Pharmacology - Exam 1

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Pharmacology - Exam 1
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2014-10-02 23:14:03
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PAP-570
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  1. Receptor
    • A receptor is a target (site-of-action) for a drug or endogenous substance, and has a distinct three-dimensional conformation
    • Receptors contain an active site where drugs bind
    • Receptors relay extracellular signals to produce a response inside the cell or in a tissue
    • Receptors may be soluble (freely floating inside the cell) or membrane-bound (anchored in the plasma membrane).
  2. Receptor occupancy
    • In a tissue, there are a limited (finite) number of receptors available to bind drug.
    • The fraction of receptors occupied by drug is called the fractional occupancy.
    • When all the receptors are occupied by drug, we say that this drug-receptor interaction is saturable.
  3. Selectivity
    • describes whether drugs interact with multiple receptors or only a few
    • Drugs will interact with different receptors to different degrees. A drug with the highest degree of selectivity interacts with only one receptor. Low selectivity is usually associated with a greater number of side effects, since the drug is activating multiple receptors, and thus causing multiple responses.
  4. Affinity
    • describes how strongly a particular drug interacts with a particular receptor
    • The highly structured nature of the binding site allows drug‑receptor interactions that are thermodynamically favorable. Therefore, the drug‑receptor interaction may be a very strong one with very low levels of drug interacting with the receptors. In this case, the receptor is very sensitive to the drug and the drug is said to display high affinity for the receptor.
  5. Ligand
    • small molecules (e.g. neurotransmitter, hormones, drugs) which are attracted and bind to the receptor
    • A ligand must have a distinct three-dimensional structure to fit into the distinct binding site on the receptor.
    • Ligands activate or inactivate receptors before changes to intracellular signaling through a pathway can occur. These changes can result in cell movement, cell division, gene transcription, electrial excitation or depression, contraction of muscle tissue, or many other responses.
  6. agonist
    An agonist is when a drug binds to its receptor and stimulates a response in the cell or tissue.
  7. antagonist
    An antagonist is when a drug binds to its receptor, and does not do anything on its own but prevents agonist binding to the receptor, then the drug is referred to as an antagonist. It can also be called a blocker (e.g. beta-blocker) or an inhibitor.
  8. G Protein-coupled Receptors
    • (GPCR)
    • largest family of receptors
    • 4 - 5% of the human genome.
    • present on most all cells of the body and regulate a wide variety of physiological processes - everything from cell survival to cell death.
    • Examples:
    • Adrenergic (α1, α2, β1-3), Serotonin (5-HT1-7), Dopamine (D1-5), Acetycholine (Muscarinic, M1-5), Histamine (H1-4), Opioids (μ, δ, κ)
  9. Ligand-Gated Ion Channels
    • (LGIC)
    • Mediate faster responses than GPCRs
    • After drug binding, they transport ions (e.g. sodium, potassium, calcium, chloride) across the plasma membrane to produce a change in cellular electrical excitation (i.e. voltage difference across the membrane)
    • Anesthetics and ethanol activate ion channels
    • Examples:
    • Acetylcholine (Nicotinic), Glutamate (NMDA, Kainate, AMPA), GABA (type A)
  10. Tyrosine Kinase Receptors
    • (trk)
    • Affect cell survival and differentiation
    • When an agonist binds to the receptor, tyrosine kinase (trk) is activated
    • Activated tyrosine kinase phosphorylates (adds a phosphate group) to the receptor complex
    • Turns on Signal Transducers and Activators of Transcription (STAT), which regulate transcription in the nucleus
    • Imatinib (Gleevec) is an anti-cancer drug that is an antagonist at trk receptors
    • Examples:
    • Insulin receptor, Growth factor receptors
  11. Steroid Hormone Receptors
    • Steroid hormones include cholesterol, glucocorticoids, and sex hormones
    • They are transported through the blood in tandem with corticosteroid binding protein (CBG)
    • Their receptors are in the cytoplasm or nucleoplasm, not in the cell membrane
    • After corticosteroid-receptor interaction, the complex translocates to DNA to directly alter gene transcription
    • Examples:
    • Estrogen Receptor, Progesterone Receptor, Glucocorticoid Receptor (many types)
  12. Kinetics of Drug-Receptor Interactions
    • D = amount of drug available to interact with the receptor
    • R = amount of receptor available to drug
    • DR = the amount of the drug bound to the receptor (drug-receptor complex)
    • kon and koff are the association and dissociation rate constants
  13. Kd
    • Kd is defined as the equilibrium dissociation constant of a drug-receptor interaction. It is also equal to the concentration of drug that occupies 50% of its available receptors.
    • At equilibrium: (D)(R)kon = (DR)koff
    • Therefore:
    • Kd is measured in mol/L (generally milli-picomolar)
    • Kd refers to the drug’s binding affinity for the receptor
    • The lower the Kd the higher the affinity
  14. Fractional Occupancy
    • When D >>> Kd then DR/RT = 1 (all receptors are occupied by drug)
    • When D <<< Kd then DR/RT = 0 (no receptors occupied by drug)
    • When D = Kd then DR/RT = 0.5 (50% of receptors are occupied by drug)
    • RT = total number of receptors
    • DR = Drug-Receptor complex
    • R = free
  15. Kd (key points)
    • Kd (in concentration units) is the concentration of drug which will occupy 50% of available binding sites on a particular protein/receptor.
    • The Kd value is the equilibrium dissociation constant for a particular drug (ligand) and a particular receptor (protein).
    • The size of a Kd value is the inverse of the drug's affinity at a given site:
    • A large Kd (eg 100 uM) indicates a low affinity where as a small Kd (eg 5 nM) indicates a high affinity.
  16. Uses for Kd
    • Can be used to compare binding affinities for a single drug on multiple receptors
    • Only one of those receptors might be the intended target; others might lead to side effects
    • Kd values provide a means for predicting if a drug will be a better therapeutic agent (with higher affinity and greater selectivity for the desired target) than other available medications.
    • For example - Several beta-blockers with anti-arrhythmic properties are not selective for β1-adrenergic receptors in the heart, as they also bind with high affinity to β2-adrenergic receptors in the lungs (which could cause serious problems especially for patients with asthma).
    • The ideal anti-arrhythmic beta-blocker would be selective for β1 receptors (ie. would have high affinity for β1 receptors and low affinity for β2 receptors).
  17. Ki
    • a measure of affinity (like Kd) that is obtained by an inhibition assay
    • Although propanolol has high affinity for Beta-1, it should not be used in patients with asthma, because it has low Beta-1 selectivity and will block Beta-2 receptors important for pulmonary function.
    • A lower number for Ki is a higher affinity
  18. competitive antagonist
    • A competitive antagonist binds to the same site as the agonist, preventing the agonist from binding to the receptor
    • Shifts the dose-response curve to the right
    • **Decreases agonist potency but does not change efficacy
    • A partial agonist can act as a competitive antagonist
  19. allosteric modulator
    A drug that binds to the receptor at a site different from the agonist binding site and modulates the ability of the agonist to produce a response.
  20. Negative allosteric modulators
    decrease the response produced by an agonist
  21. Positive allosteric modulators
    enhance the effect of the agonist (e.g. benzodiazepines)
  22. non-competitive antagonist
    • A non-competitive antagonist binds to the receptor at a location different from the agonist binding site (does not prevent agonist binding to the receptor).
    • Shifts the dose-response curve downward
    • **decreases agonist efficacy but does not change potency.
