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.
LADME is an acronym for the important phases of pharmacokinetics:
- and their interaction with the drug
- : 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)
|Overview of clinical trial phases |
|Clinical trial phase||Purpose||Study population|
|Phase 0 trial|| |
|Phase I trial|| |
|Phase II trial|| || |
|Phase III trial|| || |
|Phase IV trial|| || |
Before clinical trials begin, drugs are first tested in preclinical studies. Preclinical studies do not include human subjects.
Pharmacokinetics deals with drug absorption, distribution, metabolism, and excretion.
- 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)
- Peroral administration
- Dermal administration
- Rectal administration
- Less common routes
- Intra-articular administration
The process by which the drug reaches the bloodstream. The following factors affect drug absorption:
- 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)
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.
|Abilities of chemical compounds|
|Chemical nature||Clinical significance||Example|
|Lipophilic|| || |
Changes in advanced age
- Slowing of gastric emptying; ↑ gastric pH
- Concomitant use of > 1 drug/ingestion of food → interactions
Distribution coefficient: measure of hydrophobicity/hydrophilicity of a drug
- Corganic = drug concentration in an organic solvent
- Cwater = drug concentration in water
- Corganic/ Cwater
Volume of distribution
Vd = M/Cplasma
- Vd = volume of distribution (usually expressed in liters/kg body weight)
- M = amount of drug in the body at a specific time
- Cplasma = 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 Vd of plasma protein-bound drugs may be increased in patients with renal and liver disease due to loss of plasma proteins.
- Vd = M/Cplasma
|Volumes of distribution|
|Drugs|| || |
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: transfer of a drug between the different compartments within the human body
- Changes in advanced age
After the drug reaches the bloodstream, it is initially distributed in the most vascularized organs.
- 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 (Cp decreases linearly over time)
First order kinetics: The rate of metabolism and/or elimination is directly proportional to the plasma concentration of the drug (Cp decreases exponentially over time)
- First-order is a flow-dependent elimination.
- Applies to most drugs
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)
- 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:
- 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)
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., ).
- CL = Vd x Ke = rate of drug elimination/plasma drug concentration
- CL = rate of elimination / plasma concentration
- CL can be impaired in patients with cardiac, hepatic, or renal dysfunction.
Half-life (t½): the time required for the plasma concentration of a drug to reach half of its initial value
- Dynamic equilibrium
- Drug concentration stays constant because the rate of drug elimination equals the rate of drug administration
In first-order kinetics
- t½ = (0.7 x Vd) / 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
- Steady state
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
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.
- Main renal elimination mechanisms include
- Biliary elimination 
- Pulmonary elimination: primarily in
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.
- 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
- 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.
- Definition: The amount of a certain drug needed to achieve a steady target plasma concentration.
- Formula: maintenance dose = (Cp x Cl * τ) / F
- 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).
The main factor influencing the time to steady-state is t½, not dose or administration frequency.
Types of receptors
Every functioning molecule in an organism is a potential site of action for a drug. Means through which drugs act include:
- Interaction with receptors
- Interaction with enzymes
- Interaction with DNA (e.g., cytostatics)
- A physical/chemical effect (e.g., osmotic diuretics, antacids)
- Drug affinity: a measure of the tendency of a drug to bind to its receptor
Drug efficacy (correlates with Emax): 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.
- Residence time: : the lifespan of a drug‑receptor complex
Types of drug-receptor interactions
- Agonist: a drug that has a similar effect to that of the endogenous receptor activator (e.g., β2 agonists)
- Partial agonist
Antagonist: a drug that binds to a receptor and prevents its activation.
- 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)
- Non-competitive antagonist
- 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 modulator: Binds at a different site than the agonist and initiates conformational changes that induce modulation of ligand-binding.
- Allosteric activator
|Overview of drug-receptor interactions|
|Competitive antagonist||Noncompetitive antagonist||Partial agonist|
|Potency|| || || |
|Efficacy|| || || |
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 (Emax)
- 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.
