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98 Cards in this Set
- Front
- Back
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Efficacy
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the magnitude of the maximal effect a drug can produce
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Antagonist
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a drug that binds, generally with high affinity to a particular type (or subtype) of receptor but is devoid of efficacy
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Partial agonist
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a drug that possesses affinity for the receptor it activates/stimulates but has lower efficacy than a full agonist
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How are affinity and efficacy determined from a log dose-response (LDR) curve for a drug?
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The LDR curve is symmetrical at the point at which 50% of the maximum dose is elicited, this is affinity. Efficacy is reflected in the plateau of the LDR curve. Most potent drug (greater affinity for receptor) will be closer to the origin of the LDR plot and will be to the left. If dose rather than drug concentration is used for compression of potency, which is usual, then the higher the dose, the greater the response, which could result in death.
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Which pharmacodynamic parameter of an agonist is changed by the presence of a competitive pharmacological antagonist?
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When a competitive antagonist is present, the affinity of the agonist decreases. The efficacy of the antagonist remains unchanged.
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Log dose-response curves provide information on which terms:
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Affinity
Efficacy Potency Therapeutic index Pharmacological antagonism |
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What is the significance attached to the slope of the LDR curve?
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The slope of the LDR curve indicates the range of dosages over which the drug acts. Steep slope indicates a small increase in dose will produce a large change in intensity of the response. Extremely steep dose response may have important clinical consequences if the upper portion of the drug represents undesirable degree of response.
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On what pharmacodynamic parameter are potency and selectivity of action based?
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Affinity
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Quantal dose effect curves provide what information?
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Median effective dose
Therapeutic index Potency Selectivity of action NOT Efficacy |
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If drug A is ten times more potent than drug B, and both drugs have the same mechanism of action, what would be the dose of drug B administered by the same route relative to the dose of drug A in order to obtain a similar intensity of response?
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Need to administer 10x drug B
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Name an alternative graphical technique to the use of log dose response curves for determining the character of pharmacological antagonism?
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The double reciprocal plot can be used to determine whether action of the antagonist is competitive or non-competitive.
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What is the essential difference between physiological and pharmacological antagonism?
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Physiological antagonism occurs when two agonists, acting on different receptor types counterbalance each other by producing opposite effects on the same physiological function. In general, the effects produced by a physiological antagonist are less specific and less easy to control than effects produced by a pharmacological antagonist.
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Name drugs which owe their action to selective inhibition of certain enzymes:
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Aspirin, Theorphylline, Digoxin, Captopril, Neostigmine
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List 3 alkaloid drugs
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atropine, morphine, pilocarpine
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State an important physiochemical property possessed by alkaloids:
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They are nitrogenous organic bases that form water soluble salts with acids
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By which transport process do drugs penetrate the blood-CSF barrier and enter cerebrospinal fluid?
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Drug penetration takes place solely by passive diffusion.
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What physiochemical property of a drug is required for penetration of the blood-CSF barrier?
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Drug molecules must be non-ionized and free (not bound to albumin)
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List the features of active transport:
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- Relatively selective regarding the chemical nature of the substances transported
- Carrier-mediated - Saturable - Subject to competitive inhibition by substances of generally similar character - Require direct expenditure of energy - Can occur against a concentration or electro-chemical gradient - Increases the rate of excretion of polar drugs and metabolites (ex. conjugates) by the kidneys and liver in urine and bile. |
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The fraction of the administered dose of a drug that enters the systemic circulation unchanged (as parent drug) is expressed by what term?
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Systemic availability of the drug
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Which route of drug administration is assumed to provide complete (100%) systemic availability of the drug?
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Intravenous injection
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The pH at which drugs that are weak organic electrolytes (acids or bases) exist in equal concentrations (50% of each) as the ionized and non-ionized forms is known as what?
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pKa
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What information would be required to calculate, for predictive purposes, the equilibrium concentration ratio of total (non-ionized plus ionized) free drug that would be attained between blood plasma and a biological fluid (such as milk) which the drug enters by passive diffusion?
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The pKa of a drug and the pH of the environmental fluid
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Why are drugs administered as solid dosage forms (tablets or capsules) more slowly absorbed from the gastro-intestinal tract than oral solutions of the drugs?