  23. partial agonist
    a drug that produces a sub-maximal response as compared to a full agonist. Partial agonists represent a new avenue for drug development (e.g. using a dopamine partial agonist for the treatment of schizophrenia). The endogenous substance (dopamine) is considered to be the full agonist. Treating a patient with a drug that is a partial agonist will prevent binding of the endogenous ligand (full agonist) to the receptor and will cause a sub-maximal response. Thus a partial agonist can behave as an antagonist because it reduces the effect of the endogenous ligand (full agonist) by occupying the binding site so that the endogenous ligand can’t bind to the receptor.
  24. log dose response curve
    • a logarithmic occupancy curve (drug levels are plotted on a logarithmic scale). The curve is sigmoidal in shape (roughly S-shaped).
    • The x-axis represents the dose or concentration and the y-axis represents the percentage of response or occupancy of receptors
  25. Graded dose response curves
    describe the relationship between the dose of drug and the amount of response in a single test subject or individual. In most pharmacological studies the drug is administered in proportion to the body weight of the subject (i.e. mg/kg). Clinically, drug levels are expressed in mg/day.
  26. potency
    • EC50 refers to a drug's potency for producing a response.
    • The lower the EC50 the higher potency
    • EC50 is the Effective Concentration of drug that produces 50% of the maximum achievable response. It can be determined by constructing a log concentration-response curve.
    • Potency refers to the amount of drug that produces a given amount of response. The amount of drug that produces 50% of a maximal effect is referred to as the EC50 (effective concentration, mg/L) or ED50 (effective dose, mg/day, mg/kg). EC50 values are encountered in test‑tube experiments or studies evaluating plasma levels of drug. ED50 values describe the potency of a drug in producing a physiological response in the clinical setting. 
    • Refers to amount of drug.
  27. efficacy
    • (or "ceiling effect", how efficacious a drug is)
    • The ability of a drug to produce a response.
    • Drugs that produce the same biological response may differ in their ability to generate the response. Also refers to ceiling effect. A drug with the highest efficacy has the greatest ability to produce a response (e.g. degree of analgesia or unconsciousness). The maximal response is determined by testing increasing levels of drug until the response reaches a constant value (the top of the LDR curve where it reaches a plateau).
    • Refers to amount of response
  28. ED50
    • The Effective Dose of drug that produces 50% of the maximum achievable response.
    • It is determined by constructing a log dose-response curve (LDR)
  29. LD50
    • Lethal dose
    • the dose that is toxic in 50% of research subjects
  30. therapeutic index
    • A drug may produce a beneficial or therapeutic effect at one dose and a toxic or lethal effect at a higher dose.
    • Therapeutic Index (T.I.) = LD50/ED50
    • The ratio between the LD50 and the ED50 is referred to as the "Therapeutic Index". The larger the number the safer the drug.
  31. tolerance
    loss of responsiveness to a drug over time
  32. Tachyphylaxis
    When tolerance develops very rapidly
  33. Idiosyncrasy
    • An unusual effect of the drug that occurs in a small percentage of patients. 
    • An abnormal reaction of an individual to specific foods, drugs, or other agents
  34. Four general mechanisms which may contribute to variation in drug responsiveness among patients or within an individual patient at different times
    • 1) Patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood.
    • 2) Variations in concentration of an endogenous receptor ligand.
    • 3) Alterations in numbers or function of receptors. Genetic factors can play an important role in altering the number or function of specific receptors.
    • 4) Changes in components of response down-stream of drug-receptor interaction.
  35. Drug Biotransformation
    • One or more chemical reactions which occur in the body whereby a xenobiotic (foreign substance) is transformed to another chemical substance.
    • Also called Drug Metabolism
    • Reactions performed by specialized enzymes
    • Products are called metabolites
    • Xenobiotics - drugs, foodstuffs, herbs, environmental chemicals, etc
  36. Water soluble drugs
    • (Many antibiotics)
    • Difficult to cross membranes and enter cells
    • Are filtered and excreted by kidney
    • Tend to have shorter half-lives
    • May or may no be metabolized
    • Metabolism not required for removal from body.
    • (lipophobic/hydrophilic drugs)
  37. Lipid soluble drugs
    • (Brain-acting)
    • Easily cross membranes, enter/remain in cells
    • Are filtered and reabsorbed by kidney
    • Tend to have longer half-lives
    • Require metabolism for removal from body
    • (lipophilic/hydrophobic drugs)
  38. Principle of Drug Metabolism
    • Drug metabolism nearly always converts lipid-soluble drugs to more water-soluble metabolites
    • Drug (substrate) --> Metabolism (Enzymes) --> Metabolites (products)
    • Drug is lipid-soluble, not excreted by kidney; some by liver.
    • Metabolite is more water-soluble; excreted by kidney or more by liver.
  39. Purpose of Drug Metabolism
    Purpose is to increase drug removal from the body
  40. Sites of Drug Metabolism
    • Liver - The metabolic clearinghouse, is the single most important site for drug metabolism
    • After oral administration, metabolism by small intestines and liver can be very significant ("first pass effect")
    • 5 most important sites of drug metabolism:
    • Liver
    • Small Intestine
    • Skin
    • Lung
    • Nasal Mucosa
    • (These are all at interface/barrier to the body)
  41. First Pass Effect
    • After oral dosing drugs must survive metabolism by the small intestine, and the liver before reaching the rest of the body.
    • First pass effect can reduce bioavailability and therefore the effectiveness of many orally-active drugs.
    • After non-GI routes drugs the rest of body along with the liver.
    • Huge surface area for diffusion in the small intestines.
    • IV bypasses all this - bioavailability = 100%
    • Bioavailability is changed by dose, route, etc
  42. Consequences of Drug Metabolism
    • Active Drug -->(Metabolism)--> Inactive Metabolite (Drug Inactivation
    • Drug metabolism does not always inactivate drugs
    • Active Drug --> Toxic Metabolite
    • Active Drug --> Active Metabolite
    • Inactive Drug (Pro-drug) --> Active Metabolite (Bioactivation)
    • Biological half-life is different than the chemical half-life
  43. Pathways - How to make a drug more water-soluble?
    • Modify drug to have more polar functional groups (eg -OH, -SH, -NH2)
    • Attach hydrophilic groups such as glucuronic acid to the drug
    • Conjugation of a whole new thing to the drug.
  44. Drug-Metabolizing Pathways
    • Phase I ("oxygenases") - Modifies drug to have more polar functional groups
    • Phase II ("transferases") - Attaches hydrophilic groups such as glucuronic acid to the drug or metabolite
    • Other reactions
    • Many drugs have multiple metabolites (eg Phase I --> Phase II reactions)
  45. Drug-Metabolizing Pathways - Phase I
    • Oxygenases
    • Can product -OH, -SH, -NH2
    • Cytochrome  P450s most important example
    • Others are flavin monooxygenases (FMOs) and epoxide hydrolases
    • Eg - Codeine being metabolized to Morphine by P450.  Methyl group is removed from codeine and -OH is added.  Codeine is a pro-drug, it is inactive until reaction happens.
  46. Bioavailability
    • A ratio of PO vs IV dose measured in blood.
    • Measures rate and extent of absorption.
    • IV doses have 100% bioavailability.
    • Other routes have a much less bioavailability due to:
    • 1 - All of the drug may not be adsorbed
    • 2 - Metabolism of the drug might occur before reaching the site of action
  47. Cytochrome P450s
    • A large family of enzymes with mixed-function heme monooxygenase activity which are responsible for the metabolism of many xenobiotics and endogenous compounds.
    • 57 individual human CYP genes in humans.
