Fundamentals of pharmacology

The action of a drug depends on multiple factors. Pharmacokinetics is the study of a drug's movements in the body and can be described as what the body does to the drug, while pharmacodynamics is the study of a drug's action and effects on a body and can be described as what the drug does to the body. The administration of a drug in combination with other drugs or substances can cause a variety of interactions that can synergistically or antagonistically modify the effect of those drugs (e.g., via the activation or inhibition of cytochrome P450 enzymes by certain medications). Knowledge of interactions and pharmacokinetics help determine the ideal route of administration (topical, oral, IV). Drugs that are eliminated by the liver may attain high serum concentrations when hepatic function is impaired, which increases the risk of drug toxicity. The same principle applies to drugs that are eliminated via the kidneys.

Definitions

• LADME is an acronym for the important phases of pharmacokinetics:
  • Liberation
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
• Pharmacodynamics
  • Receptor types and their interaction with the drug
  • Dose-response relationship
• Pharmacogenetics: deals with the effect of genetic variations on drug metabolism and drug action.
• Clinical trials: phases of drug development, testing, and regulatory approval (occur after preclinical studies)

Clinical trials phases

Before clinical trials begin, drugs are first tested in preclinical studies. Preclinical studies do not include human subjects.

Drug approval ^[3]

• General: In the US, all the drugs should be approved by the Food and Drug Administration for certain indications.
• Development and approval process
  1. Development of a substance with therapeutic potential or taking a decision to repurpose an existing substance
  2. Conducting pre-clinical studies (phase 0 clinical trial)
  3. Submitting investigational new drug (IND) application
     • Types
       • Investigator IND: submitted by a physician or representative of a company who will conduct the clinical trials to initiate the standard approval procedure
       • Emergency use IND: asks for approval of an experimental drug in an emergency situation, in which the standard IND cannot be filed and there is no time for a standard approval procedure
       • Treatment IND: requests approval of use of an experimental drug to treat serious or rare conditions that showed efficacy in clinical studies before their completion (e.g., during an interim analysis) and final approval by the FDA
     • Categories
       • Research: submitted by a physician representing research or clinical institution
       • Commercial: submitted by a representative of a commercial organization, e.g., drug company
  4. Phase 1 to 3 clinical trials
  5. Filing the New Drug Application
     • A formal request to the FDA to approve the investigational agent for marketing and use in the US
     • Should include all the information about the agent (manufacturing process, quality control, formula, pharmacodynamics, pharmacokinetics, risks, indications, proposed labeling, etc.)
  6. Application review
  7. Drug labeling
  8. Inspection of manufacturing facilities
• Unlabeled uses
  • Off-label use: use of a drug approved by FDA for an unapproved indication, population, form, or dosage (e.g., tricyclic antidepressants for the treatment of chronic pain)
  • Expanded access: an FDA program that grants use of an investigational drug or medical device for the treatment of a serious condition for which there is no comparable or satisfactory alternative treatment available

Drug scheduling ^[4]

• Definition: legal classification of substances based on their abusive potential

Pharmacokinetics deals with drug absorption, distribution, metabolism, and excretion.

Liberation

• The process by which the drug is released from its pharmaceutical form (e.g., capsule, tablet, suppository, etc.)
• The most common routes of drug administration are:
  • Injection (the drug is introduced directly into the bloodstream or into tissue)
  • Inhalation
  • Peroral administration
  • Dermal administration
  • Rectal administration
• Less common routes
  • Buccal
  • Sublingual
  • Intra-articular administration

Absorption (pharmacology)

The process by which the drug reaches the bloodstream. The following factors affect drug absorption:

• Bioavailability
  • Describes the rate and concentration at which a drug reaches systemic circulation
  • Expressed as a percentage of the dose that was initially administered
  • Drugs administered intravenously have a bioavailability of 100%.
  • Can be calculated using the area under curve (AUC) of the plotted graph concentration versus time: (F) = (AUC_oral/AUC_IV) x 100
  • Bioavailability is affected by two mechanisms:
    • Ability to pass through lipid membranes: dependent on the nature of the substance (see the table below)
    • First pass effect
      • Orally administered drugs are absorbed in the GI tract and reach the liver via portal circulation
      • In the liver they undergo first pass metabolism before they enter systemic circulation → ↓ bioavailability of the drug (F < 100%).
      • Rectal or sublingual administration bypasses first pass metabolism, as the drug is absorbed directly into the bloodstream.
• Bioequivalence: Two proprietary preparations of a drug are said to be bioequivalent if they exhibit the same bioavailability when administered in equal doses.