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Solid forms must undergo disintegration and dissolution in the stomach before absorption can occur. Drug release from solid dosages forms delays the rate of absorption compared with that from oral solutions and liquids.
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List the factors which influence the absorption of drugs from the gastro-intestinal tract.
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In order to be absorbed, the drug must:
- be in solution - be relatively stable in the strongly acidic environment in the stomach - have sufficient solubility to passively diffuse through the lipoidal mucosal lining of the small intestine. |
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Explain how and why the absorption of orally administered drugs differs between dogs, horses and cattle:
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The anatomical arrangement of the GI tract and associated digestive physiology govern the pattern of drug absorption.
Horse - small stomach capacity (8.5% of GI tract); volume capacity is 7-14 liters; pH less acidic (5.5) Dog - large stomach capacity (62% of GI tract); volume capacity is 3-8 liters; pH more acidic (3-4) Cattle - large fore stomach capacity (60%); volume capacity is 100-225 liters. ***The rumen has considerable absorptive capacity. Passive diffusion, lipid soluble drugs, whether neutral molecules or non-ionized form of weak acids or bases may be absorbed in the rumen. |
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What type of oral dosage form of certain anthelmintic drugs, designed for use in either beef cattle or sheep, provides an especially long duration of action?
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Control-release ruminant bolus containing anathematic drugs (ivermectin, fenbendazole, morantel). These drugs are available for oral administration for sheep and beef cattle. Drug remains in the reticulo-rumen at least throughout the entire period of drug release over 100 days.
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Explain what is meant by the hepatic first-pass effect and how it may influence the extent of absorption (systemic availability) of orally administered drugs.
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In any species, the first pass effect can substantially reduce the systemic availability of orally administered lipid soluble drugs that undergo extensive biotransformation in the liver. Herbivores have a larger liver, the first pass effect is greater in herbivores.
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What advantage might rectal administration to dogs and cats provide over oral administration of a lipid-soluble drug in solution?
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partial avoidance of the first pass effect; greater in cats than in dogs
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When a drug is administered by continuous intravenous infusion at a constant rate, what period of time is required to achieve a steady state concentration of the drug?
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The rate of infusion determines the steady state concentration that will be attained. The time taken to reach steady state is determined solely by the rate of elimination (half life) of the drug. For clinical purposes, it can be assumed that a steady state concentration will be achieved after infusing the drug solution at a constant rate for periods corresponding to 4 times the half life of the drug.
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What does the rate of infusion determine, and on which pharmokinetic parameter is the infusion rate based?
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The rate of infusion determines the steady state. Infusion rate is based on elimination.
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By which route should long-acting parenteral preparations of drugs be administered and what process accounts for their prolonged action?
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A single intramuscular dose is how most long acting preparations are administered.
Long acting parenteral preparations are formulated in a non-aqueous (such as oil or organic) vehicle (solution), or a poorly soluble salt of the drug is used (usually an aqueous suspension). These preparations provide slow absorption of the drug over an extended period due to its gradual or staged availability for absorption. Long acting preparations are designed to provide an extended dosage interval. |
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What information is required to describe the distribution pattern of a drug?
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The distribution pattern, which describes the amount of drug that enters each organ and tissue, is determined by:
• the extent (expressed as a percentage) of a drug binding to plasma proteins • blood flow to organs and tissues • the ability of the drug to pass through cellular barriers • binding affinity to extra vascular tissue components Distribution pattern of a drug can be obtained by measuring the amount or levels of the drug in various organs or tissues in the body. |
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To what is species variations in the distribution pattern of drugs mainly attributed?
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differences in body composition.
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Explain how an increase in the free (unbound) fraction of a drug may occur and when would the decrease in plasma protein binding be clinically significant.
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An increase in the unbound fraction can occur:
• In certain diseases such as hypoalbuminaemia or uremia • Due to competitive displacements by concurrently administered drug with higher binding affinity for plasma proteins This is clinically significant for drugs that bind very extensively to plasma proteins and have a narrow margin of safety. An example is warfarin, where a small decrease in the extent of binding of this drug would result in a clinically significant increase in the unbound fraction in the plasma. |
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What factors determine the extent of plasma protein binding of a drug?
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- affinity for the binding site
- number of binding sites - concentration of binding protein in plasma. |
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To which plasma protein do weak organic acids bind?