  48. Reaction Scheme for Cytochrome P450s
    • 1. Drug binds to P450 enzyme.
    • 2. Fe (in heme) within P450 enzyme acts as an electron carrier to transfer electrons from NADPH to Molecular Oxygen
    • 3. The reduced oxygen is then transferred to the drug resulting in an additional -OH on the oxidized drug.
    • RH + NADPH + O2 --> ROH + NADP+ + H2O
  49. P450-Mediated Reactions - Phase I
    • (All oxidative reactions)
    • B-Dealkylation (RNHCH3 --> RNH2 + CH2O)
    • O-Dealkylation (ROCH3 --> ROH + CH2O)
    • Aliphatic hydroxylation (RCH2CH3 --> RCHOHCH3)
    • Aromatic hydroxylation
  50. Phase I Pathways
    • Most important:
    • **CYP3A4 alone accounts for 50% of human drug metabolism
    • CYP2C, 2D, 3A account for most human drug metabolism.
    • Many P450s are important in bile acid and fatty acid metabolism.
  51. Phase II Pathways
    • ("transferases") - Conjugation Reactions
    • A big sugar with lots of hydroxyl groups
    • Glucuoronidation (UGT)
    • Sulfotransferases (SULT) (Sulfation)
    • PAPS + ROH --> R-O-SO2-OH + PAP
    • (PAPS: 3'-phosphoadenosine-5' phosphosulfate)
    • (PAP: 3'-phosphoadenosine-5' phosphate)
    • Glutathione-S-transferases (GST)
    • GSH + R --> R-GSH
    • N-acetyltransferases (NAT) (Acetylation)
    • CoAS-CO-CH3 + RNH2 --> RNH-CO-CH3 + CoA-SH
    • Methyltransferases (eg TPMT)
    • RO-, RS-, RN- + AdoMet --> RO-CH3 + AdoHomCys
  52. Phase II Pathways
    • Most important:
    • **UGTs and GSTs account for 50% of Phase II metabolism
  53. Other Drug-Metabolism Pathways
    • Ethyl alcohol metabolism:
    • Two special enzymes (not Phase I or II)
    • Alcohol dehydrogenase
    • Aldehyde dehydrogenase
    • A special P450 (CYP2E1) also important
    • (why beer makes you fat)
    • Acetaminophen Metabolism:
    • Free -OH metabolized by Glucuronidation, Sulfation
    • NH-CO-CH3 metabolized by CYPs to toxic metabolite
    • GST Conjugation "rescues" toxic metabolite when there is sufficient glutathione (GSH)
    • Acetaminophen overdose depletes cellular GSH, resulting in cell death
    • GSH is often referred to as the body's master antioxidant.
  54. Induction of Drug Metabolism
    • Induction is the activation of gene transcription, thereby increasing the synthesis of certain P450s following repeated exposure to a xenobiotic.
    • Chronic exposure leads to induction
  55. Consequences of Induction of Drug Metabolism
    • Repeated treatments with certain drugs can increase drug metabolism, resulting in shorter half-lives, and/or lower blood levels of drugs.
    • Enzyme induction is an important mechanism for drug-drug interactions.
    • Xenobiotics that can cause induction are not limited to drugs.  Factors such as environmental chemicals, cigarette smoking, etc have documented effects.
    • Herbal remedies (eg St. John's Wort) can stimulate drug metabolism and thus make other medications (eg oral contraceptives) stop working.
    • Because P450 metabolism can produce toxicity, inducing agents can promote toxicity, even increase carcinogenesis.
  56. Mechanism of Induction
    • Inducing agents act on distinct nuclear receptor transcription factors known to increase the synthesis of specific P450s.
    • Important receptors:
    • Aryl hydrocarbon receptor (AHR) for Omeprazole Ligand
    • Pregnane X receptor (PXR) for Rifampin Ligand
    • Peroxisome proliferator activated receptor (PPAR) for Fibrates Ligand
  57. Inhibition of Drug Metabolism
    • Drugs, food stuff, and other chemicals are capable of inhibiting drug metabolic enzymes.This is the basis for a number of drug-drug interactions.The interaction can be accidental or intentional.Some food-drug interactions are well known.  A well-know example is grapefruit juice, which should not be taken with a number of medications.  The psoralen derivatives and flavenoids in grapefruit juice inhibit intestinal CYP3A4 which metabolizes many drugs.
    • Eg the HIV Protease inhibitor seqinavir should not be taken with grapefruit juice, since the juice can increase drug levels in blood.
  58. Drug Metabolism - Influenced by Many Factors
    • Genetics - Blood levels of some drugs controlled by genetic differences in enzymes (eg NAT)
    • Age - Children can show either increased or decreased drug metabolism.  Elderly often show decreases.
    • Life style - smoking, alcohol consumption can change drug metabolic activity.  Herbal remedies (eg St. John's Wort) can do the same by enzyme induction.
    • Food components - (eg grapefruit juice) can inhibit some P450s
    • Species - Drug metabolism is highly individualized for each species.  Animal studies do no accurately predict human drug metabolism.
  59. Drug Movement
    • Adsorption
    • Distribution
    • Metabolism/Elimination
    • The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamics (concentration-effect) components.  Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing.  The three primary processes of pharmacokinetics are absorption, distribution, and elimination.
    • The specific details of absorption (A), distribution (D), metabolism (M), and excretion (E) of a particular drug are commonly referred to as the ADME properties of that drug.
    • Diffusion is the only type of drug movement through the body that another drug cannot change.
  60. Absorption
    • refers to the process(es) whereby a a drug enters the plasma compartment after administration.  By definition there is no absorption after IV administration.  The rate and extent of absorption of a pharmaceutical preparation (defined as bioavailability) can be very different for different drugs as well as for the same drug when given by different routes of administration.
    • Bioavailability applies to everything in the drug not just the active ingredient.
  61. Excretion vs. Metabolism
    • The kidney is the major organ of drug excretion.
    • The liver is the major organ of drug metabolism.
    • Not all drugs undergo all processes.  Some drugs are excreted but not metabolized, some are excreted only after metabolism, and many undergo both processes.  Some drugs are inactivated by metabolism, where as others (known as pro-drugs) are inactive until they are metabolized.  Not all drugs are distributed to all body compartments.
  62. Chemical properties of drugs and diffusion
    • Drugs leaving the plasma compartment (lumen) and entering the extracellular space of various tissues (interstitium) by passing through lipid cell membranes
    • (Other methods also)
    • Drugs can move between various compartments of the body by several different mechanisms.  The commonest of these is diffusion in which the rate of drug transfer is proportional to the drug concentration gradient across the membrane.
  63. Importance of drug ionization for drug movement for acids.
    • Because most drugs are either weak acids or weak bases, they can exist in more than one form.  
    • For example, any acid HA can donate a hydrogen ion and exist in the form A-
    • HA ⇄ H+ + A-
    • Ionized (A-) form won't be absorbed/cross the membrane because it has a high water solubility (low lipid solubility).
    • A- will not be absorbed from the GI tract, will not penetrate brain capillaries, and will be rapidly filtered by the kidney and not reabsorbed (thus excreted rapidly).
    • HA on the other hand has significantly more lipid solubility and depending on its structure may be able to penetrate membranes more efficiently.
  64. Importance of drug ionization for drug movement for bases.
    • Base drug ionization reaction:
    • B + H+ ⇄ BH+
    • Weak bases are ionized in the stomach, better absorbed in the small intestines.
    • B is the uncharged (unionized) and unprotonated form and BH+ is the ionized and protonated form.
