Following a declination or total extinction in response to a previously therapeutic dose of an antidepressant, the issue is clinically addressed as stemming from tolerance development. Several strategies are available, such as exploring drug options from a different drug class used to treat depression. The patient can also choose to switch to another SSRI (or MAOI, if applicable) while maintaining proportionate dose. If tolerance develops in a drug from the same class, the clinician may recommend a regular cycle consisting of all effective treatments within the SSRI or MAOI classes, in order to minimize transitional side effects while maximizing therapeutic efficacy.

Other options include increasing dose of the same medication, or supplementation with another antidepressant. Dual reuptake inhibitors, also known as tricyclic antidepressants have been shown to have lower rates of tachyphylaxis.

Use of intranasal decongestants (such as oxymetazoline) for more than three days leads to tachyphylaxis of response and rebound congestion, caused by alpha-adrenoceptor mediated down-regulation and desensitization of response. Oxymetazoline-induced tachyphylaxis and rebound congestion are reversed by intranasal fluticasone.

In a patient fully withdrawn from opioids, going back to an intermittent schedule or maintenance dosing protocol, a fraction of the old tolerance level will rapidly develop, usually starting two days after therapy is resumed and, in general, leveling off after day 7. Whether this is caused directly by opioid receptors modified in the past or affecting a change in some metabolic set-point is unclear. Increasing the dose will usually restore efficacy; relatively rapid opioid rotation may also be of use if the increase in tolerance continues.

Emergency treatment of cocaine-associated hyperthermia consists of administering a benzodiazepine sedation agent, such as diazepam (Valium) or lorazepam (Ativan) to enhance muscle relaxation and decrease sympathetic outflow from the central nervous system. Physical cooling is best accomplished with tepid water misting and cooling with a fan (convection and evaporation), which can be carried out easily in the field or hospital. There is no specific pharmacological antidote for cocaine overdose. The chest pain, high blood pressure, and increased heart rate caused by cocaine may be also treated with a benzodiazepine. Multiple and escalating dose of benzodiazepines may be necessary to achieve effect, which increases risk of over-sedation and respiratory depression. A comprehensive systematic review of all pharmacological treatments of cocaine cardiovascular toxicity revealed benzodiazepines may not always reliably lower heart rate and blood pressure.

Nitric-oxide mediated vasodilators, such as nitroglycerin and nitroprusside, are effective at lowering blood pressure and reversing coronary arterial vasoconstriction, but not heart rate. Nitroglycerin is useful for cocaine-induced chest pain, but the possibility of reflex tachycardia must be considered. Alpha-blockers such as phentolamine have been recommended and may be used to treat cocaine-induced hypertension and coronary arterial vasoconstriction, but these agents do not reduce heart rate. Furthermore, phentolamine is rarely used, not readily available in many emergency departments, and many present-day clinicians are unfamiliar with its use and titratability. Calcium channel blockers may also be used to treat hypertension and coronary arterial vasoconstriction, but fail to lower tachycardia based on all cocaine-related studies. Non-dihydropyridine calcium channels blockers such as diltiazem and verapamil are preferable, as dihydropyridine agents such as nifedipine have much higher risk of reflex tachycardia.

Agitated patients are best treated with benzodiazepines, but antipsychotics such as haloperidol and olanzapine may also be useful. The alpha-2 agonist dexmedetomidine may also be useful for treatment of agitation, but effects on heart rate and blood pressure are variable based on several studies and case reports. Lidocaine and intravenous lipid emulsion have been successfully used for serious ventricular tachyarrhythmias in several case reports.

The use of beta-blockers for cocaine cardiovascular toxicity has been subject to a relative contraindication by many clinicians for several years despite extremely limited evidence. The phenomenon of “unopposed alpha-stimulation,” in which blood pressure increases or coronary artery vasoconstriction worsens after blockade of beta-2 vasodilation in cocaine-abusing patients, is controversial. This rarely-encountered and unpredictable adverse effect has resulted in some clinicians advocating for an absolute contraindication of the use of all beta-blockers, including specific, non-specific, and mixed. Many clinicians have disregarded this dogma and administer beta-blockers for cocaine-related chest pain and acute coronary syndrome, especially when there is demand ischemia from uncontrolled tachycardia. Of the 1,744 total patients identified in the aforementioned systematic review, only 7 adverse events were from putative cases of “unopposed alpha-stimulation” due to propranolol (n=3), esmolol (n=3), and metoprolol (n=1). Some detractors of beta-blockers for cocaine-induced chest pain have cited minimal acute mortality and the short half-life of the drug, making it unnecessary to aggressively treat any associated tachycardia and hypertension. However, the long-term effect of cocaine use and development of heart failure, with early mortality, high morbidity, and tremendous demand on hospital utilization should be taken under consideration.

