Pharmacology Flashcards
Preclinical drug testing
In vitro studies to determine a lead compound from biologic products or chemical synthesis, followed by animal testing to determine efficacy, selectivity, and mechanism of drug action as well as safety concerns including dosing, toxicity, and mutagenicity
Phase I new drug testing
20 - 100 healthy patients; intended to determine pharmacokinetics in humans, safe & effective dosing, and toxicity
Phase II new drug testing
100 - 300 patients with disease; Investigational New Drug (IND) application describes the specific disease (indication); single blind comparison to placebo or established treatment
Phase III new drug testing
1,000 - 3,000 patients with disase; double blind, randomized trial to control for placebo effect and observer bias; approval of New Drug Application (NDA), FDA allows sale as Rx or OTC agent approved for specific indications
Phase IV new drug testing
Postmarketing surveillance of drug effects under actual conditions of use in a large number of patients; monitors rare & serious side effects
Dietary Supplement Regulation
According to the DSHEA Act of 1994, dietary supplements do not need to be tested for safety / efficacy by the FDA; any health claims made on the label must include disclaimer “not evaluated by FDA, not intended to prevent, diagnose, or treat” but burden to show unsafe lies on FDA
Generic equivalency
Bioequivalent drug products are pharmaceutical equivalent drug products (same active ingredient, same dosage formulation, same ROA, same strength / concentration) that also display the same biologic effects (rate and extent of absorption into plasma)
Generic product is bioequivalent to brand name if Cmax, Tmax, and AUC are equivalent
It is assumed that, in the absence of other evidence, bioequivalence = therapeutic equivalence
Pharmaceutical equivalents vs. Pharmaceutical Alternatives
Pharmaceutical equivalents - same active ingredients, same dosage formulation, same ROA, same strength/concentration
Pharmaceutical alternatives - same therapeutic moiety but different preparation or dosage formulation (oral vs. IV, rapid vs. extended release)
Controlled Substance Regulation (Federal & Colorado)
The Controlled Substances Act requires DEA licensing to prescribe controlled substances:
Schedule I - no accepted medical use, high abuse potential, cannot be prescribed
Schedule II - accepted medical use, high abuse potential; Rxs must be hand written in prescriber’s hand writing, cannot be telephoned to pharmacist, cannot be re-filled
Schedule III, IV, and V (in Colorado) may be telephoned to pharmacist and re-filled up to 5 times in 6 months
Oral ROA Considerations
Bioavailability (AUCoral / AUCiv) can vary from 0 to 100%
Weak acids are absorbed better in the stomach pH 1 - 2); weak bases are absorbed better in the upper intestine (pH 3 - 6)
Increased GI mobility increases speed of absorption by allowing drug to reach the greater surface area of the small intestine
Bioavailability (F)
Defined as the fraction of unchanged drug reaching systemic circulation following administration by any route
Described by the area under the curve (AUC) of a graph of Cp vs. time obtained following a single dose given by any route, compared to the graph following a single dose by IV
F = AUCroute / AUC iv
Generally only a consideration for oral ROA; most other ROAs have bioavailability approaching 100%
Volume of Distribution (Vd)
Describes the size of the compartment necessary to account for the total amount of drug in the body if present at the same concentration as in plasma
The greater the tendency for a drug to remain in the plasma, the smaller the value of Vd
Vd = Dose / Cp
Phase 1 Metabolism
CYP450 enzymes catalyze oxidation reactions on lipid-soluble molecules to increase solubility
Other reactions: reduction, hydrolysis (mediated by esterases, amidases, etc.)