  65. Drug ionization can be predicted according to Henderson-Hasselbalch equation
    • pH = pKa + log (unprotonated form/protonated form)
    • X/HX is unprotonated form/protonated form
    • pH = -log[H+]
    • pKa = -log[HA] (strength of the acid or base)
  66. Ion trapping
    • Weak bases tend to be ionized (and therefore retained) by the more acidic compartment.
    • Weak acids tend to accumulated in more basic compartments.
  67. Principles of lipid soluble drugs.
    • 1. It won't work orally if it doesn't have some lipid solubility.
    • 2. Any drug that acts on the CNS must be able to penetrate the blood brain barrier (BBB) so must be lipid soluble.
    • 3. Renal reabsorption, reabsorbed in PCT or DCT (later metabolized in the liver and excreted there).
  68. Drug distribution to specialized areas
    • Most capillaries in the tissues of the body are fenestrated. 
    • Brain capillaries have "tight junctions" which are a major histological feature that contributes to the inability of many agents to penetrate the blood brain barrier.  Therefore only highly lipid soluble agents are capable of entering the CNS.  (Solutes must move through two membranes.)
    • Highly lipid soluble drugs can also leave the maternal circulation and enter the fetus.
  69. Drug metabolism
    • Also called biotransformation
    • Principle site of drug metabolism is the liver, although the brain, lung, kidney, and adrenal can also contribute in some cases.  The principle purpose of drug metabolism is to rid the body of the drug.  Since lipid soluble drugs can be repeatedly reabsorbed from the kidney (so persist in the body), water soluble drugs are excreted by the kidney (not reabsorbed), so drug metabolic mechanisms nearly always convert a drug to a more water soluble (less lipid soluble) form.
  70. 4 Main types of chemical reactions that occur in drug metabolism
    • Oxidation (Phase I)
    • Reduction (Phase I)
    • Conjugation (Phase II)
    • Hydrolysis (Phase I)
  71. Drug Elimination
    • Elimination refers to the excretion of unchanged drug from the body.  The kidney is the major organ of elimination and the most unmetabolized drugs are excreted in the urine.  
    • Some drugs are eliminated by the liver through feces, and the lung by exhaled air.
    • Drug handling by the kidney includes:
    • Glomerular filtration of unbound, low molecular weight substances
    • Tubular secretion is an additional specialized mechanism where certain acidic and basic drugs are actively secreted into the kidney from the blood.  When the renal clearance of a drug exceeds the GFR tubular secretion of the drug is a likely mechanism.
    • Renal reabsorption is a mechanism where drugs that are both filtered and secreted into the urine penetrate the renal proximal tubule and are reabsorbed into the systemic circulation.  Lipid soluble drugs are more readily reabsorbed and so have a longer duration.
  72. therapeutic window
    • The therapeutic window is the difference between a maximum and minimum therapeutic dose.  This is where the plasma levels of the drug are effective and safe.
    • This is affected by the amount and the frequency of the dose as well as the route of administration and the body weight and body surface area.
  73. dosing regimen
    amount (dose) and frequency of drug administration
  74. apparent volume of distribution
    • The body as a single compartment (a box)
    • The volume of the body is Vd (the apparent volume of distribution.
    • The apparent volume of distribution of a drug is the volume of liquid in the body that the drug appears to dissolve in.
    • 3 L of plasma
    • 40+ L if all of body.
    • Drugs can have different values of Vd because they can penetrate different body compartments and therefore dissolve in different total volumes.
    • Concentration of drug in the body is equal to amount of drug (mg) divided by volume (mL).
    • C0 = D/Vd  ( in mg/mL)
  75. First order elimination
    • Like pulling the plug on a bathtub, rate slows as the tub empties.
    • 4 important characteristics:
    • 1. The rate of disappearance of drug from plasma at any time is proportional to the concentration of drug in plasma at that time.
    • 2. Since the plasma levels fall over time the rates are constantly slowing over time yielding an exponential disappearance of drug over time.
    • 3. A plot of a logarithm of plasma drug vs. time yields a straight line. (The steeper the line the larger the K, the smaller the half life.)
    • 4. Rates of disappearance are not constant over time but a constant fraction of what remains is always eliminated per unit time.
  76. Half life
    • The time it takes to remove one-half of amount of drug in plasma.
    • First order elimination:
    • C(t) represents the plasma concentration at time t
    • C0 is the initial concentration (before elimination starts)
    • ke is the rate constant of elimination
    • Eg:
    • ln 2 = 0.7
  77. First order elimination with a single oral dose
    After oral administration a slow and often incomplete absorption of drug occurs.  Even though the drug that reaches plasma is still subject to first order elimination, this often occurs during absorption.  Therefore absorption and elimination are occurring at the same time.
  78. Binding of drugs to plasma proteins and to tissue sites.
    • Some drugs bind to plasma and tissue components, a factor that can distort the apparent distribution of the drug.
    • 3 cases:
    • 1. The drug distributes to the total body water with no biding to plasma or tissue components.  Vd is about 45 liters.
    • 2. The drug distributes in the same way but also binds to  plasma proteins.  Plasma drug levels measure bound and free so the apparent plasma concentrations are higher than just the free levels.  These higher plasma levels make it look like the drug distributed to a very small volume. So a drug that is highly bound to plasma proteins can exhibit very small apparent volumes of distribution.
    • 3. The distributes as in case #1 but also binds tightly to a tissue component.  In this case the drug gets trapped in the tissue making the plasma concentrations much lower than they would otherwise.  These very low concentrations make it appear that the same dose of drug was diluted with a very large volume of tissue water, hence a large value for Vd.  So a drug that is highly bound to tissue components can exhibit very large apparent volumes of distribution.
    • (Lipid soluble drugs like the fat cells.)
    • When the Vd value is somewhere between 3-45 liters the value suggests the drug distributed to the plasma only (3 liters), extracellular fluid (14 liters) or to the total body water (45 liters).
  79. drug clearance
    • Total Body Clearance (Cl)p
    • Defined as the volume of plasma from which all drug molecules need to be removed each minute to achieve the rate of removal of drug.
    • (Cl)p = ke Vd
    • This relationship tells you that the rate of clearance is dependent on the rate constant as well as the volume distribution.
    • The larger the volume of distribution, the greater the clearance from the body.
    • units are in volume/time (mL/min or L/hr)
  80. steady-state plasma levels
    • A continuous infusion of drug into the plasma space coupled with a first order elimination mechanism eventually leads to a steady state plasma concentration.  This is because the rate of elimination increases as the plasma levels of drug increase until the rate of elimination equals the rate of infusion.
    • Css in mg/mL
  81. Dosing Schedule
    • This can be thought of an infusion with breaks.  The fluctuations in the plasma levels between doses behave like first order elimination.  Two important concepts are:
    • 1. The smaller the intervals between doses the lower the plasma fluctuations.
    • 2. The interval must be short enough to permit drug accumulation.
  82. loading dose
    • A larger initial dose.
    • If you know the plasma steady state level you wish to achieve and you know the volume of distribution the loading dose case be calculated by:
    • C = D/Vd
    • Get the D then get Vd
  83. maintenance dose
    Every dose given is the same size.  This is after attaining the steady state, the dose is what maintains the plasma steady state.
  84. Time to steady state
    • All about the half life.
    • For all kinds of regular dosing, the size of the dose does not affect the time it takes to achieve the steady state level.  This is only dictated byt the half-life of the drug.
    • Infusions of 1, 3.3, and 5 times the half-life the plasma levels will achieve 50%, 90% and 97% of the steady state level.
