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243 Cards in this Set
- Front
- Back
What are the sponsor responsibilities of FDA?
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1. File an INVESTIGATIONAL NEW DRUG APPLICATION (INDA) prior to phase 1 testing
2. Reporting any serious and unexpected adverse effects in 10 days 3. Bioavailability studies 4. Seek final approval |
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What are legend drugs?
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by prescription only
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What are the steps of development of new drugs?(8)
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1. ID chemical compound (invitro testing)
2. Preclinical research animal testing 3. INDA 4. Phase I 5. Phase II 6. Phase III 7. NDA 8. Post Marketing Surveillance |
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What is clinical testing?
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Phase 1-3
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What is Phase 1?
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Is it safe? pharmacokinetics?....20-100 subjects
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Phase 2?
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Does it work in patients (100-200 subjects)
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Phase 3
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Does it really work? double blind. 1000-6000 patients
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Phase 4....
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Post marketing surveillance
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The orphan drug act of 1983
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provides incentives for developmnet of drugs for treatment of rare diseases/conditions....any disease that effects less than 200,000 ppl in US OR affects more than 200,000 but no expectation of making money from the drug
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Blue book
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bioequivalence
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Orange book
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Therapeutic equivalence
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TO be therapeutic equivalent must meet the following criteria
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1. safe and effective
2. identical quantities of same active ingredients 3. Same standards of strength, quality and purity 4. Bioequivalent 5. Adequate labeling 6. compliance with FDA regulations |
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Therapeutic equivalent example
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Prevacid and prilosec
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What is the GOLD Standard in clinical testing
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Randomized, Double-blind placebo controlled trial (RCT)
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US pharmacopeia (1820)
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first compendium of standard drugs for the US
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Pure Food and Drug act of 1906
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prohibited mislabeling and adulteration of drugs
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Federal Food and Drug and cosmetic act of 1938
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Required that new drugs be safe and pure (does not require proof of efficacy)
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Durham-Humphrey act of 1952
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FDA the power to determine which products could be sold without prescription
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Kefauver-Harris Ammendments (1962)
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Required proof of efficacy as well as safety for new drugs; guidelines for reporting of adverse reactions, clinical testing and ad of new drugs
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Comprehensive drug abuse prevention and control act
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strict controls in manufacture, distribution and RX of habit forming drugs; est drug schedules and programs to prevent and treat drug addiction
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Dietary supplement health and education act
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Est. standards for dietary supplements but no full FDA review of supplements. Required specific ingredient and nutrition labeling....classifies as part of the food supply but allows unregulated advertising.
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Thalidomide leads to
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Phocomelia- a condition involving shortening or complete absence of the limbs
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Which MD refused FDA approval of Thalidomide
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Frances Oldham Kelsey
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What is the misconception of ASA?
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Prevents heart attach in men more; prevents stroke in women more
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What does post market research do?
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Subgroup analysis (sex, race/ethnicity, age, co-morbidity), new indications for existing drugs, drug combinations
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When is a black box warning issued by black box warning
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1. Drug presents a unique risk/benefit concern compared to other drugs in the same class
2. Potential adverse reaction is extremely significant above the drug's benefit 3. When such adverse reaction can be prevented or reduced by limited used or defined cautions |
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With black box this needs to be
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1. prescribers are obligated to provide patients with info on treatment risks, benefits and warnings
2. Should be documented in the record |
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What is pharmacology
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defeined as the study of substances that interact with living systems through chemical processes esp by binding to regulatory molecules
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What is pharmacokinetics?
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the absorption, distribution, and elimination of drugs.
WHAT THE BODY DOES TO THE DRUG |
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What is pharmacodynamics
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the actions of the chemical on the organism. WHAT THE DRUG DOES TO THE BODY
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What is toxicology
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branch of pharmacology that deals with undesirable effects of chemicals on living systmes...ALL SUBSTANCES HAVE A POTENTIAL FOR toxicity
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Pharmacogenomics
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genetic variations that cause differences in drug response among individuals or populations
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Pharmacologic agonist
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agent binds to and activates the receptor - directly or indirectly causing an effect (FULL OR PARTIAL agonists)
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PHARMAcologic antagonist
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agent binds to a receptor - competing with other molecules and preventing binding by other molecules - inhibitor
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Pro-drug
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an inactive precursor chemical - must be absorbed and distributed and converted to the active form of the drug by biologic processes
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What makes an IDEAL DRUG? (5)
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1. Dec mortality and morbidity
2. improves quality of life 3. Effective 4. Low cost 5. Simple administration and dosing |
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Therapeutic goal -
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to obtain and maintain concentrations within the therapeutic window for desired response and minimal toxicity
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What are the fundamental pathways of drugs? (PHARMACOKINETICS)
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ADME: Absorption, distribution, metabolism, and elimination
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absorption -
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entry of the pharmacologic agent into plasma
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distribution
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agent leaves bloodstream and distributes to interstitial and intracellular fluids
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Metabolism
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agent must be metabolized via liver, kidney, or other tissue
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elimination
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agent metabolities must be elminated from the body (urine, bile, feces)
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Enteral drug administration...