• Changes in older adults
  • Despite slowing of gastric emptying and an increase in gastric pH, absorption remains typically unaffected in older adults.
  • Due to older adults often having multiple drug regimens, this group is at particular risk of drug and food interactions.

Distribution (pharmacology)

• Distribution coefficient: measure of hydrophobicity/hydrophilicity of a drug
  • C_organic/ C_water
    • C_organic = drug concentration in an organic solvent
    • C_water = drug concentration in water
• Volume of distribution
  • V_d = M/C_plasma
    • V_d = volume of distribution (usually expressed in liters/kg body weight)
    • M = amount of drug in the body at a specific time
    • C_plasma = plasma concentration of the drug at a specific time
  • The theoretical volume a drug would occupy if it was distributed evenly in fluids at plasma concentration.
  • Provides information about a drug tendency to distribute in other compartments (e.g., muscle or adipose tissue) rather than in the plasma.
  • Drugs can distribute in more than one compartment.
  • The V_d of plasma protein-bound drugs may be increased in patients with renal and liver disease due to loss of plasma proteins.

• Binding to plasma proteins: Different drugs have different affinities to bind to plasma proteins (e.g., albumin).
  • Only the unbound fraction of the drug has a pharmacological effect.
  • Different drugs may compete to bind to plasma proteins
• Redistribution (pharmacology): transfer of a drug between the different compartments within the human body
  • Lipophilic substances (e.g., inhalation anesthetics) are redistributed from plasma into fat tissue → initially decreased action of the applied drug
  • Drug is stored but over time is released again from fat tissue into plasma → delayed elimination and prolonged action of the specific drug ).
• Changes in advanced age
  • Hydrophilic drugs (e.g., digoxin): ↓ total body water → ↓ V_d
  • Acidic drugs: ↓ albumin → ↓ binding
  • Lipophilic drugs (e.g., propofol): ↑ body fat content → ↑ V_d

After the drug reaches the bloodstream, it is initially distributed in the most vascularized organs.

Renal and liver disease can increase the apparent volume of distribution of drugs bound to plasma proteins.

Metabolism (biotransformation)

• Chemical alteration of substances (e.g., drugs) within the body by the action of enzymes and mainly takes place in the liver.
• Detoxifies drugs and facilitates their elimination

Types of drug kinetics

• Zero order kinetics: The rate of metabolism and/or elimination remains constant and is independent of the plasma concentration of a drug at steady state (C_p decreases linearly over time)
  • Zero-order is a capacity-limited elimination.
  • Examples include ethanol, phenytoin, aspirin (at high concentrations)
• First order kinetics: The rate of metabolism and/or elimination is directly proportional to the plasma concentration of the drug (C_p decreases exponentially over time)
  • First-order is a flow-dependent elimination.
  • Applies to most drugs

It takes zero PHEN-tAS-E (fantasy) to remember the drugs that are eliminated by zero-order kinetics: PHENytoin, ASpirin, Ethanol.

Phases of biotransformation

• Phase I reaction: A drug is transformed into a polar, water-soluble metabolite by cytochrome P450 via one or more of the following reactions:
  • Oxidation (most common reaction)
  • Reduction
  • Hydrolysis
• Phase II reaction: A drug is conjugated and thereby transformed into a very polar metabolite (can be excreted renally) via one or more of the following reactions:
  • Glucuronidation (most common coupling reaction)
  • Acetylation (e.g., isoniazid)
  • Sulfation
  • Methylation
• Clinical significance
  • Detoxification: In most cases, the drug is inactivated and modified into a hydrophilic metabolite, allowing excretion of the drug via the kidneys or in bile.
  • Activation; : Certain drugs are transformed in the liver from their inactive prodrug state into active forms (e.g., the ACE inhibitor enalapril is transformed through ester hydrolysis into the active form enalaprilat).
  • Formation of toxic metabolites (e.g., the breakdown of paracetamol gives rise to toxic metabolites that may cause severe liver damage in large doses)
  • In individuals who are slow drug acetylators, the decreased rate of metabolism increases the risk of side effects (e.g., isoniazid).
• Changes in advanced age: ↓ metabolization (due to ↓ hepatic mass and ↓ hepatic blood flow)
  • Because phase I metabolism decreases (affecting drugs like diazepam), drugs predominantly metabolized in phase II (e.g., acetaminophen, lorazepam) are considered safer.
  • Consequently, lower therapeutic doses should be considered in elderly individuals.

