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88 Cards in this Set
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Define pharmacokinetics |
Pharmacokinetics is the action the body has on a drug (as opposed to pharmacodynamics, which is what the drug does to the body.) |
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Name four important aspects of pharmacokinetics |
A: absorption D: distribution M: metabolism E: elimination |
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Name four common routes of drug administration |
Enteral Parenteral Mucus membranes Transdermal |
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Advantages and disadvantages of the enteral route of drug administration |
oral/sublingual or buccal (aspirin) (+) simple, inexpensive, convenient, painless (-) drug exposed to GI + 1st pass metabolism, slow delivery |
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Advantages and disadvantages of the parenteral route of drug administration |
IV/SubQ/Intramuscular (morphine) (+) rapid delivery, high bioavailability, no GI or 1st pass metabolism (-) irreversible, infection, pain, fear, trained professional req’d |
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Advantages and disadvantages of the mucus membrane route of drug administration |
inhalation (albuterol) (+) rapid delivery, painless, simple + convenient, low infection, no 1st pass or GI (-) few drugs available via this route |
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Advantages and disadvantages of the transdermal route of drug administration |
patch/topical (nicotine) (+) simple + convenient, painless, no 1st pass or GI, good for continuous/prolonged administration (-) requires highly lipophilic drug, slow delivery to site of action, may be irritating |
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Factors that influence how a drug is administered are: |
Properties of the drug Site of drug action Route-specific barriers Patient comfort/safety etc Speed of delivery |
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Describe factors that influence the oral absorption of a drug |
1. Chemical properties of a drug in the GI tract: solubility, stability, formulation 2. Transport mechanisms for drug + its concentration 3.Transit time and presence of competing factors 4. First pass metabolism |
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Equation for bioavailability |
Bioavailability: (amount of drug in plasma - oral) / (amount of drug in plasma - IV) x 100 |
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Distinguish simple diffusion from other possible mechanisms for drug transport across membranes. |
Passive diffusion: drug move from high to low concentration. -Doesn’t involve a carrier, isn’t saturable and shows low structural specificity. -Water soluble drugs through aqueous channels or pores -Lipid soluble drugs dissolve in a membrane -MOST COMMON method. Favors small, partially hydrophobic drugs Other options include: Facilitated diffusion - high to low concentration - glucose Active transport - low to high concentration: P-glycoprotein Endocytosis - large molecules: B12 |
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What are the four types of diffusion |
Passive diffusion: high to low, thru pores or across membranes. Facilitated diffusion - high to low concentration - glucose Active transport - low to high concentration: P-glycoprotein Endocytosis - large molecules: B12 |
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Name two general chemical properties of most small molecule drugs. |
partially hydrophobic and... (can use passive diffusion??) maybe |
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Define ion trapping and the role of pH in drug transport across a membrane. |
-pH dependent accumulation of ionizable drugs on one side of a membrane barrier -Drugs pass thru membranes more easily if they are uncharged. The weak acid/base enters a body compartment where it ionizes and gets stuck. -Weak acids accumulate on more basic side of membrane. Better stomach absorption of protonated form. (Aspirin) -Weak bases accumulate on more acidic side of membrane. Worse stomach absorption. Accumulated in acidic endosomes + lysosomes. (Chloroquine) |
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What is meant by first-pass metabolism. When is this a concern? What is usually done to get around this problem? |
- Drugs administered orally are first exposed to the liver and can be extensively metabolized before reaching the rest of the body - This is a concern with oral drugs - IV drugs enter systemic circulation directly and can be used instead for situations in which this is a problem |
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Name three pharmacokinetic water compartments found in the body. |
- Plasma compartment - Extracellular fluid - Total body water/interstitium |
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Describe the barriers that separate the Plasma compartment and factors that influence drug distribution between them. |
- Plasma Compartment: large molecules/protein-bound molecules too large to pass small junctions of capillaries. - Mostly trapped in vascular compartment. - Low Vd (volume of distribution) |
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Describe the barriers that separate the Interstitial compartment and factors that influence drug distribution between them. |
- Interstitial: small hydrophilic drugs can pass through endothelial junctions of capillaries into interstitial fluid. - Hydrophobic cannot move across membranes. - Vd = sum of plasma + interstitial volume |
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Describe the barriers that separate the Intracellular compartment and factors that influence drug distribution between them. |
