Drug Dosage and Clinical Responses

Drug Dosage and Clinical Responses

September 12, 2007Frank 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

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!

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)

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’)

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)

Adapted from Clark’s Applied Pharmacology

Clinical Responses to Drugs are Often Expressed Quantally: Quantal Dose-Response Curve

Medical Students (?) and Intravenous Sodium Amytal (n = 55)

Adapted from Clark’s Applied Pharmacology

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.

Therapeutic Effect of Prazosin: Lowering of Blood Pressure by 10 mm Hg

Isoniazid levels in patients subjected to a standard dose - an example of pharmacokinetically

determined tolerance/sensitivity

Therapeutic and Side Effects of Drugs

• Therapeutic effect: the desired clinical effect

• Side effects: any other clinical effects(may include neutral or adverse events)

Frequency distribution and cumulative % responses of a population to a drug

Calculation of Median Therapeutic Index

Different therapeutic indices of a given drugwith more than one therapeutic effect

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

Examples of relative toxicities of some psychotropic drugs

Changes in therapeutic index of a chronically administered barbiturate:

dispositional and cellular 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

• Tachyphylaxis (e.g., indirectly acting sympathomimetic amines)

• Tolerance– Dispositional– Cellular– Behavioral

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.

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

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’

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.

Practical limitations on clinical dosing: Therapeutic and side effects of digitoxin

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

Adverse Drug Reactions Associated with Multiple Drugs

Mortality Associated with Multiple Drugs

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.

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

“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