In the elderly population, phase I reactions will usually become impaired before phase II reactions.

Excretion (pharmacology)

• Drug clearance (CL): a measure of the rate of drug elimination.
  • It is defined as the plasma volume that can be completely cleared of the drug in a given period of time (e.g., creatinine clearance).
  • CL = V_d x K_e = rate of drug elimination/plasma drug concentration
    • V_d = volume of distribution
    • K_e = elimination constant
  • CL = rate of elimination / plasma concentration
  • CL can be impaired in patients with cardiac, hepatic, or renal dysfunction.
• Half-life (t_½): the time required for the plasma concentration of a drug to reach half of its initial value
  • Steady state
    • Dynamic equilibrium
    • Drug concentration stays constant because the rate of drug elimination equals the rate of drug administration
  • In first-order kinetics
    • t_½ = (0.7 x V_d) / CL
    • It takes 1 half-life to reach 50% of the steady-state level, 2 half-lives to reach 25%, 3 half-lives to reach 12.5%, and 4 half-lives to reach 6.25%.
    • Complete steady-state attainment takes 4–5 half-lives for drugs infused at a constant rate; 90% of steady-state level is reached after 3.3 half-lives
• Effective half-life
  • The time it takes for a drug's plasma concentration to reach 50% of its initial value during the most clinically important phase of its kinetics
  • For drugs with atypical kinetics (e.g., those with a high volume of distribution), the effective half-life may be shorter than the terminal elimination half-life but more predictive of the drug's duration of effect and accumulation.

Defects in renal, hepatic, or cardiac function can impair drug clearance.

After 4 half-lives, more than 90% of the drug will be eliminated.

Drugs and/or their metabolites are excreted from the body in one or more of the following ways:

• Renal elimination: mostly hydrophilic drugs
  • Main renal elimination mechanisms include
    • Glomerular filtration
    • Tubular secretion
    • Tubular reabsorption
  • Ionized substances cannot cross renal tubular membranes and are cleared quickly.
    • Weak acidic drugs (e.g., phenobarbital, methotrexate, aspirin) are trapped in a basic environment
      • Overdoses with these drugs can be treated via alkalinization of urine (sodium bicarbonate)
      • RCOOH (lipid soluble) ⇄ RCOO^– + H⁺ (trapped form)
    • Weak basic drugs (e.g., tricyclic antidepressants, amphetamines) are trapped in an acidic environment
      • Overdoses with these drugs can be treated via acidification of urine (ammonium chloride)
      • RNH₃⁺ (trapped form) ⇄ RNH₂ + H⁺ (lipid soluble)
      • The elimination of tricyclic antidepressants, which are basic, can be increased by acidification of urine, but toxicity is generally treated with sodium bicarbonate.
  • Neutral substances can be reabsorbed.
• Biliary elimination ^[5]
  • Lipophilic and hydrophilic substances
  • Lipophilic substances that have undergone biliary elimination may be reabsorbed from the gut and then secreted again in bile (enterohepatic circulation)
• Pulmonary elimination: primarily in inhaled anesthetic drugs
• Changes in advanced age
  • ↓ Tubular secretion and ↓ GFR → ↑ concentrations of drugs that are eliminated renally
  • Consequently, lower therapeutic doses should be considered in elderly individuals.

LADME is an acronym for the important phases of pharmacokinetics: Liberation, Absorption, Distribution, Metabolism, Excretion.

Dosage intervals

Loading dose

• Definition: the amount of an initial dose of a certain drug needed to reach a target plasma concentration
• Formula: loading dose = (Cp x Vd) / F
  • Cp = target peak plasma concentration at steady state (mg/L or units/L)
  • V_d = volume of distribution (L/kg)
  • F = bioavailability
• In patients with renal and/or liver dysfunction, loading dose (which does not depend on drug clearance) and time to steady-state are usually unaffected.

Maintenance dose

• Definition: The amount of a certain drug needed to achieve a steady target plasma concentration.
• Formula: maintenance dose = (Cp x Cl * τ) / F
  • Cp = target plasma concentration at steady state (mg/L)
  • Cl = clearance (L/h)
  • τ = dosing interval (hours)
  • F = bioavailability
• In patients with renal and/or liver dysfunction, maintenance dose is decreased (because of impaired drug clearance) and time to steady-state is unchanged (time to steady state depends on t½).

