question: Why do our bodies build up a tolerance to some medications but not others?
comment: It's kinda hard without specifics, but it has to do with upregulation of receptors a lot of the time. Imagine you're delivering goods to a factory. The first delivery, they send two guys to unload a whole truck, and it ends up taking hours. The factory learns their lesson and sends two extra guys the next time, so it takes half the time. You keep making the deliveries until the factory sends out so many guys that a few of them are just standing around while everyone else grabs one box each. The factory is your cell (basic building block of you) and the workers are receptors (the bits on the cell that uptake/respond to meds). Some drugs target cells in a way that doesn't cause them to send out more receptors, while others can reach saturation/oversaturation quickly so your cell doesn't respond as strongly/for as long. Edit: this model might be a little backwards for the drugs people are picturing. The opposite version of this is if the boxes are heavy and the workers start slacking off (downregulation) and don't engage as much. After revising a few things, the model I suggested originally is one of up-regulation and doesn't quite fit the question. Hopefully it helps some of you understand/visualise cell receptors a little better, and also hammer home that this is a complex subject.
passages: One may also develop drug tolerance to side effects, in which case tolerance is a desirable characteristic. A medical intervention that has an objective to increase tolerance (e.g., allergen immunotherapy, in which one is exposed to larger and larger amounts of allergen to decrease one's allergic reactions) is called drug desensitization.
   Pharmacokinetic tolerance (dispositional tolerance) occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as ethanol.
   Pharmacodynamic tolerance begins when the cellular response to a substance is reduced with repeated use. A common cause of pharmacodynamic tolerance is high concentrations of a substance constantly binding with the receptor, desensitizing it through constant interaction. Other possibilities include a reduction in receptor density (usually associated with receptor agonists), or other mechanisms leading to changes in action potential firing rate. Pharmacodynamic tolerance to a receptor antagonist involves the reverse, i.e., increased receptor firing rate, an increase in receptor density, or other mechanisms.
   This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass first-pass metabolism. Enzyme induction is partly responsible for the phenomenon of tolerance, in which repeated use of a drug leads to a reduction of the drug’s effect. However, it is only one of several mechanisms leading to tolerance.
  
  Section::::Behavioral tolerance.
   While most occurrences of pharmacodynamic tolerance occur after sustained exposure to a drug, instances of acute or instant tolerance (tachyphylaxis) can occur.
  
  Section::::Pharmacokinetic (metabolic) tolerance.
  
  Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs (ADME). All psychoactive drugs are first absorbed into the bloodstream, carried in the blood to various parts of the body including the site of action (distribution), broken down in some fashion (metabolism), and ultimately removed from the body (excretion). All of these factors are very important determinants of crucial pharmacological properties of a drug, including its potency, side effects, and duration of action.
   Drug tolerance should not be confused with drug tolerability, which refers to the degree to which overt adverse effects of a drug can be tolerated by a patient.
  
  Section::::Tachyphylaxis.
  
  Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.
  
  Section::::Pharmacodynamic tolerance.
   The opposite concept to drug tolerance is drug reverse tolerance (or drug sensitization), in which case the subject's reaction or effect will increase following its repeated use. The two notions are not incompatible and tolerance may sometimes lead to reverse tolerance. For example, heavy drinkers initially develop tolerance to alcohol (requiring them to drink larger amounts to achieve a similar effect) but excessive drinking can cause liver damage, which then puts them at risk of intoxication when drinking even very small amounts of alcohol.
   Drug tolerance
  
