Module 1 Flashcards
Drug pharmacokinetics, metabolism, and pharmacodynamics
What are the four pharmacokinetic properties that determine the onset, intensity, and duration of drug action?
Absorption, distribution, metabolism, elimination (ADME)
Pros of oral admin
Safest and most common, convenient, and economical route of admin
Cons of oral admin
Limited absorption of some drugs, food may affect absorption, patient compliance is necessary, subject to first-pass effect
Pros of IV admin
Can have immediate effect, ideal if dosed in large volumes, suitable for irritating substances and complex mixtures, valuable in emergency situations, dosage titration permissible, ideal for high molecular weight protein and peptide drugs
Cons of IV admin
High initial toxicity, risk of infection due to invasiveness of procedure, most substances must be slowly injected
Pros of SC admin
Suitable for slow-release drugs, ideal for some poorly soluble suspensions
Cons of SC admin
Pain or necrosis if drug is irritating, limited dose by volume
Pros of IM admin
Suitable for moderate drug volumes, suitable for oily vehicles and certain irritating substances, preferable to IV if self-admin is required
Cons of IM admin
Affects certain lab tests (creatine kinase), can be painful, can cause IM hemorrhage
Pros of transdermal (patch) admin
Bypasses first-pass effect, convenient and painless, ideal for drugs that are lipophilic and have poor oral bioavailability, ideal for drugs that are quickly eliminated
Cons of transdermal (patch) admin
Some patients may be allergic to patch which can cause irritation, drug must be highly lipophilic, may cause delayed delivery of drug to target tissue, limited to drugs that can be taken in small daily doses
Pros of rectal admin
Partially bypasses first-pass effect, bypasses destruction by stomach acid, ideal for drugs that may cause vomiting and in patients who are vomiting or comatose
Cons of rectal admin
Drugs may irritate rectal mucosa, not a well-accepted route
Pros of admin by inhalation
Absorption is rapid and can have immediate effects, ideal for gases, effective for patients with respiratory problems, dose can be titrated, localized effect to target lungs, fewer systemic side effects
Cons of admin by inhalation
Most addictive route (drug can enter brain quickly), patient may have difficulty regulating dose
Pros of sublingual admin
Bypasses first-pass effect, bypasses destruction by stomach acid, drug stability maintained due to relatively neutral pH of saliva, may cause immediate pharmacological effects
Cons of sublingual admin
Limited to certain types of drugs and drugs that can be taken in small doses, may lose part of drug dose if swallowed
Absorption
The transfer of a drug from the site of administration to the bloodstream
Distribution
The process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues
Passive diffusion
When a drug moves from a region of high concentration to one of lower concentration (the vast majority of drugs are absorbed by this mechanism)
Facilitated diffusion
The passage of drugs or endogenous molecules into the interior of cells from a region of high concentration to one of low concentration through specialized transmembrane carrier proteins that undergo conformational changes (no energy required)
Active transport
An energy-dependent process of drug transportation into the cell, occurring against a concentration gradient, that involves specific carrier proteins which span the cell membrane
Endocytosis/exocytosis
A mechanism used to transport drugs of exceptionally large size across the cell membrane which involves engulfment of the drug by the cell membrane and transport into/out of the cell by pinching off a drug-filled vesicle
What is the effect of pH of the permeability of drugs through lipid membranes?
pH influences the charge of drugs causing weak acids (aspirin) to be better absorbed in an acidic environment (stomach) due to protonation which neutralizes their charge. Drugs that are weak bases are therefore better absorbed in an alkaline environment (duodenum) due to deprotonation which neutralizes their charge.
How does blood flow of the absorption site influence drug absorption?
Drug absorption is favored in an absorption site with high blood flow (duodenum) over a site with low blood flow (stomach)
How does surface area of the absorption site influence drug absorption?
Drug absorption increases with increased surface area of absorption site making absorption in the intestine (with brush borders containing microvilli) much more efficient than in the stomach
How does contact time at the absorption site influence drug absorption?