    • Value of steady state level is influenced by both the infusion rate and clearance, but the time to steady state is only determined by the half-life.
  85. Prescription Writing - Legal Document
    • Use ink
    • Write clearly
    • Do not alter
    • Proofread
    • Avoid ambiguity, I.e., abbreviations, roman numerals,Latin, etc.
    • Electronic prescribing is preferred
    • Facsimile
  86. Pharmacists determine validity of Rx
    • Is the prescription legal?
    • Therapeutic - correct dose, correct strength, drug interactions, duplications
  87. Prescription must contain
    • Heading - MD's name, address, phone number, specialty and DEA number, PA-C's name and number and DEA number if applicable.
    • Subscription - Rx
    • Patient information - name, address, age/DOB
    • Date - the day it's written (cannot post date)
  88. The body of the prescription contains
    • Inscription - Drug, dosage form and strength
    • Subscription - Direction to compounder or quantity
    • Signa - direction to patient
    • Prescriber - legal signature, must include PA-C after signature.
    • Substitute Legend - "DAW" or blank, NYS requirement (prescriber shall notify patient of brand name or generic equivalent drug)
    • Refills - authorizes repeat dispensing, numeric and written in text. (No more than 5 refills for controlled substances)
    • Max daily dose (MDD) - especially for acetaminophen.
  89. Telephone Prescriptions
    • Made by prescriber or employee of prescriber
    • Must be communicated to a pharmacist or pharmacy intern - not pharmacy tech.
    • Must contain all the information required for written prescription
    • Brand or generic
    • Additional requirements for controlled substances.
    • All verbal orders should be repeated by the receiving pharmacist or intern for confirmation and notation made.
  90. Electronic Transmission or Faxes
    • Permissible for all prescriptions except syringes/needles and controlled substances.  Law in NYS is ready for controlled substance electronic transmission, waiting for DEA.
    • Prescription shall contain the signature of prescriber or an electronic equivalent.
    • Electronic transmission other than fax, shall be encrypted to prevent alteration.
    • Controlled substances can only be faxes if being filled as "emergency Rx". (loophole)
  91. Pharmacist Interpretation
    • Review of patients medication profile with new prescription.
    • Drug selection - brand vs. generic
    • Drug processing - labeling
    • Counseling patient
    • Any doubts WRT Rx pharmacist must contact prescriber.
  92. Review of each prescription
    • Omissions
    • Ambiguity
    • Completeness - for law and insurance
    • Potentially unsafe use
    • Interaction - drugs, OTC, dietary supplements, herbals, food, homeopathic, alternative therapies
    • Contraindications
    • Controlled substances requirements must be met.
  93. Medication Errors and Non-Compliance
    • Misinterpretation of directions
    • Taking medication for incorrect indication
    • Incorrect dose
    • Dose taken at incorrect time
    • Importance of counseling
    • IOM report
    • Joint Commission
    • ISMP
    • USP - United States Pharmacopeial Convention
  94. Common Errors
    • Errors of omission - date, patient's name, address, age/DOB, quantity - even if you indicate the days supply (1 q6h for 10 days... must indicate #40), strength, complete directions for use, refills.
    • Other errors:
    • Inappropriate dose
    • Illegibility
    • Controlled substance requirements
  95. Inappropriate Dose Drug Nomenclature
    • Suffixes used to describe brand name products' dosage form.  Include suffix if used as part of the brand name; eg Cardizem SR
    • List all products by generic name in lower case
    • List appropriate brand names in upper case
    • Spell out the word UNITS
    • Use comma when expressing numbers in the thousands; eg. 5,000
    • Failure to use appropriate dosage form may result in inappropriate dosing.
  96. Expressing weights
    • Use USP standards
    • m = meter
    • kg = kilogram
    • g = gram
    • mg = milligram
    • mcg = microgram
    • L = liter
    • mL = milliliter
    • mEg = milliequivalent
    • mmol = millimole
  97. Prescribing in general
    • Do not abbreviate drug names
    • Use "tall-man" letters to help distinguish look-alike products; eg hydrOXYzine and hydraALAZINE
    • List in this order:
    • Generic drug name, brand name, strength, dose (if different than strength), and dosage form; diazepam [VALIUM] 5mg tablet; propranolol [INDERAL] 5mg [1/2 x10mg] tablet
    • Place a space between the name, strength, and dosage form; propranolol20 mg could be mistaken for 120 mg and 10Units has been misread as 100 Units.
  98. Illegible Orders
    • These lead to misinterpretation of an order
    • Look alike drugs, Celebrex and Celexa
    • Misinterpretation of abbreviations when handwritten:
    • q.d. looks like q.i.d.
    • tid looks like bid
    • 2u insulin read as 20 units; U is frequently misread as a zero or 4
    • OD - each day or right eye
    • Roman numeral V (5) often written to look like X
  99. Use of non-approved Abbreviations
    • Problems with interpretation
    • Use of only those drug name abbreviations which have been approved by the hospital or central pharmacy for retail.
    • Examples of variable interpretation:
    • HCl - hydrochloric acid, potassium chloride
    • HCTZ - hydrochlorothiazide, hydrocortisone
    • ZnSO4 - zinc sulfate, morphine sulfate
    • μg - microgram, milligram
    • SC - subcutaneous, sublingual
    • BT - bedtime, BID
    • See ISMP - Institute for Safe Medical Practices for approved acronyms
  100. Decimal Errors
    • Miscalculation, accidental misplacement, writing lightly and faint reproduction on copies
    • Always place a zero (0) preceding the decimal point and never use a zero after the decimal point.
    • Incorrect - Synthroid .1mg po qd
    • Correct - Synthroid 0.1mg po qd
    • Incorrect - Coumadin 2.0mg po qd
    • Correct - Coumadin 2mg po qd
  101. Ambiguous Orders
    • Write orders to avoid misinterpretation
    • Example - Inderal 1/2 tab 40mg po q.i.d
    • Does this mean 1/2 of an 80mg tablet (40mg) or 1/2 of a 40mg tablet (20mg)?
  102. Failure to indicate Frequency of Administration
    • Incorrect - Acetaminophen 325mg po prn pain
    • Correct - Acetaminophen 325mg q4h po prn pain
    • Do not assume that the pharmacist will determine the frequency of administration even if the number of days are included.
    • (Medicaid needs acetaminophen by Rx to pay for it.)
  103. Incomplete orders
    • Incomplete orders are considered invalid.  There is certain information that a pharmacist can add without notifying the prescriber:
    • Address
    • Age, gender, allergies, disease states
    • Any other information requires consultation with the prescriber
  104. Missing strength
    • Problem for products with multiple strengths
    • Incorrect - Acetaminophen one tablet twice daily po
    • Correct  - Acetaminophen 325mg twice daily po
    • Incorrect - Timoptic eye drops - 2 drops both eyes twice daily.
    • Correct - Timoptic eye drops 0.5% - 2 drops both eyes twice daily.
  105. Prescription refills
    • Best if written out to avoid misinterpretation and alteration
    • Recommendation by Bureau of Narcotic Enforcement for controlled substance prescriptions.  All refills written alpha and numeric.
    • Limit to a reasonable number
    • Time frame - eg for 10 days
    • PRN allows one (1) refill only - this is not preferred - do not do this.  (Zero for controlled substances)
    • Refills authorized by person legally authorized to prescribe
    • Indicate on face of prescription
    • Specific - number of times
    • Maybe be given orally if for non controls
  106. Child Resistant Packaging
    • Federal Law requires that all medication be dispensed in a child resistant container.
