Summary
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.
Overview
Before clinical trials begin, drugs are first tested in preclinical studies. Preclinical studies do not include human subjects.
Pharmacokinetics
Pharmacokinetics deals with drug absorption, distribution, metabolism, and excretion.
Absorption [pharmacology]
The process by which the drug reaches the bloodstream. The following factors affect drug absorption:
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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] =[AUCoral/AUCIV]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]
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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.
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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.
Types of drug kinetics
It takes zero PHEN-tAS-E [fantasy] to remember the drugs that are eliminated by zero-order kinetics: PHENytoin, ASpirin, Ethanol.
Phases of biotransformation
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.
- Half-life [t½]: the time required for the plasma concentration of a drug to reach half of its initial value
-
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
-
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
LADME is an acronym for the important phases of pharmacokinetics: Liberation, Absorption, Distribution, Metabolism, Excretion.
Loading dose
Maintenance dose
Renal or liver conditions lower the maintenance dose without affecting the loading dose.
The main factor influencing the time to steady-state is t½, not dose or administration frequency.
Pharmacodynamics
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.
Every functioning molecule in an organism is a potential site of action for a drug. Means through which drugs act include:
Basic principles
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-dependentfashion →higher concentration of the agonist is needed to achieve same efficacy [e.g., there is a decrease in potency]
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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.
-
Competitive antagonist
- 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
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.
- 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
- The mechanisms responsible for the development of
drug tolerance include:
-
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:
Pharmacogenetics
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:
Examples of clinically relevant variations
- CYP2D6 polymorphism
- N-acetyltransferase polymorphism
- There are hyperactive [rapid acetylators] and hypoactive [slow acetylators] variants.
- N-acetyltransferase breaks down isoniazid, sulfasalazine, and hydralazine.
- Atypical pseudocholinesterase
- Thiopurine-methyltransferase polymorphism [TPMT]: involved in the breakdown of azathioprine.
Drug interactions and the cytochrome P450 system
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
- Beers criteria is a list of over 50 drugs with potentially decreased effectiveness or increased risk of side effects or interactions in the elderly population; [see “Introduction to geriatrics” for further information].
- 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.
Types of interactions
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 2nd main family]
- Induction and inhibition: CYP induction increases the rate of metabolism of the substrate, while CYP inhibition decreases it.
- 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.
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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
Adverse effects of substances can be classified into the following groups:
We list the most important adverse effects. The selection is not exhaustive.
Cardiovascular adverse effects
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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.
Endocrine adverse effects
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!
Gastrointestinal adverse effects
Diuretics, Alcohol, Corticosteroids, Valproic acid, Azathioprine and Didanosine are Drugs that Abrupty Cause Violent Abdominal Distress.
Hematologic adverse effects
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]
Musculoskeletal/skin/connective tissue adverse effects
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!
Neurologic adverse effects
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!
Multiorgan adverse effects
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.
Respiratory adverse effects
CArmustine, NiTrofurantoin, Busulfan, Amiodarone, Bleomycin, Methotrexate: I CAN'T Breathe Air Because of these Medications.
Renal and genitourinary adverse effects
Diuretics, Penicillins, Sulfonamides, PPIs, NSAIDs and Rifampin may cause blooDy Pee, Sterile Pyuria, 'N' Rash [interstitial nephritis].