Mostly occurs within the smooth ER of liver cells
Phase I enzymes are subject to induction / inhibition
Genetic polymorphisms exist; individuals may be ultrarapid metabolizers or poor metabolizers
CYP3A4 participates in the phase I metabolsim of 50% of all commonly used drugs
Phase II Metabolism
Mainly conjugation reactions carried out by transferase enzymes, ex: glucuronyl transferase, N-acetyltransferase, glutathione transferase, sulfotransferase
Tends to increase ionization and increase size
Pathways are generally saturable due to limited supply of conjugation reactants
Induction of Phase I drug metabolism
Inducers are generally TFs that increase production of CYP enzyme protein; generally takes 48 - 72 hours to see effect
Examples of inducers: Rifampin, ethanol, St. John’s Wort, Tobacco smoke, phenytoin, phenobarbital
Enterohepatic Recirculation
Drug and metabolites with MW > 300 may be absorbed into portal circulation, stored in the gallbladder, excreted via the bile duct and delivered to the intestines where it is reabsorbed and returns to the liver; this process reduces drug elimination and prolongs duration of action by keeping the drug in the body but out of the plasma
Drug Clearance (CL)
CL is defined as the volume of plasma (Vd) that is completely cleared of drug in a given period of time by all processes
Clearance is proportional to the elimination constant
Hepatic clearance varies with blood flow to the liver and hepatic metabolic activity; renal clearance varies with kidney function, necessitating “renal dosing”
Half Life (t 1/2)
The time required to eliminate 1/2 of the drug present in the body, regardless of total amount
Elimination constant (Ke)
The fraction of drug leaving the body, per unit time, via all elimination processes
Ke is the slope of the B elimination phase in a graph of ln Cp vs. time
First order elimination kinetics
Rate of drug elimination is proportional to the concentration of the drug in the plasma
Virtually all drugs are eliminated by first order elimination kinetics at therapeutic dosage levels
Zero order elimination kinetics
The rate of elimination of a drug from the body is independent of the amount of drug in the body; most often occurs due to saturation of hepatic metabolic processes (i.e. Phase II conjugations)
Occurs at therapeutic doses for aspirin, ethanol, and with toxic doses for many hepatically eliminated drugs
Dose fluctuation
Depends on the number of drug half-lives within the dosing interval (tau)
Magnitude of fluctuation is given by 2 ^ n where n = number of half-lives in the dosage interval
Dose-response curve
Plots the percent of the maximum response possible (e/Emax) on the y-axis vs. dose (D) on the x-axis
Hyperbolic curve is relatively linear at low doses indicating that, below EC50, response is proportional to dose
Curve is level at high doses indicating that dose-response is saturable
Drug Potency
The plasma concentration of a drug required to produce 50% of that drug’s individual maximum effect (EC50)
Depends on the affinity (Kd) of receptors for binding the drug
Maximal Efficacy / Power
Used to compare the efficacy of different drugs by comparing Emax values; full agonists have an Emax of 100% whereas partial agonists have an Emax < 100%
Competitive Reversible Antagonist
A class of pharmacological antagonist; binds reversibly to the active site of the same receptor as the agonist, blocking the agonist from binding and maintaining the receptor in its inactive conformation
Reduces apparent agonist affinity for receptor (decrease in EC50) because more drug must be administered in order to see the same effect; dose-response curve shifts to the right, Emax is unchanged
Ex: Metoprolol / Propanalol are competitive reversible antagonists of NE at beta 1 adrenergic receptors in the heart –> lowers HR
Noncompetitive Irreversible Antagonist
