reactions

Adverse drug reactions

A drug’s desired effect is called the expected therapeutic response. An adverse drug reaction (also called a side effect or adverse effect), on the other hand, is a harmful, undesirable response. Adverse drug reactions can range from mild ones that disappear when the drug is discontinued to debilitating diseases that become chronic. Adverse reactions can appear shortly after starting a new medication but may become less severe with time.

Dosage dilemma

Adverse drug reactions can be classified as dose-related or patient sensitivity’related. Most adverse drug reactions result from the known pharmacologic effects of a drug and are typically dose-related. These types of reactions can be predicted in most cases.

Dose-related reactions include:

• secondary effects
• hypersusceptibility
• overdose
• iatrogenic effects.

Extra effects

A drug typically produces not only a major therapeutic effect but also additional, secondary effects that can be harmful or beneficial. For example, morphine used for pain control can lead to two undesirable secondary effects: constipation and respiratory depression. Diphenhydramine used as an antihistamine produces sedation as a secondary effect and is sometimes used as a sleep aid

Enhanced action

A patient can be hypersusceptible to the pharmacologic actions of a drug. Such a patient experiences an excessive therapeutic response or secondary effects even when given the usual therapeutic dose.

Hypersusceptibility typically results from altered pharmacokinetics (absorption, metabolism, and excretion), which leads to higher-than-expected blood concentration levels. Increased receptor sensitivity also can increase the patient’s response to therapeutic or adverse effects.

Oh no’overdose!

A toxic drug reaction can occur when an excessive dose is taken, either intentionally or by accident. The result is an exaggerated response to the drug that can lead to transient changes or more serious reactions, such as respiratory depression, cardiovascular collapse, and even death. To avoid toxic reactions, chronically ill or elderly patients often receive lower drug doses.

Iatrogenic issues

Some adverse drug reactions, known as iatrogenic effects, can mimic pathologic disorders. For example, such drugs as antineoplastics, aspirin, corticosteroids, and indomethacin commonly cause GI irritation and bleeding. Other examples of iatrogenic effects include induced asthma with propranolol, induced nephritis with methicillin, and induced deafness with gentamicin.

You’re so sensitive

Patient sensitivity’related adverse reactions aren’t as common as dose-related reactions. Sensitivity-related reactions result from a patient’s unusual and extreme sensitivity to a drug. These adverse reactions arise from a unique tissue response rather than from an exaggerated pharmacologic action. Extreme patient sensitivity can occur as a drug allergy or an idiosyncratic response.

Friend or foe?

A drug allergy occurs when a patient’s immune system identifies a drug, a drug metabolite, or a drug contaminant as a dangerous foreign substance that must be neutralized or destroyed. Previous exposure to the drug or to one with similar chemical characteristics sensitizes the patient’s immune system, and subsequent exposure causes an allergic reaction (hypersensitivity).

An allergic reaction not only directly injures cells and tissues but also produces broader systemic damage by initiating cellular release of vasoactive and inflammatory substances.

The allergic reaction can vary in intensity from an immediate, life-threatening anaphylactic reaction with circulatory collapse and swelling of the larynx and bronchioles to a mild reaction with a rash and itching.

Idiosyncratic response

Some sensitivity-related adverse reactions don’t result from pharmacologic properties of a drug or from an allergy but are specific to the individual patient. These are called idiosyncratic responses. Some idiosyncratic responses have a genetic cause.

Drug interactions

Drug interactions

Drug interactions can occur between drugs or between drugs and foods. They can interfere with the results of a laboratory test or produce physical or chemical incompatibilities. The more drugs a patient receives, the greater the chances that a drug interaction will occur.

Potential drug interactions include:

• additive effects
• potentiation
• antagonistic effects
• decreased or increased absorption
• decreased or increased metabolism and excretion.

Adding it all up

Additive effects can occur when two drugs with similar actions are administered to a patient. The effects are equivalent to the sum of either drug’s effects if it were administered alone in higher doses.

