Drug Dosage and Clinical Responses
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Drug Dosage and Clinical Responses
September 12, 2007Frank F. Vincenzi
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Learning Objectives
• Antagonism• Potency• Clinical efficacy• Slope of D-R curve• Quantal response• ED50, LD50, TI• Synergism• Summation
• Tolerance • Tachyphylaxis• Idiosyncrasy• Drug allergy• Therapeutic/side effects• Adverse effects• Toxicology
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Factors Modifying Drug Responses(The Big Three)
• Drug (pharmacodynamics)
• Dose (pharmaco/dynamics/kinetics)
• Route of Administration (pharmacokinetics)
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Factors Modifying Drug Responses (cont):The ‘big many’
• Tolerance• Dependence• Age• Weight• Sex• Pharmacogenetics
• Set• Setting• Dosing errors• Non-compliance• Drug interactions• Disease!• Attitude!
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Antagonism• Combined effect of the two drugs is less than the
sum of their individual effects
– Types of antagonism
Pharmacological (agonist/antagonist)(pure antagonist + full agonist) (i.e., 0 + 6 = 1) (partial agonist + full agonist) (i.e., 2 + 6 = 4)
– Chemical– direct chemical interaction (e.g., chelation)
– Physiological– Two drugs produce opposite effects on the same system
(epinephrine in the treatment of histamine-induced bronchospasm)
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Synergism
• The combined effect of two drugs is greater than the sum of their individual effects
i.e., 1 + 1 = 6 or 0 + 4 = 10
(often called ‘potentiation’)
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Potency and Clinical Efficacy/Efficiency
• Potency refers to the amount of drug necessary to produce a certain effect. A drug which produces a certain effect at 5 mg dosage is ten times more potent than a drug which produces the same effect at 50 mg dosage.
• Clinical efficacy (or simply efficacy) refers to the maximal clinical response that can be obtained by a particular drug (morphine is more clinically efficacious than aspirin as an analgesic) *
• Clinical efficiency is the bottom line of how well an intervention actually works (includes compliance)
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Healthy Volunteers (Medical Students?) and Intravenous Sodium Amytal (n = 55)
Adapted from Clark’s Applied Pharmacology
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Clinical Responses to Drugs are Often Expressed Quantally: Quantal Dose-Response Curve
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Medical Students (?) and Intravenous Sodium Amytal (n = 55)
Adapted from Clark’s Applied Pharmacology
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Population Quantal Dose-Response Curve
• Position is a reflection of drug potency. Drugs that produce a certain effect at a low dose are more potent than drugs that produce the same effect at a higher dose.
• Slope is a reflection of the dispersion of sensitivity to the drug among members of the population. The steeper the slope the more homogeneous the population.
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Therapeutic Effect of Prazosin: Lowering of Blood Pressure by 10 mm Hg
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Isoniazid levels in patients subjected to a standard dose - an example of pharmacokinetically
determined tolerance/sensitivity
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Therapeutic and Side Effects of Drugs
• Therapeutic effect: the desired clinical effect
• Side effects: any other clinical effects(may include neutral or adverse events)
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Frequency distribution and cumulative % responses of a population to a drug
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Calculation of Median Therapeutic Index
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Different therapeutic indices of a given drugwith more than one therapeutic effect
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Several measures of relative drug safety
• Median Therapeutic Index, TI = LD50/ED50
• ‘Conventional Index’ = LD1/ED1
• ‘Standard Safety Margin’ = ([LD1/ED99 - 1])*100
• ‘Standard Safety Margin’ = ([LD0.1/ED99.9 - 1])*100
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Examples of relative toxicities of some psychotropic drugs
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Changes in therapeutic index of a chronically administered barbiturate:
dispositional and cellular tolerance
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Tolerance
• A condition produced by repeated or continued exposure to a drug that produces decreased responses to that drug when given at a certain dosage - or that increased doses are needed to maintain a certain level of response.
• (Cross tolerance refers to the same phenomenon involving chemically or mechanistically related drugs).
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Subsets of Tolerance
• Tachyphylaxis (e.g., indirectly acting sympathomimetic amines)
• Tolerance– Dispositional– Cellular– Behavioral
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Receptor Desensitization: One Potential Mechanism of Cellular Tolerance
Reversible decrease in the sensitivity to agonist(s)of responses mediated by a particular receptor orreceptor signaling pathway.
Example: agonist binds to the beta-receptor then beta-adrenoceptor kinase (ARK), phosphorylates the beta-adrenoceptor protein - this promotes the binding of beta-arrestin and decreases interaction of the receptor with the G protein, Gs.
Removal of agonist allows phosphatases to ‘reset’ the receptor.
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Down Regulation of Receptors: Another potential mechanism of cellular tolerance
Agonist-induced decrease in the number of available receptors of a particular type. This decreases the sensitivity of the system to responses mediated by the receptor in question.
Example: altered receptor turnover that results in feweravailable receptors for activation in chronic opiate usage, etc. (basis of tissue tolerance).
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Up Regulation of Receptors
Antagonist- or ‘dis-use’-induced increase in the number of available receptors of a particular type. This increases the sensitivity of the system to responses mediated by the receptor in question (increased number of spare receptors).
Example: ‘denervation supersensitivity’
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The ‘Therapeutic Window’
Ratio of the maximum concentration that is non-toxic inmost of the population (various toxicities) to the minimumconcentration that is effective in most of the population
(e.g., theophylline 10 - 20 µg/ml)
(avg.TD/ED in the ninth edition of Goodman & Gilman’s = 2.79 ± 3.2 (0.23 - 15)
THEREFORE:
A decimal point is a potentially lethal weapon!! You MUST know pg, ng, µg, mg, g, kg, etc.
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Practical limitations on clinical dosing: Therapeutic and side effects of digitoxin
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Adverse Drug Reactions
• Overdosage (includes interactions, genetics, suicide)• Side effects (most are predictable)• Secondary effects (e.g., overgrowth)• Idiosyncrasy (unpredictable, by definition)• Drug allergy (also called hypersensitivity)
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Drugs Commonly Associated with Adverse Reactions
• In hospitalized patients:
• digoxin• heparin• hydrochlorothiazide• spironolactone
• Leading to hospitalization:
• aspirin• digoxin• hydrochlorothiazide• prednisone• warfarin
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Adverse Drug Reactions Associated with Multiple Drugs
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Mortality Associated with Multiple Drugs
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Dependence
• “A cluster of cognitive, behavioral, and physiological symptoms indicating that the individual continues use of the substance despite significant substance-related problems.” (DSM-IV)
• Psychological - withdrawal mainly psychological• Physical - the hallmark of physical
dependence is ‘physical’ withdrawal. May have cross dependence.
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Substance Abuse
• “…a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to the repeated use of substances.”(DSM IV)
(Note: The criteria do not include tolerance, withdrawal or a pattern of compulsive use. Also note, DSM IV never uses the term ‘addiction’)
•Curiously: The category of substance abuse does not apply to caffeine and nicotine - at least according to DSM IV.
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ADDICTION: A more ‘official’ view
“Uncontrollable, compulsive drug seeking and use, even in the face of negative health and social consequences”
– Alan L. Leshner, Ph.D., Director of NIDA in:
The Brain: Understanding Neurobiology Through the Study of Addiction