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easily self-administered. complicated drug aborption.
First pass metabolism affects influenced by food and other drugs |
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Parenteral drug administration
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IV, IM, SC. More control over dose of drug. bypass first pass.
CANT TAKE it back, infection risk |
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Inhalation
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rapid delivery, large surface area (good for gases)
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Rectal
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(50% of circulatory drainage bypasses portal circulation)
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Drug transport GI (3)
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Passive diffusion, active transport, and endocytosis
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Passive diffusion
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concentration gradient across a membrane
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Active transport
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energy dependent, able to move drug from lower to higher concentration
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Endocytosis
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Transport of large size molecules. Englfment of drug molecule by cell membrane and transport into cell.
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Drug abosrption...
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drugs are typically weak acids or weak bases. Acidic release an H. Drug passes readily when uncharged.
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Size and molecular weight of drugs
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play a role in drug absorption. Lithium (7) to thrombolytic enzymes (50000). Smaller...easier to cross membranes
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Concentration of drug depends upon
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pH of the drug.
pH at the compartment site pka of the drug. |
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Only the non-ionized
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form of the drug can diffuse across membranes
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the pKa of drug=
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pH of tissue or fluid when 50% ionization occurs (equalization of ions and non-ionized molecules)
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Factors in absorption and distribution
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Chemical Properties (solubility: hydrophilic vs lipophilic); chemical nature - pH and pKa. Molecular weight, partition coeffient
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Lipid: aqueous partition coefficient
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of a drug determines how easily the molecule moves between aqueous and lipid media
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pKa is the pH at which
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the concentrations of the ionized and non-ionized forms are equal
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Partition coefficient
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ratio of lipid solubility to aqueous solubility....
The higher the partition coefficient the more membrane soluble is the substance |
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Factors influencing GI absorption
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blood flow (intestinal>stomach)
pH - esp with H2 receptor blocker or PPI Surface area - intestinal surface microvilli Contact time with absorp surface |
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Contact time with absorptive surface
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- rapid versus slow GI transport.
- parasympathetic input - inc rate of gastric emptying -sympathetic input - delayed gastric emptying -food |
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Bioavailability
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-Fraction of chemically unchanged drug that reaches systemic circulation
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Factors influencing bioavailability
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- first pass metabolism
- solubility -chemical instability (like insulin in the GI tract) -Nature of the drug formation (chemistry, particle size, coatings, binders, etc) |
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First pass hepatic metabolism and bioavailability
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-drug absorbed across GI tract - enters portal circulation prior to systemic circulation
-If drug undergoes rapid metabolism by the liver, dec amount of unchanged drug enters systemic circulation |
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Solubility of drugs and bioavailaility
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hydrophilic drugs poorly absorbed (cant cross membrane)
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IDEAL drug for absorption
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- largely hydrophobic, but with some solubility in aqueous solution
-some highly lipid-soluble drugs are transported in aqueous solutions in the body via carrier proteins like albumin |
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Bioequivalence
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Comparable bioavailability and similar time to achieve peak plasma concentration; Related drugs that do not demonstrate comparable bioavailability are BIOINEAUIVALENT
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Therapeutic equivalence
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Similar drugs deemed therapeutically equivalent if comparable efficacy and safety
***Clinical effectivess is dependent on serum drug concentrations and the time it takes to reach peak drug concentrations THEREFORE. two drugs that are bioequivalent may not be therapeutically equivalent |
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Drug distribution
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process in which drug reversibly leaves blood stream and enters interstitium and/or cells
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Drug delivery is dependent upon
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1. blood flow
2. capillary permeability 3. Plasma protein binding 4. drug structure - hydrophobicity |
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Wide varience in drug distribution r/t
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unequal distribution of cardiac output
1. highest in organs, 2. lower in skeletal muscle 3. still lower in adipose tissue |
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drug distribution in capillary permeability
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governed by capillary structure and chemical nature of the drug
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Variance in capillary structure:
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slit junctions btw endothelial cells
- largely present in liver and spleen. allows passage of plasma proteins and thus drug molecules ABSENT IN THE BRAIN. (blood brain barrier) |
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in the blood brain barrier
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drugs must pass through endothelial cells of the CNS capillaries or be actively transported.