A class of pharmacological antagonist; binds irreversibly or pseudoirreversibly to the receptor active site, removing functional receptors from the system
Emax is reduced
Noncompetitive Allosteric Antagonist
A class of pharmacological antagonist; binds irreversibly to a different site on the receptor than the agonist, inhibiting the receptor from responding to an agonist
Emax is reduced
Physiological antagonist
Activates or blocks a different receptor than is bound by the agonist, usually mediating a physiologic response that is opposite to that of the action of the agonist at its receptor
Ex: The effect of histamine via histamine receptors to produce constriction of bronchiolar smooth muscle, and the antagonist action of epinephrine via adrenergic receptors to produce bronchiodialation when used in the treatment of anaphylactic shock
Chemical antagonist
Binds to the agonist directly, preventing its action
Ex: antacid neutralizing stomach acid
Quantal dose-response curves
Plotted as the fraction of a population that experiences an all-or-nothing response at each dose of a drug vs. the log of the dose
ED50 refers to the dose at which half of the individuals experienced the all-or-nothing effect
Therapeutic Index (TI)
The factor by which the dose that is effective in 50% of individuals (ED50) must be increased in order to cause death in 50% of individuals (LD50)
Standard Safety Margin (SSM)
The percent by which the dose that is effective in 99% of the population (ED99) must be increased in order to cause death in 1% of the population (LD1)
Useful when patient response to a drug varies widely
Mechanism of acetaminophen toxicity
Normally, 70 - 80% of Ac is conjugated through Phase II reactions and 5 - 10% proceeds through a phase I oxidation by CYP2E1, producing the chemically reactive Ac* metabolite which is further detoxified via Phase II
At toxic doses (> 4g/day), saturation of Phase II pathways shunts more Ac toward Phase I, producing higher levels of Ac* and leading to eventual depletion of cellular glutathione –> hepatotoxicity
Treatment: N-acetylcysteine serves as a precursor for glutathione synthesis and also functions as a nucleophile to capture Ac*
Effect of alcohol on acetaminophen toxicity
Alcohol induces CYP2E1, causing increased production of Ac*, and also decreases hepatic glutathione, leading to greater hepatotoxicity
Chronic alcoholics should not exceed 2g/day
Mechanism of methanol / ethylene glycol toxicity
Methanol is metabolized to formic acid, which causes visual disturbances followed by sudden death from respiratory suppression
Ethylene glycol is metabolized to oxalic acid, which causes kidney damage from calcium oxalate crystals leading to acute renal failure
Treatment: Giving ethanol to a BAC of .100 - ethanol competitively inhibits alcohol dehydrogenase, reducing production of toxic metabolites - or - administration of fomepizole, followed by hemodialysis to remove methanol / ethylene glycol and toxic metabolites; sodium bicarbonate to correct metabolic acidosis
Aspirin
Mechanism: Irreversible inhibition of COX1 and COX2
Effects: Analgesic, Anti-pyretic, anti-inflammatory, anti-platelet
Side effects: GI, Bleeding, Renal, delayed Labor,
Other: Reyes syndrome (contraindicated in children with viral infection), hypersensitivity allergy in 5-10% of asthmatics
Mechanisms of therapeutic uses of NSAIDS
Analgesia - inhibition of COX2 at sites of injury
Anti-pyresis - inhibition of COX2 in the hypothalamus
Anti-inflammatory - inhibition of COX2 at sites of inflammation
Anti-thrombogenesis - inhibition of COX1 in platelets
Mechanisms of NSAID side effects
GI irritation (ulceration, bleeding, nausea) - inhibition of COX1 in gastric cells
Increased bleeding - inhibition of COX1 (TXA2) in platelets
Renal failure - inhibition of COX1 and COX2 in kidney cells
Delayed labor - inhibition of COX2 in uterine smooth muscle
Thrombosis - inhibition of COX2 (PGI2) in vascular endothelial cells
tNSAIDS
i.e. Ibuprofen, Naproxen, etc.