The mixed beta/alpha blocker labetalol has been shown to be safe and effective for treating concomitant cocaine-induced hypertension and tachycardia, without any “unopposed alpha-stimulation” adverse events recorded. The use of labetalol is approved by a recent AHA/ACC guideline for cocaine and methamphetamine patients with unstable angina/non-STEMI.

ADT tachyphylaxis specifically occurs in depressed patients using SSRIs and MAOIs. Currently, SSRIs are the preferred treatment for depression among clinicians, as MAOIs require the patient to avoid certain foods and other medications due to the potential for interactions capable of inducing dangerous side effects. Provided is a list of medications known to be subject to Poop-out.

Intolerance to analgesics, particularly NSAIDs, is relatively common. It is thought that a variation in the metabolism of arachidonic acid is responsible for the intolerance. Symptoms include chronic rhinosinusitis with nasal polyps, asthma, gastrointestinal ulcers, angioedema, and urticaria.

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.

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.

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.

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 latter 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.

Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.

Cocaine can be snorted, swallowed, injected, or smoked. Most deaths due to cocaine are accidental but may also be the result of body packing or stuffing with rupture in the gastrointestinal tract. Use of cocaine causes tachyarrhythmias and a marked elevation of blood pressure (hypertension), which can be life-threatening. This can lead to death from acute myocardial infarction, respiratory failure, stroke, cerebral hemorrhage, or heart failure. Cocaine overdose may result in hyperthermia as stimulation and increased muscular activity cause greater heat production. Heat loss is also inhibited by the cocaine-induced vasoconstriction. Cocaine and/or associated hyperthermia may cause muscle cell destruction (rhabdomyolysis) and myoglobinuria resulting in renal failure. Individuals with cocaine overdose should be transported immediately to the nearest emergency department, preferably by ambulance in case cardiac arrest occurs en route. According to the National Institute on Drug Abuse, approximately 5000 deaths occur annually in the US due to cocaine overdose.

Treatment includes dietary changes (low fiber diets) and, in some cases, restrictions on fat and/or solids. Eating smaller meals, spaced two to three hours apart has proved helpful. Avoiding foods that cause the individual problems, such as pain in the abdomen, or constipation, such as rice or beef, will help avoid symptoms.

Metoclopramide, a dopamine D receptor antagonist, increases contractility and resting tone within the GI tract to improve gastric emptying. In addition, dopamine antagonist action in the central nervous system prevents nausea and vomiting. Similarly, the dopamine receptor antagonist domperidone is also used to treat gastroparesis. Erythromycin is known to improve emptying of the stomach but its effects are temporary due to tachyphylaxis and wane after a few weeks of consistent use.

Sildenafil citrate, which increases blood flow to the genital area in men, is being used by some practitioners to stimulate the gastrointestinal tract in cases of diabetic gastroparesis.

The antidepressant mirtazapine has proven effective in the treatment of gastroparesis unresponsive to conventional treatment. This is due to its antiemetic and appetite stimulant properties. Mirtazapine acts on the same serotonin receptor (5-HT3) as does the popular anti-emetic ondansetron.

In specific cases where treatment of chronic nausea and vomiting proves resistant to drugs, implantable gastric stimulation may be utilized. A medical device is implanted that applies neurostimulation to the muscles of the lower stomach to reduce the symptoms. This is only done in refractory cases that have failed all medical management (usually at least 2 years of treatment). Medically refractory gastroparesis may also be treated with a pyloromyotomy, which widens the gastric outlet by cutting the circular pylorus muscle. This can be done laparoscopically or endoscopically.

Gastroparesis can be diagnosed with tests such as x-rays, manometry, and gastric emptying scans. The clinical definition for gastroparesis is based solely on the emptying time of the stomach (and not on other symptoms), and severity of symptoms does not necessarily correlate with the severity of gastroparesis. Therefore, some patients may have marked gastroparesis with few, if any, serious complications.