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Lipid-soluble drugs penetrate the CNS by
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dissolving in the membrane of the endothelial cells
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What is the basic calculation for IBW for women
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100+5 # for ever inch over 60 inches
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What is the basic calculation for IBW for men
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100+6# for every inch over 60 inches
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Concentration of drug depends on
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pH of drug, pH at compartment site
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What form of drug can diffuse across cell membranes?
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non-ionized form of drug
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The pKa of a drug=
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pH of tissue or fluid when 50% ionization occurs (equalization of ions and non-ionized molecules)
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pKa is the pH where
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50% of the drug is ionized and 50% is not
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The higher the partition coefficient t
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then more membrane soluble is the substance
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Chemical nature of the drug
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largely determines its ability to cross cell membranes
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Hydrophobic drugs
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no net charge, uniform electron distribution. Able to dissolve in lipid membranes - permeate cell surface.
IMPACTED BY blood flood to region |
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Hydrophillic drugs
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-positively or negatively chargd
-do not easily pass through cell membranes -need slit junctions for passage |
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Plasma protein binding generally
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reversible and non-selective: drugs bind where other compounds - such as bilirubin would normally attach
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Plasma albumin
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major drug binding protein
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What may act as a drug reservoir?
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Plasma albumin. As free drug concentration decreases protein bound drug dissociates from the protein. Maintains free-drug concentration as constant fracture of total drug in plasma
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Volume of distribution
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hypothetical volume of fluid into which the drug is dispersed
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Large volume of distribution
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impacts half-life
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Drug elimination is dependent on
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-amount of drug delivered to kidney or liver (wherever metabolism occurs)...which depends on blood flow and fraction of drug in plasma
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If Volume of distribution is large
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-majority of drug is not in the plasma and is not available to excretory organs
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Factors that inc volume of distribution
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also
increase half-life extend duration of action |
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Very large Vd suggests
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DRUG SEQUESTration in organ/compartment
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Plasma protein binding
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binding capacity of albumin
competition for binding |
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ClassI drugs protein binding
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MAJORITY of agents.
-dose< albumin binding capacity -low dose/capacity ratio |
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Class II drugs protein binding
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MINORITY of agents
-High dose/capacity ratio -Highly protein bound -> less 'free drug' ex Warfarin |
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drug displacement from albumin
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substantial source of drug interactions
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Class I drug - warfarin
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highly protein bound - small fraction of free drug in plasma
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Class II drug given - sulfa
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-displaces warfarin from albumin;
- rapid rise in free drug concentration. Inc therapeutic effect - toxic effect |
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Large volume distribution
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displaced drug may distribute to periphery; insignificant change in free-drug concentration
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Small volume distribution
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displaced drug less likely to distribute to tissues -> more significant change in free drug available in plasma
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Therapeutic index
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if therapeutic index is narrow -> small increase in drug concentration may have substantial clinical impact
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First order kinetics (majority of drugs)
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- metabolic transformation of drugs by enzymes
-rate of drug metabolism is directly proportional to the concentration of free drug, so constant fraction of drug per unit of time |
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linear elimination pattern -
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reflected by the 1/2 life of the drug
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each half life cuts the drug concentration by
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50%
-at 2 half-lives - drug has been 75% removed -at 5 half-lives - drug is essentially removed from the body |
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Zero order kinetics (minority of drugs)
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- ASA, ETOH, phenytoin
-rate of metabolism is constant over time, therefore a constant amount of drug metabolized per unit of time |
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Processes of drug metabolism (Phase I)
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involves oxidation, reduction and hydrolysis to inc polarity and water solubility of the drug
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Processes of drug metabolism (Phase II)
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involves conjugation - reaction in which a large chemical group is attached to the molecule to inc solubility and facilitate excretion of the metabolite from the body
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Following phase I,
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the drug may be activated, unchanged or most often, inactivated
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Phase II
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Some drugs directly enter phase II metabolism. Following Phase II conjugated drug is usually inactive
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Kidney and lipophilic drugs
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kidney is typically unable to effectively eliminate lipophilic drugs (can cross cell membranes and reabsorb into distal tubule)
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Phase 1 metabolism and p450 system
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serves to convert lipophilic molecule into more plar molecules. Phase I metabolism can inc, dec or leave drug pharmacologic activity unchanged
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Lipid soluble agents must be metabolized
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in the liver. - phase I/Phase iI.