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albumin
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Compare the free fractions of a drug for which the extent of plasma protein binding is decreased from 98% (normal) to 92% (disease state or displacement).
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There would be a 4 fold increase in the free form, which would indicate disease or would greatly increase the intensity of the pharmacological effects. Free drugs in plasma distribute extravascularly and interact with, activate or inhibit drug receptors at the site of action.
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To what does the elimination of a drug refer?
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biotransformation (metabolism) and excretion (overall process of removing drugs from the body)
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What are the principal processes of elimination?
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Hepatic metabolism and renal excretion.
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A wide variety of structurally unrelated lipid-soluble drugs are eliminated by which metabolic pathway?
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Microsomal oxidative reactions which take place in the smooth ER.
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Name the drug metabolic reactions that ruminal micro-organisms perform.
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These micro-organisms perform reductive reactions that are capable of inactivating orally administered drugs containing a nitro group.
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Drugs with an ester or amide linkage are metabolized by which process?
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Hydrolysis via phase one biotransformation reaction
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In what way does this metabolic reaction differ between drugs with an ester and those with an amide linkage?
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Most amides are hydrolyzed more slowly than the corresponding esters.
*** Local anaesthetics contain either an ester or an amide linkage, and this influences their duration of action. |
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list the principal characteristics of phase I metabolites
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convert parent group to a more polar metabolite by introducing or unmasking a group
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compare phase II metabolites to phase I metabolites
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- polar
- less lipid soluble - less distributed extravascularly than parent drug or functional phase I metabolite |
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The active (phase I) metabolite of some drugs is commercially available and marketed as a drug in its own right, for example:
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Oxazepam (diazepam)
Ciprofloxacin (enrolfloxacin) Oxfendazole (fenbendazole, sulphoxide) |
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Explain why felidae slowly form glucuronide conjugates of drugs or phase I metabolites and how can the significant consequence of this be accommodated?
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deficiency of the transferring enzyme, microsomal glucuronyl transferase; compensated by the various endogenous compounds, such as bilirubin, thyroxin and steroids, that form glucuronide conjugates in cats.
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Canidae are unable to perform which phase II metabolic reaction on drugs containing what chemical group in their structure?
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acetylating drugs with aromatic and hydrazine amino groups.
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define acetylation
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a synthetic reaction that involves transfer of the acetyl group from acetyl coenzyme A to the amino group of the drug.
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In which organ of the body does glutathione conjugation take place and what is the limiting factor in synthesis of glutathione conjugates?
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the liver: limiting factor is the limited availability of glutathione
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Which phase II metabolic pathways (conjugation reactions) are deficient in fish?
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Fish may have a low capacity to form activated nucleotide UDPGA
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How would deficiencies in phase II metabolic pathways affect the overall rate of elimination of several drugs in fish relative to mammalian species?
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glucuronide synthesis would be limited and the rate of elimination for drugs dependent on glucuronide synthesis would decrease
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Which drug metabolic pathway would be induced or inhibited by certain drugs?
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Hepatic microsomal oxidation reactions can be inhibited, induced or altered.
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What would be the consequence of induction on the duration of a concomitantly administered drug?
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increase in the rate of biotransformation and decrease in the duration of action of the inducing substance and of the concomitantly administered drugs by the induced pathway
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How might inhibition affect the duration of action of a concomitantly administered drug?
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The metabolism of concomitantly administered drugs, which are metabolized by plasma pseudo cholinesterase, would be considerably reduced, and consequently their action prolonged.
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What is the principal process of elimination for drugs that are predominantly ionized in the blood plasma and for compounds with limited solubility in lipid (polar drugs and drug metabolites)? List the mechanisms involved in their handling, and give due consideration to plasma protein binding.
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Renal excretion is the principal process of elimination.
While plasma protein binding decreases the availability for drug glomerular filtration, it does not directly influence tubular secretion, presumably because of rapid dissociation of the drug-protein complex. Therefore tubular secretion is generally a function of total plasma drug concentration. |
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State the normal range of urine pH for dogs, cats, horses and ruminants
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Dogs & cats – 5.5 - 7
Horses & Ruminants – 7.2 -8.4 |
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Discuss the influence of alteration of urine pH on the excretion of drugs that are weak organic acids.