Intracellular: small + lipophilic drugs can move into interstitium and cross cell membranes into intracellular fluid. Vd = 60% body weight |
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What are the factors that influenced drug distribution within the body |
Blood flow to tissue capillaries Capillary permeability: Liver v. brain Binding of drugs to plasma proteins and tissues |
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Explain how a drug molecule that is bound to a carrier protein like albumin distributes differently than the free drug and why this may be important. |
Drugs binding to albumin lowers the amount of free drug in the plasma, which can’t cross plasma membranes. Albumin binds hydrophobic drugs causing accumulation in plasma. |
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Define and know the units of: 1. dose 2. C0 3. Vd 4. half-life |
1. dose: amount of drug administered to the body (mg) 2. C0: Plasma concentration of a drug at time 0 (mg/L) 3. Vd: volume of distribution (L) 4. time needed for [plasma] to be reduced by .5 |
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Equation for Vd |
Vd = dose (or amount of drug in body) / C0 (volume of distribution) |
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CL |
CL (clearance): estimation of the amount of drug cleared from body/unit of time CL=.0693 x Vd / t(1/2life) |
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Name the major drug metabolizing organ. |
liver |
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2 phases of drug metabolism |
Phase I reactions Phase II reactions |
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Phase I reactions |
Increase drug's hydrophilicity + chemical reactivity. Makes drug more polar and more likely to be excreted Reduction, oxidation, hydrolysis Catalyzed by P450 (CYP) |
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Phase II reactions |
Conjugation reactions change drug to hydrophilic carrier molecules. Polarity of the drug is increased past that of 1st phase liver metabolism. This usually inactivates the drug and makes it more susceptible to elimination/much more water soluble Glucuronidation, sulfonation, acetic acid or amino acids added |
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Name factors that may influence (increase or decrease) metabolism of a drug |
Inducers: Increased production of CYP isoenzymes/increase activity St John’s wort: induces CYP - decreased plasma concentrations/drug activity Inhibitors: competition for CYP isozyme, inhibition of CYP production Grapefruit: inhibits CYP - higher levels of drug/slowed metabolism Patient specific factors: age, genetics, liver disease |
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Name the major paths (organs) for drug elimination (or excretion or clearance). |
Kidney (urine) Liver (bile) also intestines, lungs, breast milk |
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First order elimination |
elimination rate depends on drug concentration (proportional to drug dose, which is less than Kmax) |
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Zero order elimination |
elimination rate is constant. High drug concentration overwhelms elimination routes. Dose amount exceeds Kmax. |
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Define therapeutic window |
The therapeutic window is a range of drug dosage between the minimum amount of drug needed to be therapeutic and the maximum amount of drug appropriate before it becomes toxic. |
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Explain the use of repeated dosing to maintain drug levels within the therapeutic window. |
A loading dose: a strong enough dose to get the drug to above the minimal therapeutic amount. A maintenance dose: follow up doses to keep drug levels within the therapeutic window. Important to know bioavailability, rate of admin. and rate of elimination |
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Identify (with examples) potential pharmacokinetic mechanisms for drug-drug or drug-herb interactions, such as displacement from albumin |
Drugs that bind to albumin have less bioavailability. If a drug is administered with that in mind and another drug with higher affinity for albumin is concurrently present, it will result in a higher bioavailability of the first drug and possible toxicity. Warfarin |
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Identify (with examples) potential pharmacokinetic mechanisms for drug-drug or drug-herb interactions, such as P450 induction |
Induction of CYP = decreased plasma concentrations/drug activity due to increased drug metabolism. St John’s Wort |
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Identify (with examples) potential pharmacokinetic mechanisms for drug-drug or drug-herb interactions, such as P450 inhibition |
Inhibition of CYP = increase plasma concentrations/drug activity due to decreased metabolism. Grapefruit |
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Identify (with examples) potential pharmacokinetic mechanisms for drug-drug or drug-herb interactions, such as altered urinary excretion |
Change in pH can decrease excretion levels. Phenobarbital OD (weak acid) can be handled via bicarbonate, causing urine to be basic. Keeps the drug ionized and inhibits reabsorption |
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Define pharmacodynamics |
The actions of a drug on the body and the influence of drug concentrations on the magnitude of the response. |
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Define drug receptor |
specialized target macromolecules |
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Name the forces important for drug binding |
Drugs bind thru (mostly non-covalent) chemical interactions: - Van der Waals - Hydrogen bonds - Ionic - Covalent |
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Explain the receptor occupancy theory. |