Mechanism: Reversible inhibition of COX1 and COX2
Effects: Analgesia, anti-pyresis, anti-inflammation
Side effects: GI, bleeding, renal, delayed labor
Acetaminophen
Mechanism: Inhibition of COX2 in the CNS
Effects: Analgesia, anti-pyresis; NO anti-inflammatory or platelet action
Side effects: Mild; minimal renal effects, safe in pregnancy
> 4g/day leads to hepatotoxicity; acute OD treated with N-acetylcysteine
Celecoxib
Mechanism - Selective, reversible inhibition of COX2
Effects: Analgesia, anti-pyresis, anti-inflammation
Side Effects: Renal failure, increased thrombosis, delayed labor,
COX1
Constitutively expressed
GI tract: decreases acid production, increases mucous and bicarbonate (cytoprotective)
Platelets - Pro-aggregatory (TXA2)
Kidneys: - increases renal blood flow, promotion of diuresis
Pain
COX2
Expression is induced at sites of inflammation by cytokines
Hypothalamus - Fever (PGE2)
Pain
Vascular endothelium - vasodilation and platelet anti-aggregation (PGI2)
Inflammation
Uterine contraction
Mechanism of Aspirin anti-platelet effect
Low dose aspirin is essentially selective for platelet COX1 because it inhibits irreversibly and platelets, which are anucleate, cannot synthesize new COX1 enzyme; TXA2 synthesis is inhibited, reducing clotting
The largest concentration of ASA is contained in the presystemic (portal) circulation where it can have a greater effect on circulating platelet COX1 (versus its effect on endothelial cell COX2) and so the anti-platelet effect of COX1 inhibition is amplified relative to the pro-aggregation effect of COX2 inhibition
Legally required components of a prescription
Date
Prescriber name, address, professional degree, telephone number
Patient name, address
Drug name, strength, quantity, formulation
Dosage regimen, including amount of drug to be taken; time, frequency, and route of administration; duration of therapy
Refill information - one year limit on original prescription, regardless of # refills written
Prescriber signature, DEA number
Factors affecting oral bioavailability
Ability of drug to survive in GI environment
Ability of drug to cross GI membranes (lipid solubility, size, % unionized)
Efficacy of drug metabolism by gut wall or liver (first pass effect)
Drug formulation (extended release vs. liquid)
Considerations of rectal ROA
Useful when oral route is precluded by vomiting, unconsciousness, or GI injury/irritation
First pass metabolism is less than for oral ROA as approximately 50% of dose will bypass the liver
Considerations of sublingual / buccal ROA
Venous drainage from the mouth is to the superior vena cava; therefore less first pass metabolism plus faster onset of action
Useful for drugs that are lipid soluble and relatively potent due to the smaller surface area for absorption
Considerations of intramuscular ROA
Onset and extend of absorption affected by local blood flow at site of injection but can approach equivalence with IV route
Depot forms suspended in oil or other preparations exhibit slower, more sustained absorption
Considerations of subcutaneous ROA
Usually provides slower, constant rate of absorption; rate of absorption can be intentionally altered by varying particle size, protein complexation, etc.
Only for non-irritating drugs
Considerations of inhalation ROA
Systemic effects: Rapid and complete absorption due to large surface area and high blood flow in pulmonary tissue; comparable to IV
Local effects: Application of aerosolized particles at site of action in lungs; effect depends on particle size
Considerations of Transdermal ROA
Systemic effects: Prolonged drug levels can be achieved for systemic effects; first pass metabolism is avoided
Local effects: Via skin or mucous membranes for treating inflammation, infection, etc. Generally minimal systemic absorption.
Drug must be potent, able to permeate skin sufficiently, non-irritating
Where do tight junctions limit drug absorption?
GI mucosa - limits absorption of drug into blood through oral ROA
Blood Brain Barrier - limits distribution of drug from blood into brain
Placenta - limits distribution of drug from blood into fetal circulation
Renal Tubules - following filtration, limits reabsorption of drug back into the blood, enhancing excretion
Clinical significance of ion trapping
Alteration of urinary pH to ion trap weak acids or bases and hasten renal excretion; i.e. alkalinization of urine can trap weak acid aspirin in overdose situations
Greater potential to concentrate basic drugs (i.e. opioids) in more acidic breast milk
Plasma protein binding
Reduces concentration of active, free drug in circulation
Hinders metabolism and rate of excretion; increases half life & prolongs drug action
Decreases Vd
Decreases ability to enter CNS across BBB
Acidic drugs bind primarily to albumin; basic drugs bind primarily to alpha-1-acid glycoprotein
Cytochrome P450 independent oxidations
Phase I reactions mediated by enzymes other than CYP450, most often dehydrogenases, oxidases
Ex: Monoamine oxidase, important in neurotransmitter metabolism
Alcohol dehydrogenase
Inhibitors of Phase I metabolism
Inhibitors work by many mechanisms (competitive, non competitive, etc.) but generally take effect as soon as sufficient hepatic concentration is reached
Examples of inhibitors: erythromycin, ketoconazole, fluoxetine and other SSRIs, grapefruit juice, omeprazole, HIV protease inhibitors
P-Glycoproteins
ATP-fueled active transporters located on intestinal, renal, and hepatic epithelial cells; function to move xenoiotics, including drugs, out of the cell at sites of entry into the body; in the intestine they function to decrease absorption whereas in the liver and kidney they function to enhance elimination
Inhibitors of p-glycoproteins increase drug plasma levels
Inducers of p-glycoproteins decrease drug plasma levels
How are drugs excreted by the kidney?