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
- 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:
- 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 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.
- If the enzyme in question is responsible for the breakdown of a drug, the following effects are possible:
Examples of clinically relevant variations
- 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
- 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 and the cytochrome P450 system
- 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: the effect of two substances interacting with each other corresponds to the sum of their individual effects
- Synergistic: the effect produced by the interaction of two substances is greater than the sum of their individual actions
- Potentiation: the therapeutic effect of a substance is enhanced by another substance with no therapeutic action
- Permissive: the effect of a substance can only be achieved in the presence of another substance
- Antagonistic: the effect produced by the interaction of two substances is smaller than the sum of their individual actions
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
- Opioids and drugs with antimuscarinic activity can cause urinary retention and constipation
- 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.
- 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.
- 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
- Role in carcinogenesis: metabolic activation of certain pro-carcinogens (e.g., aflatoxin, sterigmatocystin) → induction of cancer (e.g., hepatocellular carcinoma) 
|Cytochrome P450 substrates, inhibitors, and inducers |
|CYP 450 inhibitors||CYP 450 inducers|
|CYP2E1|| || |
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
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
|Overview of substances causing cardiovascular adverse effects|
|Cardiovascular adverse effects||Substance||Main clinical use|
|Coronary vasospasm|| |
|Cutaneous flushing|| || |
|Torsades de pointes after QT prolongation|| |
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
|Overview of substances causing endocrine adverse effects|
|Endocrine adverse effects||Substance||Main clinical use|
| || |
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
|Overview of substances causing gastrointestinal adverse effects|
|Gastrointestinal adverse effects||Substance||Main clinical use|
|Acute cholestatic hepatitis with jaundice|| |
| || |
|Pancreatitis|| || |
| || |
|Pseudomembranous colitis|| |
Diuretics, Alcohol, Corticosteroids, Valproic acid, Azathioprine and Didanosine are Drugs that Abrupty Cause Violent Abdominal Distress.
Hematologic adverse effects
|Overview of substances causing hematologic adverse effects|
|Hematologic adverse effects||Substance||Main clinical use|
Drug reaction with eosinophilia and systemic symptoms ( )
|Megaloblastic anemia|| |
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
|Overview of substances causing musculoskeletal/skin/connective tissue adverse effects|
|Musculoskeletal/skin/connective tissue adverse effects||Substance||Main clinical use|
| || |
Stevens-Johnson syndrome (rash)
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).
TETracyclines may discolor your TEeTh!
Neurologic adverse effects
|Overview of substances causing neurologic adverse effects|
|Neurologic adverse effects||Substance||Main clinical use|
Parkinson-like syndrome and/or tardive dyskinesia
|Peripheral neuropathy|| |
|Idiopathic intracranial hypertension|| |
Antipsychotics, Reserpine, and Metoclopramide may make your ARMs rigid as in Parkinson's disease.
Topiramate, Digoxin, Isoniazid, Ethambutol, Vigabatrin and PDE-5 inhibitors: These Drugs Induce Problems to Vision and Eyes!
Multiorgan adverse effects
|Overview of substances causing multiorgan adverse effects|
|Multiorgan adverse effects||Substance||Main clinical use|
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
|Overview of substances causing respiratory adverse effects|
|Respiratory adverse effects||Substance||Main clinical use|
|Pulmonary fibrosis|| |
CArmustine, NiTrofurantoin, Busulfan, Amiodarone, Bleomycin, Methotrexate: I CAN'T Breathe Air Because of these Medications.
Renal and genitourinary adverse effects
|Overview of substances causing renal and genitourinary adverse effects|
|Renal and genitourinary adverse effects||Substance||Main clinical use|
|Fanconi syndrome|| || |
| || |
|Hemorrhagic cystitis|| |
Diuretics, Penicillins, Sulfonamides, PPIs, NSAIDs and Rifampin may cause blooDy Pee, Sterile Pyuria, 'N' Rash (interstitial nephritis).