Phase I reactions - involve CYP450 system |
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Cytochrome P 450 System
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-Comprised of many families of isoenzymes. (found in most cells, much higher amounts in liver & GI tract) Various mutations result in INCREASED or DECREASED ability to metabolize certain drugs.
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Inducers - which increase enzyme synthesis
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drugs can be inducers of certain CYP isozymes
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Inducers results in increased biotransformation of drug
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-dec blood concentrations
-dec drug activity if metabolite is inactive -inc drug activity if metabolite is active -dec therapeutic drug effect |
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Ex of Inducer
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rimfampin dec Haart therapy - dec suppression of HIV virus
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Inhibitors- dec enzyme synthesis
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inhibitor of CYP isozyme activity is also important. Most through competition for isoenzyme
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Many drugs inhibit one or more biotransformation pathways of warfarin
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EXample omeprazole inhibits 3 pathways.
-warfarin + omeprazole => warfarin level |
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due to inhibitors....inc drug levels can occur over time leads to
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prolonged drug effects, inc drug toxicities
EX: grapefruit juice inhibits CYP3A4 |
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Phase II reactions result in
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more polar and water soluble therapeutically inacitve substances which are then able to be eliminated by the kidneys.
NEONATES are deficient in this conjugating system |
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Extraction ratio
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decline of drug concentration in the plasma from the arterial side to the venous side of the kidney
Drug concentration entering kidney=C1 exit kidney=c2 Extraction ratio = C2/C1 |
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Excretion rate=
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clearance* plasma concentration
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Drug half -life increased
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1. Diminished renal plasma flow or hepatic blood flow (shock)
2. Dec extraction ratio 3. Dec metabolism (concomittant drug inhibitiation of biotrans). Hepatic insuff |
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Drug half-life decreased
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1. inc hepatic blood flow
2. Dec protein binding 3. Inc drug metabolism |
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What do you assum in pharmacokinetics of continuous iv infusion?
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1. rate of infusion constant, first order kinetics
2. Constant fraction of agent is cleared per unit of time |
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Rate of excretion increases proportionately as the
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plasma concentration rises
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Steady-state
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achieved when the plasma concentration remains constant
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Drug input rate=
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drug elimination rate
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steady state plasma concentration is directly proportional to
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infusion rate
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Steady state concentration is inversely proportional to
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drug clearance
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Any factor increasing drug metabolism will
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dec the steady state concentration
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Rate of drug concentration decline when
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drug infusion is terminated. plasma drug concentrations dec to zero at the same time rate as when approaching steady state
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Loading dose
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used when more rapid attainment of desired plasma drug level is clinically important
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cost benefit analysis
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eval impact of intervention/program on population
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Principles of pharmacoeconomics
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all scarce items have a cost.
Ppl want what they want at a lower cost |
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Adverse drug reactions that are both serious and unexpected must be reported to FDA
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within 15 days
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all addictive drugs activate the
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mesolimbic dopamine system
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Schedule I (CI):
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The drug or other substance has a high potential for
abuse ***never RX • has no currently accepted medical use in treatment in the United States • has no accepted safe use under medical supervision. • Examples: heroin, marijuana |
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Schedule II (CII):
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The drug or other substance has a high potential for
Abuse • has a currently accepted medical use in treatment in the United States, or • has a currently accepted medical use but with severe restrictions, and • abuse of the drug or other substances may lead to severe psychological or physical dependence. • Examples: OPIOD |
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Schedule III (CIII):
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The drug or other substance has a potential for abuse less
than the drugs or other substances in schedules I and II, • has a currently accepted medical use in treatment in the United States • abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence. • Examples: hydrocodone, codeine |
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Schedule IV (CIV):
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The drug or other substance has a low potential for abuse
relative to the drugs or other substances in schedule III, • has a currently accepted medical use in treatment in the United States • abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III. • Examples: benzodiazepines |
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• Schedule V (CV):
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The drug or other substance:
• has a low potential for abuse relative to the drugs or other substances in schedule IV, • has a currently accepted medical use the U.S. • abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances |
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Psychomotor Stimulants
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Methylxanthines
• include theophylline, (found in tea) • theobromine (found in cocoa) • caffeine |
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Methylxanthines stimulate secretion of
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hydrochloric acid from the gastric mucosa
• PUD: people w/ peptic ulcers should avoid beverages containing methylxanthines. |
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A high dose of caffeine has what effect on cardiovascular
|
positive inotropic and chronotropic effects on the heart.