  Drug tolerance is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction. The process of tolerance development is reversible (e.g., through a drug holiday) and can involve both physiological factors and psychological factors.
   There are a variety of factors that can affect the MTC, which is often the subject of clinical pharmacokinetics. Variations in MTC can occur at any point in the ADME (absorption, distribution, metabolism, and excretion) process. For example, a patient could possess a genetic defect in a drug metabolizing enzyme in the cytochrome P450 superfamily. While most individuals will possess the effective metabolizing machinery, a person with a defect will have a difficult time trying to clear the drug from their system. Thus, the drug will accumulate within the blood to higher-than-expected concentrations, reaching a MTC at a dose that would otherwise be considered normal for the average person. In other words, in a person that is intolerant to a medication, it is possible for a dose of 10 mg to "feel" like a dose of 100 mg, resulting in an overdose—a "normal" dose can be a "toxic" dose in these individuals, leading to clinically significant effects.
   In humans, the gene ABCB1 encodes MDR1(p-glycoprotein) which is a key transporter of medications on the cellular level. If MDR1 is overexpressed, drug resistance increases. Therefore, ABCB1 levels can be monitored. In patients with high levels of ABCB1 expression, the use of secondary treatments, like metformin, have been used in conjunction with the primary drug treatment with some success.
   There is also an aspect of drug intolerance that is subjective. Just as different people have different pain tolerances, so too do people have different tolerances for dealing with the adverse effects from their medications. For example, while opioid-induced constipation may be tolerable to some individuals, other people may stop taking an opioid due to the unpleasantness of the constipation even if it brings them significant pain relief.
  
  Section::::Examples of drug sensitivity.
  
  BULLET::::- Tinnitus after a normal dose of aspirin
  
  BULLET::::- Aspirin-exacerbated respiratory disease
  
  BULLET::::- Liver failure (possibly also kidney failure) after a normal dose of acetaminophen
   Drug, toxin, or chemical resistance is a consequence of evolution and is a response to pressures imposed on any living organism. Individual organisms vary in their sensitivity to the drug used and some with greater fitness may be capable of surviving drug treatment. Drug-resistant traits are accordingly inherited by subsequent offspring, resulting in a population that is more drug-resistant. Unless the drug used makes sexual reproduction or cell-division or horizontal gene transfer impossible in the entire target population, resistance to the drug will inevitably follow. This can be seen in cancerous tumors where some cells may develop resistance to the drugs used in chemotherapy. Chemotherapy causes fibroblasts near tumors to produce large amounts of the protein WNT16B. This protein stimulates the growth of cancer cells which are drug-resistant. MicroRNAs have also been shown to affect acquired drug resistance in cancer cells and this can be used for therapeutic purposes. Malaria in 2012 has become a resurgent threat in South East Asia and sub-Saharan Africa, and drug-resistant strains of "Plasmodium falciparum" are posing massive problems for health authorities. Leprosy has shown an increasing resistance to dapsone.
   A drug allergy is different from an intolerance. A drug intolerance, which is often a milder, non-immune-mediated reaction, does not depend on prior exposure. 
  
  Section::::Signs and symptoms.
  
  Symptoms of drug hypersensitivity reactions can be similar to non-allergic adverse effects. Common symptoms include:
  
  BULLET::::- Hives
  
  BULLET::::- Itching
  
  BULLET::::- Rash
  
  BULLET::::- Fever
  
  BULLET::::- Facial swelling
  
  BULLET::::- Shortness of breath due to the short-term constriction of lung airways or longer-term damage to lung tissue
  
  BULLET::::- Anaphylaxis, a life-threatening drug reaction (produces most of these symptoms as well as low blood pressure)
   Risk factors for drug allergies can be attributed to the drug itself or the characteristics of the patient. Drug-specific risk factors include the dose, route of administration, duration of treatment, repetitive exposure to the drug, and concurrent illnesses. Host risk factors include age, sex, atopy, specific genetic polymorphisms, and inherent predisposition to react to multiple unrelated drugs (multiple drug allergy syndrome).
  