Drug absorption increases with slowed gastric emptying into the intestine (increased contact time) and decreases when a drug moves too quickly through the GI tract as can happen with severe diarrhea
How does expression of P-glycoprotein influence drug absorption?
In areas of high P-glycoprotein expression, drug absorption is reduced due to this transmembrane transporter’s involvement in pumping drugs out of the cells and into the blood. P-glycoprotein is also associated with multidrug resistance.
Bioavailability (F)
The rate and extent to which an administered drug reaches the systemic circulation.
How does first-pass hepatic metabolism impact bioavailability?
When a drug is absorbed from the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased.
How does solubility of a drug impact bioavailability?
Extremely hydrophilic drugs are poorly absorbed because of their inability to cross lipid-rich cell membranes whereas extremely lipophilic drugs are also poorly absorbed because they are totally insoluble in aqueous body fluids (blood) preventing them from gaining access to the surface of cells. A drug must be largely lipophilic but also have some solubility in aqueous solutions for it to be readily absorbed (weak acid or base).
How does drug chemical stability impact bioavailability?
A drug must be chemically stable in the pH of the GI tract in order for it to reach the systemic circulation.
How does drug formulation impact bioavailability?
Particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients can influence the ease of dissolution and alter the rate of drug absorption.
How does blood flow influence distribution?
“Vessel-rich organs” such as the brain, liver, and the kidneys permit rapid distribution whereas organs with slower rates of blood flow result in slower distribution.
How does capillary permeability influence distribution?
In the liver and spleen, a significant portion of the basement membrane is exposed due to large discontinuous capillaries through which large plasma proteins can pass (called slit junctions). In the brain the capillary structure is continuous and there are no slit junctions. To enter the brain, drugs must pass through the endothelial cells of the CNS or be actively transported.
How does plasma protein binding influence distribution?
Reversible binding to plasma proteins (albumin) sequesters drugs in a nondiffusible form and slows their transfer out of the vascular compartment. Many drugs accumulate in tissues leading to higher concentrations in tissues than in extracellular fluid and blood.
How does lipophilicity of a drug influence distribution?
The more lipophilic a drug is, the easier it is for it to cross cell membranes and penetrate the cell surface.
Volume of distribution (Vd)
The fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma.
Vd = the dose of drug (mg)/plasma concentration of drug (C0)
Drug with low Vd
Has a high molecular weight or is extensively protein-bound and cannot pass through the slit junctions of the capillaries and thus is effectively trapped within the plasma (vascular compartment.
Drug with medium Vd
Has a low molecular weight but is hydrophilic allowing it to pass through endothelial slit junctions of the capillaries into the interstitial fluid. However it still cannot pass through the cell membrane due into the intracellular fluid so is localized to the extracellular fluid compartment.
Drug with high Vd
Has a low molecular weight and is lipophilic allowing it to move into the interstitium through slit junctions and also pass through the cell membranes into the intracellular fluid.
Half-life (T1/2)
The time it takes to reduce the drug plasma concentration by half (T1/2 = 0.693 Vd/CL). At 4-5 half-lives, most of drug is gone.
Clearance (CL)
An estimate of the rate at which a drug is cleared from the body. (CL = 0.693 Vd/T1/2)
How does Vd influence half-life?
A drug with a large Vd would increase half-life due to most of the drug being in the extraplasmic space and unavailable to the excretory organs.
Dosing rate
Dosing rate = (Target plasma concentration)(CL)/F (bioavailability)
Loading dose
Loading dose = (Vd)(desired steady-state plasma concentration)/F
Loading dose for IV admin
Loading dose = (Vd)(desired steady-state plasma concentration)
Bioequivalent
When two drugs show comparable bioavailability and similar time to achieve peak blood concentrations.
Therapeutically equivalent
When two drugs are bioequivalent and pharmaceutically equivalent (same dosage form, same active ingredient, and same route of administration).