Renal or liver conditions lower the maintenance dose without affecting the loading dose.

The main factor influencing the time to steady-state is t_½, not dose or administration frequency.

Pharmacodynamics deals with the effect of a drug at its site of action, the dose-response relationship of the drug, and the influence of other factors on the drug effect.

Types of drug targets

Every functioning molecule in an organism is a potential site of action for a drug. Means through which drugs act include:

• Interaction with receptors
  • Cell membrane receptors
    • G-protein coupled receptors (e.g., adrenergic, dopamine, angiotensin, M‑cholinergic, opioid receptors)
    • Ion channels (e.g., GABA_A receptors)
    • Protein kinase receptors (e.g., insulin receptors)
  • Intracellular receptors (e.g., receptors for glucocorticoids, NO)
• Interaction with enzymes
• Interaction with DNA (e.g., cytostatics)
• A physical/chemical effect (e.g., osmotic diuretics, antacids)

Drug-receptor interactions

Basic principles

• Drug affinity: a measure of the tendency of a drug to bind to its receptor
  • Most drug-receptor bonds are reversible
  • Covalent drug-receptor bonds, which are less common, are almost always irreversible (e.g., the binding of aspirin to cyclooxygenase enzyme).
• Drug efficacy (correlates with E_max): the maximum degree to which a drug activates receptors after binding and triggers a cell response
  • On an efficacy graph, the difference in efficacy of the two drugs is determined by the difference in the maximal effect exerted by each of them (shown on the y-axis); drugs with different efficacy will have different heights, with the difference in efficacy represented on the y-axis.
  • Not related to potency (drugs with a high efficacy can have a low potency)
  • Partial agonists are less efficacious than full agonists.
• Structure-activity relationship ^[6]
  • The relationship between a chemical compound's structure and its biological activity
  • Modeling of the structure-activity relationship can help predict the biological action of a substance and, accordingly, plays a major role in the development of drugs with a specific target. ^[7]
• Residence time: : the lifespan of a drug‑receptor complex

Antagonists have zero efficacy, agonists have maximum efficacy, and partial agonists (see below) have submaximal efficacy.

Types of drug-receptor interactions

• Agonist: a drug that has a similar effect to that of the endogenous receptor activator (e.g., β2 agonists)
  • Full agonist: a molecule that binds to a receptor and activates the receptor with the highest response it can elicit
  • Partial agonist
    • A substance that has some agonistic action at a receptor but does not elicit the complete response of a true agonist
    • Act at the same site as full agonists
• Antagonist: a drug that binds to a receptor and prevents its activation.
  • Competitive antagonist
    • Agonist and the antagonist compete to bind to the same receptor.
    • Inhibition of the effect of the agonist in a dose-dependent fashion → higher concentration of the agonist is needed to achieve same efficacy (e.g., there is a decrease in potency)
      • Reversible competitive antagonists
      • Irreversible competitive antagonists
  • Non-competitive antagonist
    • The drug binds at a site other than the agonist-binding site, changes the structure of the agonist binding site, and decreases the affinity of the agonist.
    • As a result, the efficacy of the agonist is decreased and increasing the agonist concentration does not achieve the same efficacy.
  • Functional (physiological) antagonist; : In this type of antagonism, two different molecules working through separate receptors produce physiologically opposite effects.
• Inverse agonist: Binds to the same receptor as an agonist, but not to the same active site. It elicits a response that is opposite to the agonistic response and has a negative efficacy.
• Allosteric regulation
  • Allosteric modulator: Binds at a different site than the agonist and initiates conformational changes that induce modulation of ligand-binding.
  • Allosteric activator
    • Binds at a site other than the agonist-binding site (also called allosteric site) and changes the structure of the active binding site to increase affinity to the substrate
    • For more information on enzyme kinetic, see also “Enzymes and biocatalysis.”

