81. Cytotoxic and embryotoxic effects of drugs. Drug allergy

Last updated on December 5, 2019 at 20:08

Harmful effects of drugs on the person

Drugs rarely have their intended therapeutic effect without causing some harmful effects too, most often mild effects but sometimes severe.

What are the “side effects” of a drug? Can what qualifies as side effects of a drug change? The truth is that we decide which effects a drug has are its “main” effects and which are its “side” effects. When minoxidil was used as an antihypertensive the increased hair growth was called a side effect. Nowadays minoxidil is used exclusively for its hair growth effect. Sildenafil was also tried as an antihypertensive. During the trials its erection-stimulating effect was called a side effect. Nowadays this is the main effect of sildenafil.

The following are examples of side effects:

  • Dryness of mouth with atropine
  • Sedation with first-generation H1 antagonists
  • Constipation with anti-tussives
  • GI symptoms with virtually all drugs

An adverse drug reaction (ADR) or adverse effect is an unwanted, possibly harm-causing reaction which occurs when talking a drug normally. The terms “side effect”, “adverse effects” and “toxic effects” are often used interchangeably, but the latter two often refer to more severe effects than the former.

An adverse drug reaction can be related to its main pharmacological effect (its known mechanism of action), or it can be unrelated to it.

Adverse effects related to the drug’s main pharmacological effect:

The following examples show adverse effects which are related to the main pharmacological effect:

  • Postural hypotension with α1 antagonists
  • Bleeding with anticoagulants and antiplatelets
  • Sedation with anxiolytics

These effects are often dose-dependent and can therefore be prevented or mitigated by decreasing the dose. They’re often also reversible.

Adverse effects not related to the drug’s main pharmacological effect:

The following examples show some adverse effects which are not related to the therapeutic effect:

  • Predictable
    • Hepatotoxicity with paracetamol
  • Unpredictable, idiosyncratic
    • Aplastic anaemia from chloramphenicol
    • Anaphylaxis with penicillin
    • Halothane hepatitis

When the adverse effect of a drug is unrelated to its main pharmacological effect they’re often caused by reactive metabolites or immunological reactions. Many of these reactions are unpredictable and not dose-dependent, making them idiosyncratic or type B (B for bizarre) reactions, like halothane hepatitis or chloramphenicol-induced aplastic anaemia. These effects are often irreversible.

Overdose:

Overdosage can be due to increased consumption of the drug or due to decreased excretion, like due to kidney or liver failure. The following are examples of toxic effects of overdose:

  • Hepatotoxicity with paracetamol
  • Coma with barbiturates
  • Heart block with digoxin
  • Bleeding with anticoagulants and antiplatelets

Adverse effects due to reactive metabolites:

Some drugs are metabolized into reactive metabolites. These reactive metabolites can then directly cause cellular damage by different mechanisms. The most common example of this is paracetamol, which is metabolized into NAPQI.

Reactive metabolites often produce reactive oxygen species, which will mediate the cytotoxicity. Reactive oxygen species can oxidize DNA, RNA, lipids and proteins, eventually causing damage or death to the cell. They can also bind to glutathione, thereby reducing the pool of GSH, which reduces the cell’s defence against oxidative stress.

Hepatotoxicity:

Many drugs can cause hepatotoxicity. These effects can range from clinically manifest liver damage (hepatitis) to liver damage only visible on lab tests. Some important examples are:

  • Paracetamol
  • Isoniazid
  • Halothane
  • Chlorpromazine

Fun fact: the drug which causes the most cases of drug-induced hepatotoxicity is amoxicillin-clavulanate.

The hepatotoxicity of halothane is immune-mediated and described later in the topic.