    • Exceptions - sublingual nitroglycerin, steroid dose packs, oral contraceptives, patient requests and/or physician requests for non-child resistant. (Need to sign waiver to get non-child proof containers)
  107. Syringes/Needles
    • Quantities great than 10 require a prescription (in one transaction)
    • Law allows for persons 18 year of age or older to purchase 10 syringes/needles per transaction over the counter.  ESAP - Expanded Syringe Access Program
    • Prescriptions must be written, no fax.  If faxed it must be treated as "emergency prescription".  100 syringe only.  May not indicate refills on an emergency prescription.
    • Specific directions for use.  Refills as indicated.
    • Prescription valid up to 2 years.
    • If faxed (emergency prescription) a written follow up must be sent to the pharmacy within 72 hours.
    • Must state on the prescription "Emergency Prescription"
    • Syringes/needles are not controlled substances but they are regulated by the Bureau of Narcotic Enforcement, Department of Health.
  108. Copies of Prescriptions
    • Non-controlled - may be furnished to patients.
    • "For informational use only" or "VOID" should be written on the face of prescription so the patient cannot have it filled at another pharmacy.
    • Copies for controlled substances - may be furnished only to practitioners authorized to write controlled prescriptions (valid DEA number)
  109. Confidentiality
    • Issue among health care practitioners
    • HIPAA - Health Insurance Portability and Accountability Act
  110. Controlled Substances C-1
    • Schedule I controlled substances
    • High potential for abuse
    • No currently accepted medical use under medical supervision.
    • Lack of accepted safety for use under medical supervision
    • Hallucinogenic - LSD, heroin, crack cocaine, marijuana*, mescaline, peyote, bath salts.
  111. Controlled Substances C-2
    • Schedule II
    • High potential for abuse
    • Currently accepted medical use in US.
    • Abuse may lead to severe psychological or physical dependence.
    • Codeine, cocaine, amphetamines, methadone, opium tincture, fentanyl
    • Hydrocodone combination products, vicodin, and lortab
    • Anabolic steroids in NY are schedule II but are federally C-III
  112. Controlled Substances C-3
    • Schedule III
    • Potential for abuse lass than Schedules I and II
    • Currently accepted medical use in the US
    • Abuse - moderate or low physical dependence or high psychological dependence.
    • Federal - anabolic steroids, butabarbital, fiorinal, dronabinol (F-III, NYS-II)
    • Schedule II products in combination with acetaminophen, aspirin, or in suppository form are rescheduled to Schedule III
  113. Controlled Substances C-IV
    • Schedule IV
    • Low potential for abuse relative to C-III
    • Currently accepted medical use in US
    • Abuse of drug may lead to limited physcial or psychological dependence relative to C-III.
    • Benzodiazepines, phentermine, propoxyphene, meprobamate, chloral hydrate, phenobarbital.
    • Benzodiazepines are schedule IV but are treated as a schedule II for quantity and refill.  Eg. Valium.
  114. Controlled Substances C-V
    • Schedule V
    • Low potential for abuse relative to C-IV
    • Currently accepted medical use in US
    • Limited physical or psychological dependence relative to C-IV
    • Antitussives and antidiarrheals - contain limited quantities of narcotics such as codeine, di-hydro-codone, ethylmorphine or diphenoxylate
  115. NYS Schedule Controlled Substances
    • NYS controlled substance law and schedule
    • Title 10, Part 80
  116. Prescribing Controlled Substances (CS)
    • Person authorized to obtain controlled substances shall not use them for treatment of his/her own addition or habitual use.
    • Practitioner may prescribe CS for treatment other than addition in any manner ordinarily recognized by the profession.
    • Practitioner may issue for legitimate medical purpose only.  Need to have patient record, patient identifiable information, chief complaint, diagnosis, drug name, amount, strength, and directions for use.
    • PAs in all settings can prescribe all Schedules of CS, II through V except buprenorphine for the drug addition treatment program (DATA)
    • Benzodiazepines are Schedule IV in NYS but they are treated as though they are Schedule II.
    • Anabolic steroids are federally schedule III but NYS has rescheduled them to a Schedule II controlled substance.
    • Rx written is valid for 30 days from the day written, no refill.
    • DEA number from DEA not NYS Bureau of Narcotic Enforcement.
    • All prescription blanks available from DOH.
  117. Serialized Prescriptions for NYS
    • Out of state prescriptions - no longer require the official Rx for schedule II and benzodiazepines.  Regular blank for controlled substances.
    • Out of state prescriptions must comply with all required information.
    • No refills.
  118. Electronic Prescribing
    • Permissible for non-controls
    • DEA authorized e-prescribing of controlled substances June 1, 2010
    • NYS has not yet implemented rules and regulations to allow e-prescribing of controlled substances.
    • NYS DOH is working on updating regulations.
  119. More on Prescribing Controlled Substances
    • Preprinted prescriptions are not allowed.
    • Stamped/computer generated at time of prescribing are not considered preprinted. (Fine line)
    • Initial exam - chief medical complaint
    • Prescriptions are for outpatient use and medical orders are for inpatient use.
    • Who may issue CS prescriptions? Authority to prescribe - registered and authorized by supervising physician.
    • Must have Federal DEA registration.  When applying you identify what schedule of controlled substances you will be prescribing.
    • Do not obtain DEA number from Bureau of Narcotic Enforcement
    • Schedule II prescriptions, anabolic steroids and benzodiazepines - no refills, no more than 30-day supply (exceptions for certain medical conditions), prescription valid for 30 days from date written.
  120. PAs Prescribing Controlled Substances
    • PAs have the authority to prescribe Schedule II, III, IV, and V controlled substances in the outpatient setting.
    • No authority to prescribe Schedule III buprenorphine.
    • Benzodiazepines are Schedule IV controlled substances but are treated like Schedule II - no refills allowed and quantity of 30 unless an exception is used.
  121. Schedule II and Benzodiazepine Prescriptions - Writing the Rx
    • Required information:
    • Prescriber info, preprinted.
    • Patient info
    • Drug info
    • eg - Percocet, Demerol, Anabolic Steroids.
    • Prescriber info includes:
    • Printed name of PA
    • Printed name of supervising MD
    • Address
    • DEA registration number
    • Telephone number
    • Date written/issued
    • Signature of prescriber
    • Patient info includes:
    • Name
    • Address
    • Age/DOB
    • Gender
    • Drug info includes:
    • Drug name
    • Strength
    • Specific directions for use
    • Quantity
    • Maximum daily dose (MDD) **because they're pain meds!
  122. Schedule II and Benzodiazepine Prescriptions
    • Institutional use of the Official NYS Prescription Forms - prescriber's name must be stamped or imprinted on the form.  Case law.
    • For PAs prescribing on the Official Prescription form the name of the supervising MD must appear and that may be handwritten - if in an institutional setting, the prescriber's name is not printed, it may be handwritten.  Only exception to imprinted or printed.
    • No additional prescriptions may be written for the same drug within 30 days from the date of issue until all but 7 days supple has been exhausted.  (NYS law)
    • Exceptions to the 30 day supply rule:
    • Up to 3 months supply including chorionic gonadotropin permitted for the following:
    • Practitioner writes either a Code or diagnosis on face of prescription.
    • Code  Diagnosis
    • A       Panic Disorder
    • B       Minimal Brain Dysfunction or ADHD
    • C       Chronic debilitating neurolgical
    • D       Condition or disease known to be chronic or incurable
    • E       Narcolepsy*
    • F       Hormone deficiency states (males); gynecological conditions, breast cancer, anemia, and angioedema.