Dose-response relationship

The following terms are used to describe dose-response relationships:

• Potency (EC₅₀): The potency of a drug is measured as the concentration required to produce a pharmacological response of a specified intensity.
  • Not related to efficacy (drugs with a high potency can have a low efficacy) but dependent on affinity
  • EC₅₀ = the effective concentration required to produce 50% of the maximum possible response (E_max)
  • A left shift of the curve is a sign of decreased EC₅₀ and increased potency, meaning a lower concentration of the drug is needed.
  • EC₅₀ is not to be confused with ED₅₀; ED₅₀ is the median effective dose that produces a desired beneficial effect in 50% of the population.
    • ED₅₀ = 5 mg implies that administration of 5 mg of the drug achieves a desired effect in 50% of the studied population
    • The same drug may have different ED₅₀ values based on the indication (e.g., aspirin has different ED₅₀ values for headache and for thromboembolism prophylaxis).
• Therapeutic index (TI): a measurement of the safety of a drug
  • TI = median toxic dose (TD₅₀)/median effective dose (ED₅₀)
  • The greater the therapeutic index, the safer the drug
    • High therapeutic index: e.g., glucocorticoids, penicillin
    • Narrow therapeutic index: Drugs with a narrow TI require monitoring (e.g., lithium, theophylline, warfarin, digoxin, and antiepileptic drugs).
• Therapeutic window: the range of doses that is effective for treating a condition with a minimum of adverse effects
• Lethal dose (LD₅₀): The dose that is lethal for 50% of the test population in animal experiments.

TILE: Therapeutic Index = TD₅₀/ED₅₀

Drug tolerance and tachyphylaxis

The effect of a drug can decrease with repeated dosing:

• Drug tolerance (e.g., opioids, benzodiazepines, barbiturates, alcohol)
  • The mechanisms responsible for the development of drug tolerance include:
    • Down-regulation of receptors
    • Increased synthesis of enzymes that metabolize the drug
  • Can be overcome by increasing the dose
  • Develops slowly over a few weeks
• Tachyphylaxis
  • The underlying mechanism responsible for the decreased effect of a drug involves depletion of the body's stores of an endogenous mediator and downregulation of receptors.
  • Cannot be overcome by increasing the drug dose.
  • Develops quickly (within a few hours of dosing)
  • Examples include:
    • Nitrates
    • Hydralazine
    • Indirect sympathomimetic drugs (e.g., ephedrine)
    • Direct sympathomimetic drugs (e.g., phenylephrine, niacin, LSD, MDMA; ): the response to the repeated use of nasal decongestants (e.g., oxymetazoline) reduces the response over a short period of time and may cause rebound congestion

Overview

• Pharmacogenetics deals with genetic variation in the expression of enzymes that metabolize drugs.
• These genetic differences can cause a drug response to deviate from the expected response and/or increase the risk of side effects:
  • If the enzyme in question is responsible for the breakdown of a drug, the following effects are possible:
    • A hyperactive variant of the enzyme decreases the drug response.
    • A hypoactive variant of the enzyme can cause cumulative drug effects and thus increase the risk of side effects.
  • The reverse is true if the enzyme is responsible for the activation of a drug.

Examples of clinically relevant variations

• CYP2D6 polymorphism
  • There are hyperactive and hypoactive variants.
  • CYP2D6 is involved in the metabolism of many drugs (e.g., the breakdown of antiarrhythmics and tricyclic antidepressants; the activation of codeine).
  • Gender-specific differences in CYP2D6 have been observed (e.g., CYP2D6-mediated breakdown of beta blockers (such as metoprolol) is greater among women).
• N-acetyltransferase polymorphism
  • There are hyperactive (rapid acetylators) and hypoactive (slow acetylators) variants.
  • N-acetyltransferase breaks down isoniazid, sulfasalazine, and hydralazine.
• Atypical pseudocholinesterase
  • Pseudocholinesterase is responsible for the breakdown of succinylcholine through ester hydrolysis.
  • Atypical pseudocholinesterase breaks down succinylcholine slowly and thus prolongs the duration of muscle relaxation during anesthesia from a few minutes to a few hours; this may cause respiratory depression.
• Thiopurine-methyltransferase polymorphism (TPMT): involved in the breakdown of azathioprine.