• Increased contractility can be harmful to patients with angina pectoris. • In others, an accelerated heart rate can trigger premature ventricular contractions • Diuretic action: Caffeine has a mild diuretic action that increases urinary output of sodium, chloride, and potassium. |
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Therapeutic uses: Caffeine
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relax the smooth muscles of the
bronchioles. (Previously the mainstay of asthma Rx) |
|
Pharmacokineticsof caffeine
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well absorbed orally
• Caffeine distributes throughout the body, (including the brain) • cross the placenta to the fetus and is secreted into the mother's milk • All methylxanthines metabolized in the liver • metabolites excreted in urine |
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Nicotine enters brain Stimulation of
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nicotine receptors
Dopamine release Dopamine Reward Pathway Prefrontal cortex Nucleus accumbens Ventral tegmental area |
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pharmacokinetics of nicotine
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Highly lipid soluble, absorption readily occurs via the oral mucosa, lungs, gastrointestinal mucosa, and skin
• Crosses placenta and secreted in breast milk • Average smoker takes in 1 to 2 mg of nicotine per cigarette • (most cigarettes contain 6 to 8 mg of nicotine) • > 90% of the nicotine inhaled in smoke is absorbed |
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nicotine receptors
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Receptors sites in the CNS- part of stimulant properties of nicotine
• Actions: • CNS: Nicotine- highly lipid soluble, readily crosses BBB |
|
• Smoking cessation:
|
combining pharmacologic and
behavioral therapy most successful to stop smoking |
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Bupropion
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(antidepressant) can reduce the craving for cigarettes.
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Partial nicotinic receptor agonist
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Varenicline (competes with the nicotine receptors)
|
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Partial agonist
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produces less euphoric effects than nicotine itself (nicotine is a full agonist at these receptors)
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VARENICLINE:
Mechanism of Action |
Competitively inhibits binding of nicotine...Patients should begin therapy 1 week PRIOR to quit date.
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BUPROPION SR: Mechanism of Action
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Atypical antidepressant thought to affect levels of various brain neurotransmitters:
Dopamine, Norepinephrine |
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Drugs of Abuse: Cocaine
• Mechanism of action: |
• Primary mechanism causing central and peripheral effects of cocaine is blockade of reuptake of the monoamines (norepinephrine, serotonin, and dopamine) into the presynaptic terminals
• Prolongation of dopaminergic effects in the brain's pleasure system (limbic system) produces intense euphoria that cocaine causes • Chronic intake of cocaine depletes dopamine. • depletion triggers vicious cycle of craving for cocaine that temporarily relieves severe depression |
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Drugs of Abuse: Cocaine
• Actions: CNS |
Behavioral effects d/t stimulation of the cortex and brainstem
• Acutely increased mental awareness, produces feeling of well-being and euphoria (similar to amphetamine) |
|
Drugs of Abuse: Cocaine
• Sympathetic nervous system: |
Peripherally, cocaine potentiates the action of norepinephrine, and it produces the “fight or flight” syndrome
• tachycardia, hypertension, pupillary dilation, peripheral vasoconstriction • ability of baroreceptor reflexes to buffer the hypertensive effect may be impaired • Hyperthermia: Unique aspect of Cocaine - death can result secondary to dose but also d/t propensity to cause hyperthermia. |
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Amphetamine:
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noncatecholaminergic sympathetic amine that shows neurologic and clinical effects similar to cocaine
|
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• Amphetamine achieves effect by
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releasing intracellular stores of catecholamines
• behavioral effects of amphetamine are similar to cocaine |
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Elimination of THC
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via biliary route
|
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Oxidation of acetaldehyde inhibited by disulfiram
|
Drug used to deter drinking in alcohol dependent patients
• If ethanol consumed in the presence of disulfiram: • acetaldehyde accumulates - causes facial flushing, nausea, vomiting, dizziness, h/a |
|
Naltrexone, relatively long-acting opioid receptor antagonist, FOR ETOH
|
→ blocks the effects at opioid receptors
• dose-dependent hepatotoxicity • caution w/ elevated LFTs • Also causes opiate withdrawl |
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best overall index of kidney function
|
Glomerular filtration rate (GFR)
|
|
• Variables due to pharmacokinetics include:
|
impaired renal and liver clearance, circulatory impairment or failure, altered drug binding to plasma proteins, impaired GI absorption, and pharmacokinetic drug interactions
|
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Therapeutic Index
|
Expression of relative safety of a drug.