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Alteration of urinary pH may affect the excretion rate of weak organic electrolytes. Urinary alkalinization promotes the reabsorption from the distal nephron of weak organic bases and enhances the renal excretion of weak organic acids, and vice versa. When urine pH becomes more acidic, more basic drugs are excreted.
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Describe what the enterohepatic circulation (cycling) of a drug entails.
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The enterohepatic circulation refers to the process when some of the components in bile (bile salts) and certain biliary excreted drugs are reabsorbed in the intestine, conveyed back to the liver in the portal vein and re-excreted in the bile.
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What would be the influence of extensive enterohepatic circulation on the overall rate of elimination of a drug?
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When a significant fraction of the dose undergoes enterohepatic circulation, elimination of a drug is slow. It is usual for these drugs to be gradually eliminated by renal excretion.
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Which metabolite of drugs is likely to be excreted both in urine and bile?
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The conjugates, phase II metabolites, are almost invariably highly polar and rapidly excreted by the kidneys and liver, in urine and bile.
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What conclusion would you draw from the table on p.10 on the half lives of trimethoprim and sulphadiazine in fish?
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?
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List the significant terms that are associated with the plasma drug concentration-time curve following extra vascular (PO, IM) administration of a drug as a conventional dosage form.
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Cmax – maximum concentration
Tmax – time of peak AUC – area under the curve |
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What is meant by the therapeutic range of plasma concentrations for a drug that produces a certain pharmacological effect?
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A defined range of plasma concentrations associated with a desirable intensity of the principal pharmacological (therapeutic) effect.
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State the information which is required to calculate the usual dosage regimen (size of the dose and the dosage interval) for a drug preparation.
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The info needed for the calculation is:
- the therapeutic concentration range - the pharmacokinetic parameters that describe the bioavailability and disposition of the drug. |
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List a fact (1)
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Plasma protein binding displacement, induction and inhibition of a major metabolite pathway are important pharmacokinetic interactions that may have clinical consequences.
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List a fact (2)
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Because antimicrobial (unlike pharmacological) agents do not have a refined range of therapeutic plasma concentrations, the desired average steady-state plasma concentration is a multiple of MIC90. MIC90 is the minimum inhibitory concentration, measured in vitro, for 90% of susceptible bacterial pathogens.
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To what does the disposition curve for a drug refer?
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the decline in plasma drug concentrations
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The elimination phase of drug deposition is characterized by which pharmacokinetic parameters?
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the half life and the apparent volume of distribution of the drug.
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List the factors that influence the disposition of drugs.
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- Systemic (body) clearance
- Volume of distribution - Half life - Mean residence time (MRT) – average time the # of drug molecules introduced reside in the body - Systemic availability |
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Define systemic (body) clearance and state the units in which it is usually expressed:
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measures ability of body to eliminate drug
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Define volume of distribution (Vd) and state the units in which it is usually expressed:
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shows the apparent space in body available to contain drug
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Define systemic availability (F) and state the units in which it is usually expressed:
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fraction of dose that reaches systemic circulation unchanged
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Define half life (t1/2) and state the units in which it is usually expressed:
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overall rate of drug elimination
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Define the term bioavailability.
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Defined as rate and extent (more important than rate) to which drug enters systemic circulation unchanged following administration by any route
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List the pharmacokinetic parameters for which area under the curve (AUC) is applied in the calculation of their values.
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AUC is used to calculate: clearance, volume of distribution, rate of absorption, mean residence time, and systemic availability.
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State the significant characteristic of first-order elimination of a drug.
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a constant fraction is eliminated per unit time; therefore, systemic clearance of a drug is usually constant over the range of plasma concentrations that are of clinical interest.
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What are the implications of first-order elimination to systemic clearance?
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Those drugs that exhibit saturable or dose dependent elimination, clearance will vary with plasma concentration. These drugs obey zero order elimination meaning that a constant amount of drug is eliminated per unit time.
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List the components which comprise the dosing rate for a drug.
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Available system dose of the drug, divided by the dosage intervals.
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State the objective in designing a dosage regimen.
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to maintain plasma drug concentration within therapeutic range of the drug.
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When a drug is administered by continuous (constant rate) intravenous infusion, what information is required for calculation of the infusion rate?