More drug binding receptors = more effect on the body |
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Name four general types of physiological receptors that also bind drugs. |
- Ligand gated ion channels : cholinergic nicotinic receptors - G protein coupled receptors: a + B adrenoceptors - Enzyme linked receptors: insulin receptors - Intracellular receptors: steroid receptors. |
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Define signal transduction and give an example |
Signal Transduction: the process of converting an extracellular signal into a cellular message. Signal binds receptor → G-protein → Adenylyl cyclase → cAMP → protein kinase A activation |
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Define second messenger and give an example |
cAMP in G-protein signal transduction pathway |
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Recognize other types of molecules in your body that may serve as drug receptors. |
Cell surface proteins: Ca2+ channel Intracellular enzymes: Vitamin K epoxide reductase Extracellular enzymes: ACh-esterase Nucleic acids: DNA Pathogen-specific: bacterial cell wall enzymes |
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Differentiate between Graded and Quantal (in reference to the two types of graphs used to illustrate the relationship between drug dose and drug effect) |
Graded: drug effect in one patient. Quantal: drug effect in many patients Know the graphs |
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Differentiate between placebo and pharmaceutical effect |
Placebo effect: a physiological outcome that derives from a patient’s expectations of a specific drug. Pharmacological effect: a drug’s actions on the body |
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Describe in words and graphically: EC50 |
EC50: the concentration of a drug that produces a response equal to 50% of the max response. Smaller E50 = stronger drug. |
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Describe in words and graphically: Emax |
Emax: Highest possible effect of a drug |
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Describe in words and graphically: potency |
Potency: How effective a drug is a low concentrations |
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Describe in words and graphically: efficacy |
Efficacy: maximal response |
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Describe properties derived from binding curves in words and graphically:
KD
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Kd: disassociation factor. Higher Kd is associated with lower binding affinity
(relates to EC50) |
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Describe properties derived from binding curves in words and graphically: RT or Bmax |
Rt or Bmax: Maximum number of receptors that can be bound (relates to Emax) |
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Describe properties derived from binding curves in words and graphically: Affinity |
Affinity: The strength at which a drug binds to receptors |
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Describe in words and graphically: agonist |
Agonist: produces complete activation of a receptor at high drug concentrations |
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Describe in words and graphically: partial agonist |
Partial Agonist: binding results in less than 100% activation, even at high concentrations |
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Describe in words and graphically: antagonist |
Binds at receptor and blocks other agents from binding. Doesn’t change receptor. - Blocks binding of endogenous hormone to receptor. Propranolol - Blocks binding of substrate to enzyme. Atorvasatin blocks HMG CoA reductase |
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Differentiate between a competitive and a non-competitive pharmacological antagonist. |
Competitive antagonist: Makes it less likely agonist will bind to receptor Doesn’t change number of receptors Non-competitive antagonist: Reduces the number of receptorsIrreversible effect, cannot become by more agonist |
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Competitive agonist |
Makes it less likely agonist will bind to receptor Doesn’t change number of receptors Reversible effect, can be overcome by adding more agonistCurve shows: Emax unchanged, apparent EC50 is increased |
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Non-competitive agonist |
Reduces the number of receptors Irreversible effect, cannot become by more agonist Emax decreased, EC50 is unchanged. |
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Give examples of chemical antagonism |
Chemical antagonist: decrease the amount of agonist in the body Adalimumab: tnf receptor |
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Give examples of physiological antagonism |
Physiological antagonist: act as a distinct receptor to elicit opposite physiological effect as the agonist Glucagon: insulin receptor |
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Describe in words and graphically: ED50 |
The dose that produces a clinically effective response in ½ the population |
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Describe in words and graphically: TD50 |
The dose that produces toxicity in ½ the population |
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Describe in words and graphically: therapeutic index |
TD50 / ED 50. Lower TI = more dangerous drug |
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Describe in words + graphically: Therapeutic window |
Range of drug dosage between the minimum amount of drug needed to be therapeutic and the maximum amount of drug appropriate before it becomes toxic. Larger therapeutic window is associated with higher TI (safer drug) |