• The closer the ratio is to 1, the less safe the drug (Digoxin) • Calculated as the toxic dose for 50% of people (TD50) divided by the Effective dose for 50% |
|
Chronotherapy considerations
|
statins more effective taken at night
|
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Additive effect
|
(drug A + drug B = effects A+B)
• When 2 drugs w/ similar action taken together and combined effect is summative (1+1=2) |
|
Synergistic effect
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Result of 2 drugs that when combined have > results than the sum of both drugs given alone (1+1=3) GREATER EFFECT
|
|
Drug Efficacy
• Efficacy - |
determined by the number of receptor-drug couplings formed and the efficiency of these activations to produce a cellular response.
|
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Agonists
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fit into the lock and key and ACTIVATES it
|
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antagonist
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fit into the lock and key and breaks off the key….DOESNT ACTIVAT
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Down regulation:
|
• constant stimulation of receptor → leads to ↓ responsiveness
• (Receptors move intracellularly because the receptor gets tired |
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• Refractoriness:
|
• severe down regulation leading to lack of response to drug
|
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Up regulation:
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occurs following period of down regulation, → then absence of stimulation (by the drug), → followed by hypersensitivity to the drug…..because the receptor hasn’t seen the drug in awhile
• (Receptors return to cell surface) |
|
ligand
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Any chemical that will react with or bind to a receptor site
|
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• Receptors:
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protein molecules embedded in cell membranes with ligand binding sites located on the outer surface of cells
|
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Flomax – BPH –
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alpha blocker, relaxes smooth muscle in urinary tract. Also causes syncope…due to dilated vessels in legs
|
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htn result of
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increased peripheral vascular smooth muscle tone
|
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baroreflexes
|
sense changes in BP
|
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Arterial Blood Pressure=
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= Cardiac output * Peripheral Resistance
|
|
Angiotensin II is a POTENT circulating vasoconstrictor-so if we suppress this,
|
we can REALLY decrease BP
|
|
first line treatment for mild htn
|
Thiazide Diuretics
|
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How do thiazide diuretics work?
|
inhibit Na reabsorption in distal tubules, excrete NA, water, K and H
|
|
Adverse effects of Thiazides
|
o Electrolyte disturbances (hypokalemia & hypomagnesemia)
o Hyperuricemia o Hyperglycemia o Photosensitivity ....• Avoid With severe renal disease & liver dysfunction…. • Drug interactions: Digoxin, lithium, cyclosporine |
|
Side effects to monitor with thiazides
|
orthostatic hypotension, weight change, I/O, electrolytes, renal function ….TAKE In AM
|
|
• Mechanism of action of Beta blockers
|
dec CO through
o Neg chronotropic (dec HR) and inotropic effects (dec contractility) • Use in HTN, CHF, glaucoma, etcetc |
|
Side effects of beta blockers
|
• AV conduction abnormality! (heart block), acute heart failure, and bradycardia...Sweating. Hyperglycemia.
side effect of blockage with others are bronchospasm and dec peripheral blood flow (arteriolar) |
|
Whats another use for beta blockers
|
liver patients
|
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When do you never initiate therapy of beta blockers
|
acute decompensated heart failure
|
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What are the benefits of ACE inhibitors
|
slow progression of heart failure, Post MI, slows diabetic nephropathy
|
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What are side effects of ace inhibitor
|
! Small bump in creatinine, cough, rash (spotty, macular, papillary), angioedema. Start low and go slow
|
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diff between hypertensive urgency and emergency?
|
urgency - no end organ damage
|
|
What are the 3 's of Sodium Nitro?
|
Closely monitor >3 micro grams per kilo per min.