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Ro=Cp(ss)*Clb
When a drug is administered IV, the infusion rate (Ro) is required to provide a desired steady state plasma concentration. To calculate infusion rate (Ro), the systemic state of plasma clearance (Cp(ss)) and body clearance (Clb) of a drug must be known. |
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The mean concentration attained at steady-state is determined by what variable?
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The mean concentration at steady state is directionally proportional to the rate of infusion and inversely proportional to the systemic clearance of the drug.
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The time required (duration of continuous IV infusion) to reach within 90% of the predicted steady-state concentration is dependent on which pharmacokinetic parameter?
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The time required is dependant on the length of the half-life.
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Describe the technique that may be used to overcome the delay in attaining a desired steady-state concentration of a drug with a half-life longer than arbitrarily 1.5 hours.
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The delay in attaining a desired steady state concentration of a drug with a ½ life longer than 1.5 hours can be overcome by simultaneously administering a loading dose, either as a single entity or as increments at short intervals, and commencing continuous infusion of the drug.
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What useful information is provided by the volume of distribution term and what is its application in the calculation of size of the dose (dose level, mg/kg body weight)?
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The volume of distribution relates the amount of drug in the body to the concentration in the plasma, providing an estimation of the extent of distribution of a drug. It also quantifies the apparent space, both in systemic circulation and the tissue of distribution. Its application serves as a proportional factor that relates the plasma concentration to the amount of drug in the body.
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List the factors that influence the distribution pattern of a drug and how is the pattern of distribution determined?
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Distribution pattern is influenced by where and how much of the drugs are administered. The volume of distribution is determined by the chemical nature and physico-chemical properties of the drug and by the degree of binding to plasma proteins and extravascular tissue components.
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List a fact (3)
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An important characteristic of first-order elimination is that the time required for a given concentration to decrease by a certain percentage is independent of the concentration. The half-life of a drug which undergoes first-order elimination expresses the time required for the plasma concentration, as well as the amount of drug in the body, to decrease by 50% through the process of elimination.
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If overall elimination rate constant (B) for a drug administered as a single intravenous dose is 0.0575 h-1, what is the half-life of the drug?
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12 hours
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State whether the half-life of the majority of drugs, which are eliminated mainly by hepatic microsomal oxidation, are shorter in herbivorous or carnivorous species.
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The half life is shorter for herbivores and longer in carnivores.
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State the physiochemical properties of drugs that are mainly eliminated by renal excretion.
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Renal excretion is the principal process of elimination for drugs that are predominantly ionized at physiological pH and for compounds with limited solubility in lipid (polar drugs and drug metabolites).
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When glucuronide conjugation is a major pathway for biotransformation of a drug, in which domestic animal species will the half-life of the drug be longest?
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The half life will be longer in cats than in any other domestic species.
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Describe the mechanism whereby urinary alkalinization will decrease/shorten the half-lives of drugs that are weak organic acids which are at least partly (>20% of the systemically available close) eliminated by renal excretion.
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Alkalization of the normally acidic urine decreases the half life by increasing the ionization of the drugs (weak organic acids) in the distal tubule fluid.
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State whether half-life is a pure or hybrid (composite) pharmacokinetic parameter.
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Hybrid.
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With reference to the administration of drugs, state two useful applications of half-life.
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- reach steady state of a drug
- forms the basis for selection of an appropriate dosage interval |
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Name the physiologically-based pharmacokinetic parameters which influence the half-life of a drug administered as a single intravenous dose.
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The elimination phase of drug disposition.
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When a drug is administered orally as a suspension (to ruminant animals), a paste (to horses) or a tablet (to dogs), or by intramuscular injection as a long-acting potential preparation (to any animal species), which additional pharmacokinetic variable influence the half-life of the drug?
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The absorption process.
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With reference to interspecies allometric scaling of the rate of drug elimination versus average body weights of mammalian species, which pharmacokinetic parameter is generally used?
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The use of clearance, a physiologically based parameter, may be more appropriate than half life (a hybrid parameter) for interspecies allometric scaling of drug elimination.
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When calculating in intravenous infusion rate or designing a dosing rate with the objective of maintaining a desired average steady-state plasma concentration within the therapeutic range for a drug, which pharmacokinetic parameter is the most important?
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Half life
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