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Drug Dosage and Clinical Responses. September 12, 2007 Frank F. Vincenzi. 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

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drug dosage and clinical responses

Drug Dosage and Clinical Responses

September 12, 2007

Frank F. Vincenzi

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

Learning Objectives
factors modifying drug responses the big three
Factors Modifying Drug Responses(The Big Three)
  • Drug (pharmacodynamics)
  • Dose (pharmaco/dynamics/kinetics)
  • Route of Administration (pharmacokinetics)
factors modifying drug responses cont the big many
Tolerance

Dependence

Age

Weight

Sex

Pharmacogenetics

Set

Setting

Dosing errors

Non-compliance

Drug interactions

Disease!

Attitude!

Factors Modifying Drug Responses (cont):The ‘big many’
antagonism
Antagonism
  • Combined effect of the two drugs is less than thesum of their individual effects
    • Types of antagonismPharmacological (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)
synergism
Synergism
  • The combined effect of two drugs is greater than the sum of their individual effectsi.e., 1 + 1 = 6 or 0 + 4 = 10(often called ‘potentiation’)
potency and clinical efficacy efficiency
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)
healthy volunteers medical students and intravenous sodium amytal n 55
Healthy Volunteers (Medical Students?) and Intravenous Sodium Amytal (n = 55)

Adapted from Clark’s Applied Pharmacology

medical students and intravenous sodium amytal n 55
Medical Students (?) and Intravenous Sodium Amytal (n = 55)

Adapted from Clark’s Applied Pharmacology

population quantal dose response curve
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.
slide13
Isoniazid levels in patients subjected to a standard dose - an example of pharmacokinetically determined tolerance/sensitivity
therapeutic and side effects of drugs
Therapeutic and Side Effects of Drugs
  • Therapeutic effect: the desired clinical effect
  • Side effects: any other clinical effects(may include neutral or adverse events)
several measures of relative drug safety
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
slide20
Changes in therapeutic index of a chronically administered barbiturate:dispositional and cellular tolerance
tolerance
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).
subsets of tolerance
Subsets of Tolerance
  • Tachyphylaxis(e.g., indirectly acting sympathomimetic amines)
  • Tolerance
    • Dispositional
    • Cellular
    • Behavioral
receptor desensitization one potential mechanism of cellular tolerance
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 thenbeta-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.

down regulation of receptors another potential mechanism of cellular tolerance
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).

up regulation of receptors
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’

the therapeutic window
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 ofGoodman & 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.

adverse drug reactions
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)
drugs commonly associated with adverse reactions
In hospitalized patients:

digoxin

heparin

hydrochlorothiazide

spironolactone

Leading to hospitalization:

aspirin

digoxin

hydrochlorothiazide

prednisone

warfarin

Drugs Commonly Associated with Adverse Reactions
dependence
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 physicaldependence is ‘physical’ withdrawal. May have cross dependence.
substance abuse
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.
addiction a more official view
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