Drug Toxicity and Receptors

Partial agonist

Agonist that never reaches maximum effect

Partial agonist with Agonist curve

acts as antagonist → change potency and efficacy

Agonist and reversible Antagonist curve

Shifts curve RIGHT (change potency)

Potency

EC50/ED50

Agonist and Irreversible Antagonist

Receptors permanantly decrease, Changes Efficacy

As Irreversible Antagonist Increases

Receptors Decrease

Regardless of [Irreversible Antagonists] as time increases

Effect Increases

Spare Receptors

number of R’s vs number of Effectors, don’t use up R’s for full effect

Spare receptors vary between ____ type

tissue

Dose response curves v. Tissues

Left to right most R’s to least R’s, difference in potency

Quantal dose response…

does an effect occur or not (yes/no)

Quantal dose response relates ___ and ___

dose;frequency in population

Antagonist in absence of spare R’s is _____

uncommon

Reversible Antagonists in absence of spare R’s causes curve to shift ____ and changes ____

right;potency

Irreversible Antagonists in absence of spare R’s causes curve to shift ____ and changes ____

down;efficacy

irreversible Antagonists in presence of spare R’s is ____

common

irreversible Antagonists in presence of spare R’s causes curve to shift ____ and changes ____

right and down;potency and efficacy

Therapeutic Index

Toxic dose/Effective dose (TD50/EC50)

Therapeutic Window

Range of dose of drug taken without toxicity

TD50 (Toxic Dose) is not a ______

set value

Toxic dose depends on

Type of toxicity studied (cough vs low BP)

Therapeutic Index does NOT give ____

whole picture → may be look good but doesnt give all info on toxicity v. ED

Side Effect

secondary therapeutic or negative effect

Adverse Effect

undesired harmful effects

Toxic Effect

Toxicity occuring at a dose higher than ED

Toxicity effects can

decrease adherence

Toxicity can lead to cell death in 2 ways:

Apoptosis or Necrosis

Apoptosis

Peaceful → shrink and condense then eaten by phagocytes

Necrosis

Violent death → swell and burst then spills toxins

Mechanisms of drug toxicity

1. Immune-mediated

2. Idosyncratic

3. On target

4. Off target

Immune-mediated mechanism

Drug seen as threat and body attacks

Idiosyncratic

Unpredictible and unknown cause

On Target

On target but unintended effect (antihistamines and drowsiness)

Off Target

Off target with unintended effect (Low BP with Antipsychotics)

Types of Toxicity (2)

1. Overdose

2. Drug-Drug intxns

Drug-Drug intxns (3)

1. Pharmacokinetic

2. Pharmacodynamic

3. Drug-Herb intxn

Pharmacokinetic (D-D)

Drug changes ADME of another drug

Pharmacodynamic (D-D)

Drug changes response of tissue to another drug

Drug-Herb intxns (D-D)

Safety or Efficacy affected by non-pharmaceutic

Drug Induced Toxicity types (10)

1. Harmful Immune Response

2. Immunotoxicity

3. Hepatotoxicity

4. Renal Toxicity

5. Neurotoxicity

6. Skeletal muscle toxicity

7. Cardiovascular toxisity

8. Pulmonary toxicity

9. Carcinogens

10. Teratogens

Harmful Immune Response

Hypersensitivity → Autoimmunity

Immunotoxicity

myelosuppresion → decrease lymphatocytes, platelets and RBCs

Hepatotoxicity

Cholestatic (biliary block) or Hepatocellular (hepatocyte death)

Renal toxicity

Change of blood flow to kidneys

Neurotoxicity

axon interference

Skeletal muscle toxicity

weakness, atrophy, pain

Cardiovascular toxicity

prolong QT interval (heart)

Pulmonary toxicity

Cough, Lung toxicity

Carcinogens

Tumor growth

Teratogens

Defects to fetus

Treatments to drug induced toxicity (4)

1. Decrease drug exposure

2. Block MOA (antidote)

3. Change metabolism

4. Manage toxic symptoms