No longer than 3 days. Not with creatinine greater than 3 |
|
What test for statins?
|
baseline liver function and continuuous monitor
|
|
What are the 3 approved Beta blockers for HF?
|
carvedilol, metoprolol succinate (Toprol XL) and bisoprolol
|
|
What is the best drug for HF pt with arrythmias?
|
Digoxin
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Angiotensin converting enzyme (ACE) converts angiotensin I to
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angiotensin II. POTENT circulating vasconstrictor. SOOOO we really want to block this!
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Why use thiazide diuretics?
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mild to mod HTN.
Treatment of edema and nephrotic syndrome. |
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examples of thiazide diuretics
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HCTZ & metolazone
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What are the uses of beta blockers
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HTN, CHF, glaucoma, hyperthyroidism, angina pectoris, & post MI therapy
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Beta 1 receptors stimulation
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*heart, kidney*
contractility, conduction velocity, renin release, |
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Blockade of beta 1 leads to reduction in
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CO, renin release, sympathetic activity, workload, and oxygen demand....SE of blockade= AV conduction abnormality, acute heart failure, and bradycardia
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Stimulation of beta 2 receptors
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*lungs, liver, pancreas, smooth muscle*
vasodilation, bronchodilation, smooth muscle relaxation. |
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SE of blockade of Beta 2
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bronchospasm and dec peripheral blood flow
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SE of beta blsockers
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fatigue, dizzy, hypotension, bradycardia, inc sweating, hyperglycemia....can mask signs of hypoglycemia
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All the side effects of Ace inhibitors
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1. hypotesn
2. inc K 3. cough 4. rash 5. renal dys 6. angioedema 7. neutropenia, agranulocytosis, proteinuria |
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mechanism of action with angiotensin receptor blockers
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block the AT-1 receptors, preventing the activity of angiotensin II. Produce arterial and venous dilation and blocks the aldosterone sec
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uses of angiotensin receptor blockers
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alternative to ACE inhibitor or with ACE inhibitor in heart failure. Treat HTN with diabetic nephropathy, 2ndary stroke prevent, and left ventricular hypertrophy
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What are the advantages over ace inhibitors for angiotenin recept. blockers
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no inc in bradykinin. so no cough. dec angioedema risk
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Side effects of angiotensin receptor blockers
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renal insufficiency, hyperkalemia, angioedema. contraindicated in preg
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Mechanism of action of selective renin inhibitors
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directly inhibits renin....as effective as ACE inhibitors and ARB at BP control
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What are the SE of Selective renin inhibitors?
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cough, angioedema, diarrhea,
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Mechanism of action of Ca Channel blockers
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dec the force of contraction of the myocardium, slows the conduction of electrical activity, relax cardiac and smooth muscle
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Dihydropyridines
Nifedipine, Amlodipine Use |
Reduce systemic vascular
resistance and arterial pressure Chronic stable angina |
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Side effects of ca channel blockers
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Side effects
Peripheral edema, bradycardia, gingival hyperplasia, reflex tachycardia, constipation, dizziness, headache, flushing |
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selective alpha 1 blockers mechanism of acction
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Inhibit catecholamine uptake in the smooth muscle
cells of the periphery resulting in vasodilation |
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use and benefit of alpha 1 blockers
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In combination with other therapies for HTN
All equally effective; differ in duration Benefits Use in benign prostatic hyperplasia (BPH) No effects on glucose or lipids |
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Clonidine
Mechanism of action |
α2-receptor agonism to diminish central
adrenergic outflow Uses HTN therapy if two or more drugs are failing Monitoring Can cause sodium and water retention Compliance – rebound hypertension Side effects Sedation, drying of mucous membranes |
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Methyldopa
Mechanism of action |
Prodrug converted to methylnorepinephrine
centrally to diminish outfrom from the CNS Uses HTN therapy with one or more agents in patients with renal insufficiency HTN in pregnancy Side effects Sedation, drowsiness |
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Hydralazine (vasodilator)
Side effects |