Metabolism
The process by which lipid soluble drugs are chemically modified in the liver producing metabolites that can be cleared from the body through elimination.
Three major routes of elimination
Hepatic metabolism, biliary elimination, and renal (urinary) elimination
First order (linear) kinetics
When the rate of drug metabolism and elimination is directly proportional to the concentration of free drug and a constant fraction of drug is eliminated per unit of time. For each half-life, the concentration decreases by 50%.
Zero order (nonlinear) kinetics
When the rate of drug metabolism and elimination is constant over time and does not depend on drug concentration. This is due to the enzyme being saturated with a high free drug concentration.
Phase I reactions
Phase I reactions occur in the liver and convert lipophilic compounds into more polar molecules by introducing or unmasking a polar group functional group such as -OH or -NH2. The phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system and include oxidation, reduction, and hydrolysis.
Phase II reactions
Phase II reactions consist of conjugation reactions resulting in a polar molecule that is more water-soluble. Glucuronidation is the most common conjugation reaction but others include the addition of sulfuric acid, acetic acid, or an amino acid.
Hepatic metabolism
When lipid soluble compounds are metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called Phase I and Phase II.
Renal elimination
Elimination of drugs via the kidneys into the urine which involves the processes of glomerular filtration (20%) active tubular secretion (80%), and passive tubular reabsorption.
Biliary elimination
When drugs are not absorbed after oral administration or when they are secreted directly into the bile from the liver resulting in elimination through the feces.
Cytochrome P450 (CYP450)
Large super-family of heme-containing monooxygenase enzymes that can metabolize (oxidize or reduce) a large number of structurally different endogenous or exogenous compounds. P450 enzymes are primarily active in the liver.
Clinical factors that affect drug metabolism
Inhibiters of CYP450 (grapefruit juice), inducers of CYP450 (cigarette smoke), degree of plasma protein binding, tissue-specific accumulation, physiological barriers, transport across membranes, disease states, treatments (radiation therapy), genetics, and developmental age.
Three drugs that inhibit metabolism of other drugs (inhibit several CYP isozymes)
erythromycin, ketoconazole, and ritonavir
Three drugs with well-defined, genetically determined differences in metabolism
Codeine, clopidogrel, and tamoxifen
Effect of liver and kidney disease on drug elimination
In liver and kidney disease, drug metabolism is decreased leading to buildup of the drug in the tissues and possible toxicity.
Effect of cigarette smoking on drug elimination
Cigarette smoking increases drug metabolism (decreases half-life) with certain drugs and can result in a decreased therapeutic effect of the drug.
Ligand-gated ion channels
Span the plasma membrane and cause changes in membrane potential and ion concentration within the cell which lasts for milliseconds. (Ex: cholinergic nicotinic receptors)
G protein-coupled receptors
Heptahelical membrane-spanning receptors coupled to intracellular G-proteins that employ second messengers to convey information. These responses usually last seconds to minutes. (Ex: alpha and beta adrenoreceptors - 30% of drugs target these type of receptors)
Enzyme-linked receptors
Consists of a protein that may form dimers or multisubunit complexes and undergo conformational changes when activated. This results in increased cytosolic enzyme activity which lasts on the order of minutes to hours. (Ex: insulin receptors)
Intracellular receptors
The ligand must have sufficient lipid solubility to diffuse into the cell to interact with the receptor. The activated ligand-receptor complex then translocates to the nucleus where it often dimerizes before binding to transcription factors that regulate gene expression. The time course of activation and response of these receptors is on the order of hours to days. (Ex: steroid receptors)
Receptor binding
Governed by the affinity of the protein-ligand interaction and primarily mediated through noncovalent (weak) molecular forces (hydrogen bonding, ionic bonding, hydrophobic interactions, and Van der Waals)
Receptor activation
The interaction of the receptor with cellular molecules to cause a biological response after binding of the ligand. Receptor activation and response is governed by drug efficacy.