Giving two drugs together, such as two analgesics (pain relievers), has several potential advantages: lower doses of each drug, decreased probability of adverse reactions, and greater pain control than from one drug given alone (most likely because of different mechanisms of action). There’s a decreased risk of adverse effects when giving two drugs for the same condition because the patient is given lower doses of each drug’the higher the dose, the greater the risk of adverse effects.

A synergistic situation

A synergistic effect, also called potentiation, occurs when two drugs that produce the same effect are given together and one drug potentiates (enhances the effect of) the other drug. This produces greater effects than when each drug is taken alone.

Fighting it out

An antagonistic effect occurs when the combined response of two drugs is less than the response produced by either drug alone.

An absorbing problem

Two drugs given together can change the absorption of one or both of the drugs:

• Drugs that change the acidity of the stomach can affect the ability of another drug to dissolve in the stomach.
• Some drugs can interact and form an insoluble compound that can’t be absorbed.

Sometimes, an absorption-related drug interaction can be avoided by administering the drugs at least 2 hours apart.

Bound and determined

After a drug is absorbed, the blood distributes it throughout the body as a free drug or one that’s bound to plasma protein.

When two drugs are given together, they can compete for protein-binding sites, leading to an increase in the effects of one drug as that drug is displaced from the protein and becomes a free, unbound drug.

Toxic waste

Toxic drug levels can occur when a drug’s metabolism and excretion are inhibited by another drug. Some drug interactions affect excretion only.

Back to the lab

Drug interactions can also alter laboratory tests and can produce changes seen on a patient’s electrocardiogram.

Pharmacotherapeutics

Pharmacotherapeutics is the use of drugs to treat disease. When choosing a drug to treat a particular condition, health care providers consider not only the drug’s effectiveness but also other factors such as the type of therapy the patient will receive.

Not all therapy is the same

The type of therapy a patient receives depends on the severity, urgency, and prognosis of the patient’s condition and can include:

• acute therapy, if the patient is critically ill and requires acute intensive therapy
• empiric therapy, based on practical experience rather than on pure scientific data
• maintenance therapy, for patients with chronic conditions that don’t resolve
• • supplemental or replacement therapy, to replenish or substitute for missing substances in the body
  • supportive therapy, which doesn’t treat the cause of the disease but maintains other threatened body systems until the patient’s condition resolves
  • palliative therapy, used for end-stage or terminal diseases to make the patient as comfortable as possible.
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  I can only be myself

  A patient’s overall health as well as other individual factors can alter that patient’s response to a drug. Coinciding medical conditions and personal lifestyle characteristics must be considered when selecting drug therapy.
  
  Decreased response…

  In addition, it’s important to remember that certain drugs have a tendency to create drug tolerance and drug dependence in patients. Drug tolerance occurs when a patient develops a decreased response to a drug over time. The patient then requires larger doses to produce the same response.
  …and increased desire

  Tolerance differs from drug dependence, in which a patient displays a physical or psychological need for the drug. Physical dependence produces withdrawal symptoms when the drug is stopped, whereas psychological dependence is based on a desire to continue taking the drug to relieve tension and avoid discomfort.

Pharmacodynamics

Pharmacodynamics

Pharmacodynamics is the study of the drug mechanisms that produce biochemical or physiologic changes in the body. The interaction at the cellular level between a drug and cellular components, such as the complex proteins that make up the cell membrane, enzymes, or target receptors, represents drug action. The response resulting from this drug action is the drug effect

It’s the cell that matters

A drug can modify cell function or rate of function, but it can’t impart a new function to a cell or to target tissue. Therefore, the drug effect depends on what the cell is capable of accomplishing.

A drug can alter the target cell’s function by:

• modifying the cell’s physical or chemical environment
• interacting with a receptor (a specialized location on a cell membrane or inside a cell).