Headache, tachycardia, nausea, sweating
Arrhythmia with risk of angina precipitation Dose-dependent lupus-like syndrome Reversible on discontinuation of drug Concerns Can lose hypotensive effectiveness over time unless given with beta blocker and diuretic |
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Minoxidil
Mechanism of action |
Dilation of arterioles
Uses Treatment of severe to malignant HTN that is refractory to other drugs Side effects Reflex tachycardia, sodium and water retention (volume overload, edema, CHF) Hypertrichosis |
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Sodium Nitroprusside
Mechanism of action |
Causes prompt arterial and venous dilation with
reflex tachycardia Uses Hypertensive emergency as continuous IV infusion Side effects Hypotension Nitroprusside metabolized into cyanide ions Treated with infusion of sodium thiosulfate |
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Nitroglycerin
Mechanism of action |
Nitrate resulting in vasodilation
Uses Hypertensive emergency as continuous IV infusion Side effects Headache, lightheadedness Hypotension |
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Fenoldopam
Mechanism of action |
Peripheral dopamine-1 receptor agonist that
lowers BP while maintaining renal perfusion Uses Hypertensive emergency as continuous IV infusion Side effects Headache, flushing, dizziness Hypotension Cardiac dysrhythmia |
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Carbonic Anhydrase Inhibitors
Mechanism of action |
Inhibits intracellular carbonic anhydrase on the
apical membrane of the proximal tubule Decreases ability to exchange Na+ for H+, resulting in a mild diuresis Uses Glaucoma, mountain sickness, contraction alkalosis (↑ HCO3 -, ↓ Cl-) Available agent Acetazolamide |
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Carbonic Anhydrase Inhibitors
Side effects |
metabolic acidosis
Hypokalemia Renal stone formation Drowsiness Paresthesia Decreased excretion of NH4 + in liver failure |
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Nitroprusside (Nipride)
Actions |
Nitric oxide mediated vascular smooth muscle
relaxation Potent arterial and venous vasodilator Indications Hypertensive urgencies or emergencies Congestive heart failure (increased afterload) Aortic dissection or trauma Pulmonary edema (with severe hypertension) Perioperative blood pressure control |
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Hemodynamic Effects of NItroprusside
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Reduces arteriolar smooth muscle tone
Reduces venous return Dose range of 0.5 - 10 mcg/kg/min |
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CoA reducatase inhibitors
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Adverse effects
Liver abnormalities Evaluate liver function through serum transaminase levels (baseline, @ 3 mos., Q 6 mos.) Myopathy and rhabdomyolysis (destruction of muscle) Rare but dangerous Unexplained muscle weakness Monitor plasma creatine kinase levels Contraindicated in pregnancy and nursing mothers |
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Bile Acid-Binding Resins
Mechanism |
Inhibition of bile acid reabsorption
Clinical efficacy Reduces LDL 15-30% Increases HDL 3-5% May increase triglycerides 10-15% |
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Bile Acid-Binding Resins adverse effects
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Gastrointestinal disturbances
Nausea, vomiting, diarrhea, constipation Impaired absorption of fat-soluble vitamins Many drug-drug interactions Contraindications Hypertriglyceridemia |
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Cholesterol Absorption Inhibitors: mechanism
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Mechanism
Inhibition of intestinal absorption of dietary and biliary cholesterol in small intestine No effect on fat-soluble vitamins Pharmacology Enterohepatic circulation Intestinal wall localization Minimal systemic exposure Available agents Ezetimibe (Zetia) |
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Niacin (Nicotinic Acid) mechanism of action
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Mechanism
Inhibition of lipolysis in adipose tissue Clinical efficacy Reduces triglycerides 30-60% Reduces LDL 15-25% Raises HDL 20-35% Most effective agent for raising HDL Dosage orally (immediate |
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Fibric Acid Derivitaves (Fibrates)
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Mechanism
Increases lipoprotein lipase activity Increases VLDL clearance |
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ASA
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Targets inhibition of thromboxane A2
synthesis Irreversible binding Effects last 7-10 days Indications Prophylaxis of cerebral ischemia, reduction of recurrent MI, decrease mortality in pre and post MI patients |
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Thienopyridines (plavix, ticlid)
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Block platelet aggregation by irreversibly
inhibiting the binding of ADP to its receptors on platelets—thus preventing activation of GP IIb/IIIa receptors |
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GP IIb/IIIa Inhibitors
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Used in patients with ACS
Block binding of fibrinogen and von Willebrand factor Major side effect = bleeding |
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vitamin K antagonist
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warfarin
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Adenosine (Adenocard)
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Inhibits SA nodal, atrial, and AV nodal conduction
More sensitive to effects on AV node Inhibits cAMP-induced Ca2+ influx, suppressing Ca2+ dependent action potentials Uses: Narrow complex paroxysmal supraventricular tachycardia (PSVT)– 90% effective WPW NOT for Afib, Aflutter, ventricular tachycardia |