    • *Only legal use of amphetamines.
    • Up to 6 months of anabolic steroids.
  123. Emergency Oral Prescriptions
    • Definition of emergency:
    • Immediate administration is necessary.
    • No alternative treatment available.
    • Practitioner cannon provide written prescription.
    • Pharmacists will ask if this is an emergency especially for C-IIs and benzos because follow up is an issue.
    • Quantity may not exceed a 5 day supply.
    • Follow up written prescription to pharmacy within 72 hours.  If not received by the pharmacy the pharmacy must notify the Bureau of Narcotic Enforcement, DOH within 7 days from date of dispensing that they have not received the follow up.
    • Follow up prescription must have "authorization for emergency dispensing" written on face of the prescription.
  124. Schedules III, IV, & V CS
    • All prescriptions require the official NYS prescription form.
    • Practitioner info - same
    • Patient info - same (except sex)
    • Drug infor - same, MMD is required on CIII-V.
    • 30 day supply with same exceptions as are listed above.
    • Refills are allowed as designated by prescriber.
    • 5 refills within a 6 month period.
    • Prescription expires 6 months from the date of issue.
    • Prescription valid for 30 days from date of issue.
    • For exception prescriptions, for quantities greater than 30 day supply, only 1 refill is allowed. (Phenobarbital 30mg, 1 po qid, #360, Code C. 1 refill is authorized for this prescription provided the prescriber so designates.
    • Early refills:
    • If a prescriber changes the dosage or directions then a new prescription needs to be written.  Notifying patient to take more than prescribed will cause prescription to run out before it is due and patient will attempt to refill too early.
    • 7 day cushion over life of prescription.  All but 7 days must be exhausted before refilled or filled if new prescription.
    • Oral emergency prescriptions:
    • No more than a 5 day supply, except C-IVs (other than benzodiazepines).
    • C-IVs (other than benzodiazepines) - quantity, 30 day supply or 100 dosage units whichever is less.  (Phenobarbital 60mg - 1 po qid.  A 30 day supply would be 120 tablets; oral emergency prescription would allow 100 tablets, 25 day supply.
    • Practitioner must send written follow up within 72 hours.
    • If not received by pharmacy within 72 hours, pharmacy indicates on the back of the prescription that it is not received.
    • DOH is not notified by pharmacy.
    • DOH may look for this information during an inspection.
  125. Institutional Dispensers
    • Administration upon written order by authorized practitioner except:
    • Emergency - oral order reduced to writing and countersigned by practitioner within 48 hours.
    • PRN orders not valid beyond 72 hours, as needed within the 72 hour time frame.
    • Routine orders (non specific) not permissible
    • Standing orders valid for 7 days, eg Morphine 1q4h (7day life) - Stabilized patient convulsive disorders or chronic spasticity or min brain dysfunction, RHCF, prison (Class 3 license) valid for 30 days.
    • PAs may write order if authorized by the supervising physician.
    • Countersignature is not required unless the supervising physician requires it.
    • If required countersignature must be done within 24 hours.
    • Outpatient pharmacies dispensed pursuant to prescriptions not medical orders.
    • May only procure controlled substances from a distributor or wholesaler.
    • Institutions may not accept patient's meds brought into the hospital either for safeguarding or patient use.
    • Community pharmacies may not take back patient's meds.
  126. Institutional Dispensers, Limited
    • Emergency admin from sealed medication kid:
    • Administration to a patient upon an oral order of an authorized practitioner.
    • Oral order for emergency admin immediately:
    • Reduced to writing
    • Notation about the condition which required the administration of the drug.
    • Order signed by the practitioner within 48 hours.
    • Institutional dispensers limited:
    • CS prescribed for individual patient use only, pursuant to Rx's filled in a registered pharmacy.
    • Except for adult care facilities, sealed emergency medication kits.
    • 24 hour supply for up to 10 different CS unit dose packaged, no more than 3 in injectable form.
    • Stored stationary, double-locked system.
  127. Practitioner Dispensing
    • Dispense from office:
    • Allowed however same prescribing requirements apply:
    • Labeling
    • Counseling
    • Record keeping
    • Child resistant packaging
    • (Act like a pharmacy)
    • Label requires:
    • Name, address ultimate user
    • Name, address and phone number of dispensing practitioner.
    • Legend "Controlled Substance, Dangerous Unless Used As Directed", upper case lettering.  Label in orange or red!
    • Date of dispensing
    • Drug name and directions for use.
    • Any auxillary labels if necessary.
  128. Safeguarding Controlled Substances
    • If dispensing from office:
    • Keep CS safe and at DEA address
    • Access limited
    • Safeguarding of Official NYS Prescription forms
    • Records of all CS received and dispensed.
  129. General Info for Prescibing
    • PA may write for prescriptions for patients of the physician who supervises the PA provided that is the understanding between PA and MD.
    • Prescriptions must be written on MD's blank
    • Prescriptions must contain printed name of supervising MD, printed name of PA, signature of PA, DEA registration number of PA.
    • Does not need to be countersigned by MD.
    • Must include DEA number if prescribing controlled substances
    • One prescription per blank.
  130. Generic v. Brand Prescribing
    • All prescriptions must be written on a conforming blank.
    • Generic product will be dispensed, if available, unless the prescriber writes "DAW" in the designated box.
    • Medicaid will reimburse for brand products that have generic equivalents available only if prescriber obtains prior approval from MA.
    • If no DAW, by law the pharmacist must provide the cheaper (generic) med.
    • The requirement to substitute is a consumer protection law.  This cannot be rescinded but the pharmacist or the patient.
    • Substitution is required only when the brand name is prescribed and a generic is commercially available.  See Orange book.
    • If the pharmacist does not have a generic the brand may be dispensed at the generic price.
    • If a medical emergency, pharmacist may dispense brand at brand price.
  131. Federal v. State Controlled Substances
    • Anabolic steroids and chorionic gonadotropin - C-II in NYS, C-III for Fed.
    • This includes injectable testosterone, testosterone compounds, testosterone patches, Androjel.
    • Exempt - Estratest, Estratest HS, Premarin with methyl testosterone.  These products are no longer controlled substances.
  132. Applying to the DEA
    • DEA asks you to check what schedules you are registering for:
    • You can register for Schedules II, III, IV, and V only.
    • You will also need on the DEA form that you can dispense, prescribe, administer, and procure CD in the above schedules.
  133. Sulfonylureas
    • (type of insulin secretagogue)
    • Glyburide, Glipizide, Glimerpiride
    • More potent
    • Risk of hypoglycemia
    • Makes beta cells secrete insulin (doesn't work for DMI)
    • Works 12-24 hours
  134. Non-sulfonylureas
    • (type of insulin secretagogue)
    • Repaglinide, Nateglinide
    • Less potent
    • Lower risk of hypoglycemia - good for elderly
    • Rapid onset - 20 minutes
    • Kicks in when blood glucose increases
  135. Biguanides
    • (type of insulin secretagogue)
    • (Metformin)
    • First line treatment (with lifestyle management)
    • Decreases hepatic gluconeogenesis
    • Not good for renal/hepatic dz, EtOH
  136. Thiazolidinediones
    • (TZD)
    • (type of insulin secretagogue)
    • Pioglitazone, Rosiglitazone (Avandia - Increased risk of MI)
    • Makes patient's own insulin work better (increases insulin sensitivity)
    • Side effects include weight gain, fluid gain, edema
    • Metabolized in the liver
    • Not for DMI
  137. Alpha-Glucosidase Inhibitors
    • (type of insulin secretagogue)
    • Acarbose, Miglitol
    • Side effect of flatulence - not generally used because of this.