Nephrotoxicity:

Many drugs are nephrotoxic. Different drugs cause different forms of kidney injury. Here are some important examples:

  • Acute renal failure
    • NSAIDs
    • ACE inhibitors
  • Interstitial nephritis
    • NSAIDs
  • Chronic kidney disease
    • Aminoglycosides
    • Antivirals
    • Lithium
  • Analgesic nephropathy
    • Aspirin
    • NSAIDs
    • Paracetamol
  • Variable
    • Cyclosporin
    • Amphotericin B
    • Cisplatin
    • Beta-lactams

NSAIDs and aspirin inhibit COX, thereby reducing the production of prostaglandins which normally cause vasodilation. This causes the blood flow to the kidney to decrease, which primarily affects the most ischaemia-sensitive parts of the kidney, the renal papillae.

Angiotensin II is nephroprotective as it keeps the GFR at a normal level despite low renal blood flow. ACE inhibitors reduce the amount of nephroprotective angiotensin II and can cause acute renal failure.

Mutagenesis and carcinogenesis:

Mutagenesis refers to the induction of mutations in DNA by drugs. The term is closely related to carcinogenesis, as these mutations can cause cancer. Chemotherapeutical agents can cause cancer if the cell doesn’t die from the mutations induced.

Drugs which are carcinogenic can be genotoxic or epigenetic carcinogens. Genotoxic drugs cause mutations directly of after being converted to reactive metabolites. Epigenetic carcinogens increase the possibility that a mutagen will cause cancer but are themselves non-mutagenic.

The so-called Ames test can be used to test whether a chemical is mutagenic. Salmonella require histidine to live, which it normally synthesizes itself. However, the type of Salmonella used in the Ames test has been genetically modified so that it cannot produce histidine anymore.

The chemical to be tested is then introduced to the bacteria. If the bacteria eventually start growing, we know that the chemical has caused mutations in the histidine-producing genes in the Salmonella which restored its ability to produce histidine, and so we can conclude that the chemical is a mutagen. If it is not a mutagen the Salmonella will never grow.

Not all chemicals are mutagens by itself; some chemicals only produce mutagenic metabolites. To test for this scenario rat liver enzymes are introduced together with the chemical. The liver enzymes will metabolize the chemical. This is how we can test whether the chemical’s metabolites are mutagenic as well.

Harmful effects of the drug on the embryo (teratogenesis)

Teratogenesis refers to the induction of gross structural malformations in the foetus. With regards to adverse drug effects on foetuses we can divide the embryonic development into three phases:

Timeframe (days after implantation)

Phase Occurrences Affected by
0 – 16 Blastocyst formation The blastocyst is formed. Lots of cell division occurs.

Cytotoxic drugs, alcohol

17 – 60

Organogenesis Structural organization of organs Teratogens
60 – birth Histogenesis and functional maturation Maturation and differentiation of cells

Alcohol, nicotine, steroids, ACE inhibitors, …

During the first phase drugs can kill the embryo by inhibiting cell division. However, if the embryo survives the subsequent development doesn’t seem to be compromised. The only exception is alcohol, which can permanently affect development even at this stage.

During the second phase drugs can cause gross malformations. The specific malformation depends on exactly when the exposure to the teratogen occurs, as the structural organization of the embryo occurs in a well-defined sequence. Technically, teratogenesis refers only to those malformations which occur during the second phase.

During the last phase drugs can’t cause gross malformations but they can still severely impact later growth and development. The foetus is especially sensitive to changes in the hormonal environment.

Mechanisms of teratogenesis:

There is large overlap of mutagenicity and teratogenicity, but damage to the DNA isn’t the only mechanism of teratogenicity. The control of the morphogenesis is poorly understood but it’s clear that many drugs can interfere with it.

Drugs which inhibit folate synthesis like methotrexate and phenytoin are teratogenic, and their teratogenicity can be reduced by folate supplementation. Retinoids are potent teratogens. Thalidomide inhibits angiogenesis.

Important teratogens:

Drug

Mechanism Deformity
Thalidomide Inhibition of angiogenesis

Absence of development of the long bones of the extremities (seal arms)

Alkylating agents, antimetabolites, folate antagonists

Mutagenicity Abortion, other malformations
Retinoids Altered epidermal differentiation

Skeletal deformities

Heavy metals

Forming covalent bonds with enzymes Impaired brain development
Phenytoin ?