  A drug allergy is more likely to develop with large doses and extended exposure.
   Drugs in systemic circulation have a certain concentration in the blood, which serves as a surrogate marker for how much drug will be delivered throughout the body (how much drug the rest of the body will "see"). There exists a minimum concentration of drug within the blood that will give rise to the intended therapeutic effect (minimum effective concentration, MEC), as well as a minimum concentration of drug that will give rise to an unintended adverse drug event (minimum toxic concentration, MTC). The difference between these two values is generally referred to as the therapeutic window. Different drugs have different therapeutic windows, and different people will have different MECs and MTCs for a given drug. If someone has a very low MTC for a drug, they are likely to experience adverse effects at drug concentrations lower than what it would take to produce the same adverse effects in the general populace; thus, the individual will experience significant toxicity at a dose that is otherwise considered "normal" for the average person. This individual will be considered "intolerant" to that drug.
   BULLET::::- Enzymatic saturation: When the dose of a drug whose elimination depends on biotransformation is increased above a certain threshold the enzymes responsible for its metabolism become saturated. The drug's plasma concentration will then increase disproportionately and its elimination will no longer be constant.
   Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross-tolerance has been observed with pharmaceutical drugs such as anti-anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never even used before.
   In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults.
  
  Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs.
  
  With N-acetyltransferases (involved in "Phase II" reactions), individual variation creates a group of people who acetylate slowly ("slow acetylators") and those who acetylate quickly, split roughly 50:50 in the population of Canada.
  
  This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity.
   Section::::Relevance to chronic infections.
   BULLET::::- Induction or enzymatic inhibition: Some drugs have the capacity to inhibit or stimulate their own metabolism, in negative or positive feedback reactions. As occurs with fluvoxamine, fluoxetine and phenytoin. As larger doses of these pharmaceuticals are administered the plasma concentrations of the unmetabolized drug increases and the elimination half-life increases. It is therefore necessary to adjust the dose or other treatment parameters when a high dosage is required.
  
  BULLET::::- The kidneys can also establish active elimination mechanisms for some drugs, independent of plasma concentrations.
   Sometimes cross-tolerance occurs between two drugs that do not share mechanisms of action or classification. For example, amphetamine and amphetamine-like stimulants have been shown to exhibit cross-tolerance with caffeine, and it is likely the mechanism of cross-tolerance involves the dopamine receptor D. Amphetamines also have cross-tolerance with pseudoephedrine, as pseudoephedrine can block dopamine uptake in the same manner that amphetamines do, but less potently.
   Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states.
  
  The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia(MATCH-D) criteria warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms.
  
  Section::::Mechanisms.:Abnormal pharmacokinetics.:Genetic factors.
  
  Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.
   Reverse tolerance
  
  Reverse tolerance or drug sensitization is a pharmacological concept describing subjects' increased reaction (positive or negative) to a drug following its repeated use. Not all drugs are subject to reverse tolerance.
   Behavioral tolerance occurs with the use of certain psychoactive drugs, where tolerance to a behavioral effect of a drug, such as increased motor activity by methamphetamine, occurs with repeated use. It may occur through drug-independent learning or as a form of pharmacodynamic tolerance in the brain; the former mechanism of behavioral tolerance occurs when one learns how to actively overcome drug-induced impairment through practice. Behavioral tolerance is often context-dependent, meaning tolerance depends on the environment in which the drug is administered, and not on the drug itself. Behavioral sensitization describes the opposite phenomenon.
   For most severe cases and some milder cases, a combination of medications are used. Individual responses to different medications vary widely, and a drug which dramatically improves one patient's symptoms may make another patient's symptoms much worse. Medications focus on three main issues:
  
  Medications that increase blood volume:
  
  BULLET::::- Fludrocortisone (Florinef)
  
  BULLET::::- Erythropoietin
  
  BULLET::::- Hormonal contraception
  
  Medications that inhibit acetylcholinesterase:
  
  BULLET::::- Pyridostigmine
  
  Medications that improve vasoconstriction:
  
  BULLET::::- Stimulants: (e.g., Ritalin or Dexedrine)
  
  BULLET::::- Midodrine (ProAmatine)
  
  BULLET::::- Ephedrine and pseudoephedrine (Sudafed)
  
  BULLET::::- Theophylline (low-dose)
  
  BULLET::::- Selective serotonin reuptake inhibitors (SSRI's - Prozac, Zoloft, and Paxil)
  