Glomerular Filtration - drugs smaller than albumin will be filtered at a rate of 120ml/min; glomerular filtration rates are affected by renal blood flow & function
Active tubular secretion - drugs are transported directly from blood into urine at a rate of 120-600mL/min
HPA Axis
Stress stimulates the release of corticotropin releasing hormone (CRH) in the hypothalamus; CRH stimulates the release of adrenocorticotropic hormone in the hypothalamus which stimulates the production of cortisol and aldosterone in the adrenal gland.
Cortisol produced from the adrenal gland negatively regulates the production of both CRH and ACTH in the hypothalamus
Metabolic effects of glucocorticoids - Carbohydrates
Stimulates gluconeogenesis, leading to increased blood sugar and subsequent insulin release
Can lead to a diabetes-like state
Metabolic effects of glucocorticoids - Protein
Decreases protein synthesis, and increases breakdown of protein to glucose (gluconeogenesis)
Can result in peripheral muscle wasting
Metabolic effects of glucocorticoids - Fat
Increased breakdown of triglycerides into free fatty acids; elevated insulin caused by increased blood sugar stimulates the uptake of free fatty acids into triglycerides in the central body
Can lead to centripetal obesity
Mineralcorticoid effects of glucocorticoids
Mimic the effects of aldosterone on mineralcorticoid receptors in response to reduced blood flow
Increased reabsorption of Na+ and H2O coupled with loss of K+ and H+ can lead to hypertension, edema, hypokalemia, and metabolic alkalosis
Cellular & Vascular effects of glucocorticoids
Vascular effects: reduced vasodilation, decreased fluid exudation
Cellular effects: Decreased activation and chemotaxis of neutrophils in areas of acute inflammation; decreased activity of monocytes and lymphocytes, decreased angiogenesis and fibrosis at areas of chronic inflammation
Glucocorticoid Metabolism
11-keto glucocorticoids (i.e. Cortisone, Prednisone) are prodrugs that must be activated by 11B hydroxysteroid dehydrogenase I (11B-HSD I) in the liver to form active 11-hydroxy glucocorticoids (i.e. Cortisol, Prednisolone)
11-hydroxy glucocorticoids are inactivated in the kidney by 11B-HSD2, which converts them back to 11-keto glucocorticoids
Hydrocortisone
11-keto glucocorticoid pro-drug, must be activated to cortisol by 11B-HSDI in the liver; activated upon first pass metabolism when given orally (no topical activity)
Drug of choice for replacement therapy, i.e. Addison’s Disease
Glucocorticoid and mineralcorticoid action
Prednisone
11-keto glucocorticoid, must be activated to prednisolone by 11B-HSDI in the liver; activated by first pass metabolism when given orally (no topical action)
Most commonly used oral agent for steroid burst therapy
Methylprednisolone
Major parenteral (IV) agent for steroid burst therapy
Glucocorticoid action only; no mineralcorticoid activity
Dexamethasone
Most potent anti-inflammatory agent; no mineralcorticoid action
Used when water retention is undesirable, as in cerebral edema
Triamcinolone
No mineralcorticoid action; used topically
Fludrocortisone
Drug of choice for mineralcorticoid effects
Lipid:water partition coefficient
Describes the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium
Drugs with a high lipid:water partition coefficient are highly lipid soluble