  138. SGLT2 Inhibitors
    • (type of insulin secretagogue)
    • Sodium glucose cotransport inhibitor
    • Canagliflozin, Dapagliflozin, Empagliflozin
    • Side effect of more glucose in urine --> results in more UTIs and yeast infections
    • Works dependant on blood glucose levels
    • Metabolized in liver
    • Bad for patients with renal failure - causes volume depletion
  139. GLP-1 Analogs
    • (type of gut hormone)
    • Glucagon like peptide
    • Exenatide, Liraglutide
    • Administered by injection
    • Works on alpha & beta cells (↓ glucagon, ↑ insulin)
    • Side effects of weight loss, gastric paresis, satiety
    • Low risk of hypoglycemia
    • Works depending on blood glucose levels
    • Bad for patients with pancreatitis
  140. DPP-IV Inhibitors
    • (type of gut hormone)
    • Sitagliptin, Saxagliptin, Linagliptin, Alogliptin
    • Administered orally
    • "GLP-1 lite" --> less potent
    • Good first line treatment if can't use metformin
  141. Amylin analog
    • (type of gut hormone)
    • Pramlintide
    • not used much in practice
    • decreases glucagon, decreases gastric emptying, stimulates satiety
    • Can be used in DMI&II
    • less use in DMI because it's a second injection
  142. Rapid Acting Insulin
    Insulin Aspart, Insulin Lispro, Insulin Glulisine
  143. Regular and NPH Insulin
    • Old school
    • Short/Intermediate acting
  144. Long Acting Insulin
    Insulin Glargine, Detemir
  145. Insulin Metabolism
    • Endogenous - Liver 60%, Kidneys 35-40%
    • Exogenous - Liver 35-40%, Kidneys 60%
    • (Reversed!!)
  146. Mineralocorticoid
    • Fludrocortisone (synthetic)
    • Used for replacement
    • GC potency is 10
    • MC potency is 125
  147. Glucocorticoids
    • Lower potency used for chronic, replacement treatment
    • Higher potency used for limited, interventional treatments
    • Some common and inexpensive glucocorticoids require conversion to active forms by the liver to be effective
  148. Cortisol/cortisone
    • Used for replacement/anti-inflammatory
    • GC potency is 1
    • MC potency is 1
    • Cortisone is not for use with impaired liver function because it's a pro-drug, give cortisol
  149. Prednisone/Prednisolone
    • Used for replacement/anti-inflammatory
    • GC potency is 4
    • MC potency is 0.8
    • Prednisone is not for use with impaired liver function, give prednisolone
  150. Betamethasone, Dexamethasone
    • Intervention:
    • Anti-inflammatory; prenatal therapy
    • GC potency is 30
    • MC potency is 0
  151. Fluticasone, Flunisolide*, Budesonide, Beclomethasone*
    • Intervention:
    • Anti-inflammatory
    • (*inhalation only)
    • GC potency is 65-5,000
    • MC potency is 0
  152. Mineralocorticoids and Glucocorticoids
    • Ease of use
    • Slow to take effect
    • Liver function affects clearance and bioactivity
    • Deficiency can be fatal:
    • Physical deficiency - Addison's, Adrenalectomy, Congenital Adrenal Hyperplasia, Renal failure (MC)
    • Drug induced deficiency - Gluco & Mineralocorticoids (Ketoconazole, mitotane), Glucocorticoids (Metyrapone {for Cushings}, glucocorticoids <-- most common cause of 2°, Mineralocorticoids (if combined with renal impairment) - NSAIDs, ACE inhibitors, ARBs, Ca2+ channel blockers, Heparin, Cyclosporine (Hep and Cyclo interfere with aldosterone production)
    • Glucocorticoid administration can be inadequate or excessive, depending on liver function.
    • Strategy is to maintain replacement levels, give well in advance of need.
    • Give bioactive forms in liver failure (eg NOT cortisone, prednisone) - Give cortisol/prednisolone instead (these are the already metabolized forms of the pro-drug)
    • Consider increasing steroid dose if patient using - barbiturates (methohexital, thiopental, phenobarbital), anti-epileptics (phenytoin, phenobarbital), antibiotics for TB/meningitis (rifampin) ----  Liver enzyme inducers
    • Consider decreasing steroid dose if patient using - macrolide antibiotics (erythromycin, clarithromycin), antifungal (itraconazole), anti-retroviral (ritonavir), maybe also for estrogens, quinolone antibiotics, nondihydropyridine Ca2+ blockers ---- Liver enzyme inhibitors
  153. Glucocorticoids
    • Sustained effects
    • Slow to wear off (potential for long-lasting & dangerous side effects)
    • Excess can be debilitating or fatal - infection, impaired wound healing, muscle, bone loss in bed rest, diabetes, hypertension, ulcers (w/ NSAIDs), psychiatric symptoms
    • *Can get GC-induced adrenal suppression
    • Strategy is to minimized systemic dosing - local administration, lowest potency, alternative day dosing, morning administration.  Monitor diet, infection.  Taper withdrawal, delay elective surgery, avoid NSAIDs
  154. addition
    • the effect of two drugs given together that would be predicted by the addition of their individual effects. This usually implies a common mechanism of action.
    • 1+1=2
  155. synergism
    • supra-additive effects. These effects are more than expected from addition. This may imply different mechanisms for the two drugs.
    • 1+1>>2
  156. potentiation
    • the action of a drug itself inactive which causes an active drug to produce a much greater response. This usually occurs when the inactive drug has enhanced the blood level of the active drug, by enhanced absorption, displaced plasma binding, inhibition of metabolism or excretion, etc.
    • 0+1>>1
  157. antagonism
    • the combined effect of two drugs is less than addition, or less than one active component alone. The second drug may or not be active alone. There are several types of antagonism.
    • 1+1<<2
    • 0+1<1
  158. neutralization antagonism
    the reduction of drug effect by the addition of a second drug that combines chemically with the first. Such interactions can occur outside of organisms, e.g. in IV bag.
  159. pharmacological antagonism
    antagonism at a receptor site, or alteration of the drug-receptor interaction by another drug. This can be competitive, or non-competitive.
  160. physiological antagonism
    • any type of antagonism other than pharmacological that occurs only in organisms.
    • Any xenobiotic, eg food, pesticide
  161. The mechanisms by which drugs can interact...
    are limited only by the number of processes each drug undergoes while in contact with a biological system. For each process, the possibility exists that another drug could modify it. In addition to their direct interactions (neutralization antagonism), drugs can interact with drug absorption, distribution, tissue uptake mechanisms, receptor activation, metabolism and excretion.
  162. Drug interaction
    The modification of a drug response by another drug.
  163. Drug interactions classification
    • according to combined effect
    • according to mechanism
  164. Related terms
    drug-drug interaction, drug-food interaction
  165. Oral absorption
    • Requires drug to penetrate membrane barriers (linings of the small intestines)
    • Some foods, pH changes, or other drugs can reduce drug absorption - eg Ca2+, Mg2+, or Al3+ containing foods or medications can reduce the absorption of the antibiotics tetracycline or ciprofloxacin
  166. Drug Interactions Mechanisms - Receptor
    • Digitalis and some diuretics
    • Because cardiac patients can be prescribed digitalis plus a diuretic, a potassium supplement is often added to prevent the digitalis-diuretic interaction.
    • Not all diuretic cause potassium loss! Potassium-sparing diuretics are so-named because they do not cause potassium loss so they do not show the digitalis-diuretic interaction.

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