Drug affinity
The strength of the interaction between a drug and its receptor as measured by the dissociation constant (Kd). A drug’s affinity and intrinsic activity are determined by its chemical structure and bonds.
Kd
The concentration of a ligand which results in 50% of the bimolecular target being bound (or unbound) to that ligand. The smaller the value of Kd, the tighter the binding.
IC50
The concentration of a ligand which results in binding inhibition of another ligand to the
bimolecular target by 50%.
Ki
The concentration of an enzyme inhibitor required to reduce the maximal rate of an
enzyme by 50%.
Km
The concentration of substrate required for an enzyme to reach 50% of its maximal velocity. (Michaelis-Menten Constant)
ED50 or EC50
The ligand or drug concentration that produces 50% of the maximum possible effect/response (plotted on the x-axis of a dose response curve). The smaller the value of EC50 for a specific drug, the higher potency of the drug.
Emax
The maximal effect a drug achieves (plotted on y-axis of a dose response curve). The greater the value of Emax for a specific drug, the higher the efficacy of the drug.
Dose response curve
Useful when measuring and comparing potency and efficacy of a specific drug.
Albumin
A plasma protein that circulates in the blood and has the highest affinities for anionic drugs (weak acids) and hydrophobic drugs.
AGP, AAG, tor
A plasma protein that circulates in the blood and binds basic drugs. (aka ɑ1-acid glycoprotein)
Partial agonist
When a ligand binds to a receptor but does not produce the maximal effect even when all receptors are occupied. When in the presence of an agonist, partial agonists can act as antagonists of the full agonist. (Ex: aripiprazole, buprenorphine)
Full agonist
When a drug binds to a receptor and produces a maximal biologic response
that mimics the response to the endogenous ligand.
Antagonist
When a drug binds to a receptor with high affinity but possesses zero intrinsic activity. Antagonists have no effect in the absence of an agonist but can decrease the effect of the agonist when present.
Competitive antagonists
When both the antagonist and the agonist
bind to the same site on the receptor in a reversible manner. A competitive antagonist prevents an agonist from binding to its receptor and maintains the receptor in its inactive state. However, this inhibition can be overcome by increasing the concentration of agonist relative to antagonist. Competitive antagonists increase the EC50 value (decrease potency) of the agonist but do not effect Emax. (Ex: terazosin)
Irreversible antagonists
Bind covalently to the active site of the receptor, thereby reducing the number of
receptors available to the agonist. An irreversible antagonist causes a downward shift of the Emax (reduces agonist efficacy), with no shift of EC50 values (unless spare receptors are present). In contrast to competitive antagonists, the effect of irreversible antagonists cannot be overcome by adding more agonist
Allosteric antagonists
An allosteric antagonist causes a
downward shift of the Emax (reduces agonist efficacy), with no change in the EC50 value of the agonist. This type of antagonist binds to a site other than the agonist-binding site and prevents the receptor from being activated by the agonist. (Ex: picrotoxin)
Functional (physiologic) antagonists
May act at a completely separate receptor, initiating effects that are functionally opposite those of the agonist.
(Ex: functional antagonism by epinephrine to histamine-induced bronchoconstriction)
Efficacy
Maximal response of a drug (represented by high Emax)
Potency
Measure of the dose (concentration) required to produce a response (represented by low EC50)
Therapeutic Index (TI)
A measure of a drug’s safety, because a larger value indicates a wide margin between doses that are effective and doses that are toxic. (TI = TD50/ED50) The TI should be >1, ideally >10 (bigger is better).
TD50
The dose at which 50% of the animal/human subjects experience a
specific toxicity.
LD50
The dose at which 50% of animal subjects die.
M1 and M3 receptors
Stimulate phospholipase C (PLC) through Gq followed by the release of IP3 and DAG. This leads to an increase in calcium within the cell and hyperpolarization (relaxation).
M2 receptors
Activate potassium channels to increase conductance and inhibit adenylyl cyclase through Gi.