Drug interactions

• Drug interactions can cause an increase or decrease in the potency of a drug or result in additional side effects.
• The greater the number of coadministered drugs, the greater the chance of drug interaction

Types of interactions

• Additive drug interaction: the effect of two substances interacting with each other corresponds to the sum of their individual effects
  • A + B = AB
  • Example: aspirin coadministered with acetaminophen
• Synergistic drug interaction: the effect produced by the interaction of two substances is greater than the sum of their individual actions
  • A + B > AB
  • Example: aspirin coadministered with clopidogrel
• Drug potentiation: the therapeutic effect of a substance is enhanced by another substance with no therapeutic action
  • A + 0 > A
  • Examples:
    • Carbidopa coadministered with levodopa (carbidopa blocks the peripheral conversion of levodopa)
    • Cobicistat: used in antiretroviral therapy of HIV infection to decrease breakdown of antiretrovirals (e.g., darunavir, atazanavir)
• Permissive drug interaction: the effect of a substance can only be achieved in the presence of another substance
  • A - B = 0
  • Example: cortisol coadministered with catecholamine (cortisol increases the sensitivity of adrenoreceptors to catecholamines)
• Antagonistic drug interaction: the effect produced by the interaction of two substances is smaller than the sum of their individual actions
  • A + B < AB
  • Example: Ethanol is used to treat methanol toxicity (ethanol binds alcohol dehydrogenase with higher affinity than methanol and thereby competitively inhibits the formation of toxic metabolites),

Beers criteria (Beers list)

Beers list is a list of over 50 drugs with potentially decreased effectiveness or increased risk of side effects or interactions in the elderly population.

• CNS-active drugs can cause sedation, cognitive impairment, and/or delirium → ↑ risk of falls and fractures; physicians should avoid prescribing three or more CNS-active drugs in combination
  • Antidepressants
  • Antipsychotics
  • Antiepileptics
  • Benzodiazepines
  • Nonbenzodiazepine hypnotics
  • Opioids
• Opioids and drugs with antimuscarinic activity can cause urinary retention and constipation
  • Muscarinic receptor antagonists
  • Tricyclic antidepressants
  • Antipsychotics
  • First-generation antihistamines
• NSAIDs, since they bear the risk of causing GI bleeding, especially in combination with anticoagulation.
• Proton-pump inhibitors are suspected to increase the risk of C. difficile infection.
• α-Blockers, as they may elevate the risk of hypotension.
• The most common form of drug interaction results from the induction of the cytochrome P450 enzyme system; interactions as a result of drug inhibition are less common.

Metabolic proficiency

Cytochrome-P450 system

• Overview
  • Cytochrome P450 is a superfamily of heme-containing, primarily oxidative enzymes that take part in phase 1 reactions.
  • There are 200 cytochrome P450 enzymes, which are classified into 43 subfamilies and 18 families based on the similarity of amino acid sequences.
    • Of these 200, only 12 are involved in drug metabolism.
    • They belong to the first three families:
      • CYP1 family (CYP1A1, CYP1A2),
      • CYP2 family; (CYP2A6, CYP2B6, CYP2C8, CYP2C9; , CYP2C19; , CYP2D6; , CYP2E1)
      • CYP3 family; (CYP3A4, CYP3A5, CYP3A7)
  • The highest concentration of CYP enzymes is found within the centrilobular hepatocytes.
• Nomenclature: the prefix "CYP" (which stands for cytochrome P450)- PLUS family number PLUS a letter representing the subfamily PLUS isoenzyme number (e.g., CYP2D6 means isoenzyme no. 6 of subfamily "D" of the 2^nd main family)
• Induction and inhibition: CYP induction increases the rate of metabolism of the substrate, while CYP inhibition decreases it.
  • The effects of drugs that are activated by CYP enzymes (e.g., prodrugs) are increased by enzyme induction and decreased by enzyme inhibition.
  • The effects of drugs that are broken down by CYP enzymes are decreased by enzyme induction and increased by enzyme inhibition.
• Ultrarapid metabolizers
  • Activity of CYP2D6 is increased in individuals with a duplication on chromosome 22.
  • These individuals require a significantly higher dose to achieve the desired effect.
• Role in carcinogenesis: metabolic activation of certain pro-carcinogens (e.g., aflatoxin, sterigmatocystin) → induction of cancer (e.g., hepatocellular carcinoma) ^[8][9][10]

Carbamazepine acts as both substrate and inducer of CYP3A4.

Rifampicin and carbamazepine are some of the strongest inducers of cytochrome P450 enzymes and can thus interact with many drugs.