Agonist drugs

Many drugs work by stimulating or blocking drug receptors. A drug attracted to a receptor displays an affinity for that receptor. When a drug displays an affinity for a receptor and stimulates it, the drug acts as an agonist. An agonist binds to the receptor and produces a response. This ability to initiate a response after binding with the receptor is referred to as intrinsic activity.

Antagonist drugs

If a drug has an affinity for a receptor but displays little or no intrinsic activity, it’s called an antagonist. An antagonist prevents a response from occurring.

Reversible or irreversible

Antagonists can be competitive or noncompetitive.

• A competitive antagonist competes with the agonist for receptor sites. Because this type of antagonist binds reversibly to the receptor site, administering larger doses of an agonist can overcome the antagonist’s effects.

• A noncompetitive antagonist binds to receptor sites and blocks the effects of the agonist. Administering larger doses of the agonist can’t reverse the antagonist’s action.

Regarding receptors

If a drug acts on a variety of receptors, it’s said to be nonselective and can cause multiple and widespread effects. In addition, some receptors are classified further by their specific effects. For example, beta receptors typically produce increased heart rate and bronchial relaxation as well as other systemic effects.

Beta receptors, however, can be further divided into beta₁ receptors (which act primarily on the heart) and beta₂ receptors (which act primarily on smooth muscles and gland cells).

Potent power

Drug potency refers to the relative amount of a drug required to produce a desired response. Drug potency is also used to compare two drugs. If drug X produces the same response as drug Y but at a lower dose, then drug X is more potent than drug Y.

As its name implies, a dose-response curve is used to graphically represent the relationship between the dose of a drug and the response it produces.

Maximum effect

On the dose-response curve, a low dose usually corresponds to a low response. At a low dose, a dosage increase produces only a slight increase in response. With further dosage increases, the drug response rises markedly. After a certain point, however, an increase in dose yields little or no increase in response. At this point, the drug is said to have reached maximum effectiveness.

Margin of safety

Most drugs produce multiple effects. The relationship between a drug’s desired therapeutic effects and its adverse effects is called the drug’s therapeutic index. It’s also referred to as its margin of safety.

The therapeutic index usually measures the difference between:

• an effective dose for 50% of the patients treated
• the minimal dose at which adverse reactions occur

Narrow index = potential danger

Drugs with a narrow, or low, therapeutic index have a narrow margin of safety. This means that there’s a narrow range of safety between an effective dose and a lethal one. On the other hand, a drug with a high therapeutic index has a wide margin of safety and poses less risk of toxic effects.

Half-life

Half-life = half the drug

The half-life of a drug is the time it takes for one-half of the drug to be eliminated by the body. Factors that affect a drug’s half-life include its rate of absorption, metabolism, and excretion. Knowing how long a drug remains in the body helps determine how frequently it should be administered.

A drug that’s given only once is eliminated from the body almost completely after four or five half-lives. A drug that’s administered at regular intervals, however, reaches a steady concentration (or steady state) after about four or five half-lives. Steady state occurs when the rate of drug administration equals the rate of drug excretion.

Onseet of Action

Onset, peak, and duration

In addition to absorption, distribution, metabolism, and excretion, three other factors play important roles in a drug’s pharmacokinetics:

• onset of action
• peak concentration
• duration of action.

Lights, camera… action!

The onset of action refers to the time interval from when the drug is administered to when its therapeutic effect actually begins. Rate of onset varies depending on the route of administration and other pharmacokinetic properties.

Peak performance

As the body absorbs more drug, blood concentration levels rise. The peak concentration level is reached when the absorption rate equals the elimination rate. However, the time of peak concentration isn’t always the time of peak response.

Sticking around

The duration of action is the length of time the drug produces its therapeutic effect.

Excretion

Excretion

Drug excretion refers to the elimination of drugs from the body. Most drugs are excreted by the kidneys and leave the body through urine. Drugs can also be excreted through the lungs, exocrine (sweat, salivary, or mammary) glands, skin, and intestinal tract.