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Explain (with examples) ways by which drugs may cause adverse or toxic effects Single drug toxicity |
On-target dose: OD - too much drug acting on same receptors that make it therapeutic (Warfarin) Off-target dose: toxic by acting on a different receptor (Acetaminophen: therapeutic at COX, toxic at hepatocytes) Idiosyncratic: unpredictable, unknown mechanism Allergic response: unpredictable (penicillin) |
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Explain (with examples) ways by which drugs may cause adverse or toxic effects Multiple drug toxicity |
Pharmacokinetic - changes pharmaceutical concentration of drug. Grapefruit juice + Atorvastatin // St. Johns wort + Atorvastatin Pharmacodynamic - both drugs have same action via different mechanisms. Dose of second drug effects the second. St. John’s wort and Fluoxetine (SSRI that blocks serotonin uptake @ nerve terminals) |
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Know where to find information on drug toxicities and how to report serious adverse events that may be associated with specific drugs. |
Report adverse responses to MedWatch FDA safety info program toxicities at online at: fda.gov, toxnet, etc |
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Outline the stages of an inflammatory response and distinguish between acute and chronic inflammation. |
1) Trauma/chemicals/microbes/allergens 2) Acute inflammation - appropriate response Expose, attack, remove, repair: RECOVER 3) Chronic inflammation - inappropriate response or persistent aggravation Unresolvedstimulus/hypersensitivity/autoimmunity: CHRONIC DISEASE |
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ID the three main broad classes of anti-inflammatory drugs |
non-steroidal anti-inflammatory drugs (NSAIDs) corticosteroids anti-histamines |
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Drugs classified as non-steroidal anti-inflammatory drugs (NSAIDs) |
Aspirin Celecocib Ibuprofen Methyl salicylate Naproxen |
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Drugs classified as corticosteroids |
Dexamethasone Fluticasone Hydrocortisone Mometasone Prednisone |
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Drugs classified as anti-histamines |
Cyproheptadine Diphenhydramine Hydroxyzine Loratadine |
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Name three types of chemical mediators of an inflammatory response that are especially important in pharmacology. |
AUTACOIDS: locally acting hormone Histamine Eicosanoids (prostaglandins) SYSTEMIC HORMONE: Cytokines + other immune proteins (IL2, TNFa) |
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Define autacoids |
Autacoids: act like local hormones. -Made/released in response to stimulus/signal -Diffuse to neighboring target cell w/o needed blood transport, short lived. -Paracrine or Autocrine -Regulate function at target cell |
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Differentiate paracrine from autocrine |
Paracrine: from a different cell type Autocrine: from the same cell type |
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Identify the first branch point in eicosanoid synthesis and name the two competing enzymes. |
First branch point from Arachidonic acid: Cyclooxygenase or Lipoxygenase |
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Name three types of eicosanoids downstream of cyclooxygenases (COX) and disease-related conditions (symptoms) they mediate. |
Prostaglandins (PGE): modulate pain, inflammation, fever. Also allergic response Prostacyclins (PGI): inhibits blood clot formation, promotes vasodilation Thromboxanes (TXA): blood clotting, vasoconstriction |
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Name the receptor(s) for NSAIDs. |
Selective NSAIDS - differentiate COX1 from COX2 NON-selective NSAIDS - block both COX1 + COX2 |
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Name the class of eicosanoids synthesized by lipoxygenases. |
Leukotrienes |
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What is the receptor + mechanism for aspirin? |
Receptor: COX 1 + 2 Mechanism: irreversible, covalent + noncompetitive agonist Primary mechanism: acetylation of COX by aspirin is a covalent modification of its receptor |
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What are the therapeutic uses for aspirin? |
1. Decrease inflammation - high doses (Less common use due to undesirable side effects 2. Decreased pain/fever - medium doses Via effects on the nervous system (PGE) 3. Decreased blood clots - low dose Via anti-platelet effects (TXA): Chronic use |
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What are the side effects of aspirin? |
GI distress - inhibits COX1 in stomach cells Increased bleeding - inhibited clot formation Increased gout attacks - interferes with body's secretion of uric acid in the kidney |
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Understand the FDA system for classifying drug risk in pregnancy. |
Category A: human studies show no risk (Safe in pregnancy) rare Category B: animal studies show no risk, no adequate human studies. More common Category C: some animal studies show fetal defects/toxicity. No human studies. More common Category D: known fetal risk in humans, benefit may outweigh risk Category X: known risk in animals/humans. DON’T GO THERE. Risk clearly outweighs benefit |
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Name an herbal source of methyl salicylate. |
Methyl salicylate: Wintergreen oil |
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Compare methyl salicylate (herbal form) and aspirin |
Wintergreen oil: - Reversible COX antagonist - Used in OTC creams for muscle aches: Less potent than aspirin, absorbed thru skin - Not usually used as antithrombotic or for chronic inflammation - Side effects are few when used in low doses, internal use can be toxic to GI, kidney and liver |