Cleft palate

Valproate

? Neural tube defects
Carbamazepine ?

Spina bifida, hypospadias

Warfarin

? Saddle nose, retarded growth, CNS abnormalities
Ethanol ?

Foetal alcohol syndrome

Antibiotics and pregnancy:

The following antibiotics are safe during pregnancy:

  • Penicillins
  • Cephalosporins
  • Clindamycin
  • Erythromycin
  • Metronidazole
  • Fluoroquinolones

Penicillins are always the first choice during pregnancy. Some antibiotics are safe in certain trimesters only.

The following antibiotics are contraindicated during pregnancy:

  • Tetracyclines
  • Aminoglycosides
  • Chloramphenicol
  • Sulphonamides
  • Trimethoprim
  • Linezolid
Drug allergies and other immune-mediated adverse drug reactions

Drug allergies are common adverse effects of drugs. Most drug allergies cause harmless skin rashes, but sometimes they can cause severe reactions like anaphylaxis, haemolysis and bone marrow depression.

Drug allergies follow usually follow certain main rules:

  • They occur a few days after exposure to the drug, or only after repeated exposure
  • Allergic reaction may occur in small doses, often too small to elicit any pharmacodynamic effect
  • The result is a clinical syndrome which are associated with type I, II, III or IV hypersensitivity reactions
  • The allergic reaction is unrelated to the main pharmacological effect of the drug

Type I hypersensitivity reactions:

These reactions can cause anything from urticaria to hypotension and anaphylaxis. The treatment of this is 0,5 mg adrenaline IM and IV steroids. The following drugs are the most common causes of drug-related type I hypersensitivity:

  • Penicillin
  • Streptokinase
  • Heparin
  • Radiological contrast material
  • Vaccines

Type II hypersensitivity reactions:

A type II hypersensitivity reaction is one where antibodies are “tricked” into binding to antigens on the host cells. When talking about drugs this often refers to when drugs act as haptens, meaning that they become immunogenic when bound to endogenous proteins. The target cells are often RBCs, causing haemolysis, or cells of the bone marrow, which causes cytopaenias. The following drugs are the most common causes of drug-related type II hypersensitivity, categorized according to what condition they cause:

  • Haemolytic anaemia
    • Sulphonamides
    • Methyldopa
    • Dapsone
    • Ribavirin
  • Agranulocytosis
    • NSAIDs
      • Especially phenylbutazone
    • Thioamides
    • Clozapine
    • Sulphonamides
  • Thrombocytopaenia
    • Quinine
    • Heparin
    • Thiazides
  • Aplastic anaemia
    • Chloramphenicol
  • Hepatitis
    • Halothane

Halothane hepatitis occurs as a reactive metabolite of halothane acts as a hapten, which binds to proteins on hepatocytes. These proteins will then become immunogenic, causing antibodies to bind to these cells and kill them.

Type III hypersensitivity reactions:

Type III HS reactions are caused by the formation of antibody-antigen complexes which deposit in organs, causing damage in the organs. These immune complexes deposit in the kidneys, skin, lungs, joints and CNS. The result can be drug-induced systemic lupus erythematosus. The following drugs cause these reactions, although none of them are on the market anymore:

  • Hydralazine
  • Procainamide

Type IV hypersensitivity reactions:

The IV hypersensitivity reactions can cause anything from simple dermatitis to potentially fatal conditions like Stevens-Johnsons syndrome and toxic epidermal necrolysis. The latter two reactions are most commonly caused by:

  • Allopurinol
  • Antiepileptics
    • Carbamazepine
    • Lamotrigine
    • Phenytoin
  • Sulphonamides

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82. Pharmacogenetics, pharmacogenomics. Effects of age, diet and disease on drug action

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