P450 inducers: ↓ warfarin levels (Chronic Alcoholics Steal Phen-Phen and Never Refuse Greasy Carbs): C - Chronic alcohol use, S - St. John's wort, P - Phenytoin, P - Phenobarbital, N - Nevirapine, R - Rifampin, G - Griseofulvin, C - Carbamazepine

P450 inhibitors can be remembered with “sickfaces.com group”: S - Sulfonamides, I - Isoniazid, C - Cimetidine, K - Ketoconazole, F - Fluconazole, A - Alcohol (binge drinking), C - Ciprofloxacin, E - Erythromycin, S - Sodium valproate, C - Chloramphenicol, O - Omeprazole, M - Metronidazole, G - Grapefruit juice

The P450 substrates beta-BLOCKers, THEophylline, WARfarin, STATins, ORAL contraceptives, and antiPSYCHOtics: Let's BLOCK THE WAR between STATes with ORAL and PSYCHOlogical tools.

Adverse effects of substances can be classified into the following groups:

We list the most important adverse effects. The selection is not exhaustive.

Dilated cardiomyopathy caused by Doxorubicin and Danurobicin can be prevented with Dexrazoxane.

ABCDE to recall the 5 class of drugs potentially causing torsades de pointes: antiArrhythmic, antiBiotics, antiCychotics, antiDepressants and antiEmetics.

Hydrochlorotiazide, Niacin, Tacrolimus and corticoSteroids can lead to High amouNT of Sugars in your blood.

SUlfonamides, Lithium and AMiodarone may induce SUdden Lethargy And Myxedema (hypothyroidism).

If patients taking Carbamazepine, Cyclophosphamide or SSRI get SIADH, they Can't Concentrate Serum Sodium!

Diuretics, Alcohol, Corticosteroids, Valproic acid, Azathioprine and Didanosine are Drugs that Abrupty Cause Violent Abdominal Distress.

Clozapine, Propylthiouracile, Methimazole, Carbamazepine, Ticlopidine, Dapsone, Colchicine, Chemotherapeutics and Gangiclovir Causes Pretty Major Collapse To Defense Cells Called Granulocytes (agranulocytosis).

Carbamazepine, Methimazole, NSAIDs, Benzene, Chloramphenicol, Propylthiouracile Can't Make New Blood Cells Properly (aplastic anemia).

MetHyldopa, Penicilline, and Cephalosporins may induce HeMolytic anemia (Positive Coombs test).

YoU'RE Having a MEGA BLAST with Plays, Music, and Snacks! (HydroxyUREa, Phenytoin, Methotrexate and Sulfonamides may induce MEGAloBLASTic anemia)

Methyldopa, Phenytoin, Hydralazine, Isoniazid, Procainamide, Sulfonamides, Minocycline and Etanercept may provoke Malar rash, Painful HIPS, & Myalgia (Systemic Lupus Erythematous).

Protease Inhibitors and Corticosteroids PICk your FAT somewhere else!

Cyclosporine, CA2+ channel blockers, and Phenytoin can Cause Chubby Puffy Gums!

Pyrazinamide, Furosemide, Niacin, Cyclosporine and Thiazides may induce Pain on your Feet, Needle-shaped Crystals, and Tophi (gout).

With 5-FLuorouracil, Amiodarone, Sulfonamides & Tetracyclines you may geT sunburn in a FLASh (photosensitivity)!

AntiEpiLEpTIC drugs, Penicillin, ALlopurinol and SULFonamides may provoke STEVE JOHNSON (syndrome), an EcLEcTIC PAL who loves SUrF!

TETracyclines may discolor your TEeTh!

Antipsychotics, Reserpine, and Metoclopramide may make your ARMs rigid as in Parkinson's disease.

Isoniazide, Bupropion, Imipenem/cilastatin, Tramadol and Enflurane lower seizures threshold (I BITE my tongue).

Topiramate, Digoxin, Isoniazid, Ethambutol, Vigabatrin and PDE-5 inhibitors: These Drugs Induce Problems to Vision and Eyes!

To remember that Sulfonylureas, Cephalosporines, Metronidazole, Griseofulvin and Procarbazine can cause disulfiram-like reaction: Sorry, Can't Mess with Gin and Port wine.

If you use Loop diuretics, Amphotericin B, cisPlatin, Vancomycin, or Aminoglycosides Listening And Peeing Vanish Away.

CArmustine, NiTrofurantoin, Busulfan, Amiodarone, Bleomycin, Methotrexate: I CAN'T Breathe Air Because of these Medications.

Diuretics, Penicillins, Sulfonamides, PPIs, NSAIDs and Rifampin may cause blooDy Pee, Sterile Pyuria, 'N' Rash (interstitial nephritis).