Dose Response | High drug utilization hazards

The dose is the amount of a medicine/Drug given to a patient; at a particular time for the treatment of disease e.g. Erythrocin 250mg is given to a patient for the treatment of throat disease, mainly to kill the harmful bacteria of the throat.

Types of dose

Following are the types of dose

Exposure dose

Exposure does the number of xenobiotics (foreign chemical substances) in the environment.

Absorbed dose

Absorbed dose is the type of dose in which an amount of irradiation that is ionizing mop up my body. It measures in grays which means energy sucks the upper unit of mass.

Administered dose

The administered dose is the type of dose that gives to the specific test organism which may human or any other organism. This use to find out the dose-response relationship.

Total dose

It the total of all discrete doses gives to an organism.

Units of Dose:

  • Toxicology uses the same units as used mostly in medicines.
  • Its quality unit is the gram.
  • Smaller amounts of exposure use milligram e.g. the usual adult dose of Erythrocin is 500mg.
  • Commonly a dose measures by the unit mg/k
  • The unit of dosage is mg/kg/day which also includes the duration of exposure.

Response

Outcome visualized by the body to a specific drug e.g. an antipyretic medicine named paracetamol is given to normalize the temperature of the body.

Drug Response

It often refers to PD which stands for Pharmacodynamics. It responds to any bodily functioning and diseased process, which either leads to worse or effective relations.

The following equation explains how the response of a certain dose can be obtained:

Drug + Receptor → Drug – Receptor → Response

Dose-Response Relationship

Science on which toxicological science base, according to it a relationship exists between a poisoned relation which refers to as response and the received poison quantity which is known as dose.

The dose-response relationship also known as the exposure-response relationship, explains the immensity to give the response to an organism, as it is the work of a dose or exposure to stimulant or pain after the dose is exposed to it.

A stimulus-response function also known as stimulus-response curve defined as when a stimulus of any type gives a response broadly which means it is not only restricted to chemicals.

The motivation for learning dose-response relationships:

Every day humans and all other organisms are exposed to many dangerous environmental factors like pollutants and other chemicals influencing the atmosphere. So here the study of dose-response and the development of the models of dose-response is the main thing that helps to determine dangerous or safe and determines the drug dosages with their non-hazardous levels.

Dose-response relationships may be followed in populations or individuals.  In populations, exposure is expressed at different stages and then finds out how people are affected by this. In pharmacology, the modeling of the dose-response relationship is widely done by dose-response curves. The same method is also used in drug development. In particular, the shape of a drug’s dose-response curve (quantified by EC50, NH, and max parameters) reflects the biological activity and strength of the drug.

Example stimuli and response

There is a fact that each sensory stimulus is specified for a specific sensory receptor. Eg for mechanical pressure there are mechanoreceptors, nicotinic acetylcholine receptor is specified for nicotine.

 However, the physiological process affects by stimuli away from the sensation. There is the record for responses as constant data (e.g. muscle contraction force) or detached data (e.g. deaths number)

Important assumptions in this relationship

A specific dose requires for response below this dose no result will found. When the total response from a drug obtains then there will be no further effect of the medicine will obtain.

The dose-response relationship is equal to the source and outcome relationship in chemical revelation and sickness. Allergic responses are distinct types of immune system changes; they are not certainly noxious responses. Not permanently observe with D-R molds.

Allergies vs. toxic reactions

A toxic effect is the outcome of the poisonous chemical performing on cells. Allergic responses are the outcome of a chemical motivating the body to relieve natural compounds that are in order unswervingly for the results seen.

Dose-Response Curve

Association of dose to reaction can explain by a graph known as the dose-response curve

Dose-response curve needs

  1. Drug deciding dose.
  2. Comparing dosage to the percentage of people showing different effects

The intensity of response increases with an increase in dose and the dose-response curve is a rectangular hyperbola.

Construction of dose-response curves

dose-response curve is a coordinate graph relating to the magnitude of a stimulus to the response of the receptor. Several effects (or endpoints) can be studied. The measured dose is generally plotted on the X-axis and the response is plotted on the Y-axis. In some cases, it is the logarithm of the dose that is plotted on the X-axis, and in such cases, the curve is typically sigmoidal, with the steepest portion in the middle. Biologically based models using dose are preferred over the use of log (dose) because the latter can visually imply a threshold dose when in fact there is none.

Statistical analysis of dose-response curves may perform by regression methods such as the probity model or logic, or other methods such as the Spearman-Karber method. Empirical models based on nonlinear regression usually prefer the use of some transformation of the data that linearizes the dose-response relationship.

Typical experimental designs for measuring dose-response relationships are organ bath preparations, ligand binding assays, functional assays, and clinical drug trials.

Why dose-response curve is rectangular hyperbola?

This is because drug-receptor interaction obeys the law of mass action, accordingly

E   =    E max  ´  [D]  ¤  Kd + [D]

Where E = Observed effect of dose of the drug

E max = maximal response

Kd = dissociation constant of the drug-receptor complex

Types of dose-response curves

  • Graded dose-response curves
  • Quantal dose-response curves

Graded Dose-Response Curves:

The Graded dose-response curves constructed for a response that measures on a continuous scale e.g. heart rate. Graded dose-response curves relate the intensity of response to the size of the dose hence used in characterizing actions of the drug. Graded dose-response means a slight increase of drug brings a small increase in response e.g. increased dose of Histamine causes gradual contraction of guinea pig ileum.

  • A very low dose of histamine has no effect and response obtain only beyond the threshold dose of 20 mg
  • A very high dose of more than 50 mg has no additional effect and response remains constant at these maximal levels
  • Graded dose-response means the pharmacological effect of drug expressed in quality or number such as heart rate by beat and blood pressure by mmHg

Dose-response curve studying the effect of aspirin

  • LINEAR PLOT (Left)
  • SEMILOG PLOT (Right)

Quantal Dose-Response Curves

Quantal dose-response curves built for those drugs that provoke all or no response e.g. absence or presence of epileptic seizures This Shows that a given dose of the drug or not evoke a specific effect in the subject under examination. Pharmacological effects express in positive or negative.

Quantal dose-response curves

An experiment executes on 100 subjects. The effective dose to yield a quantal response determine for each individual 

Dose-Response Curve Information

Mentioned are four significant values:                             

  • Potency
  • Efficacy
  • Slope
  • Variability

Drug Potency and Efficacy

  • Drug potency denotes the amount of drug required to yield a response. Relative potency is meaningful more than that of absolute potency e.g. If 10 mg of morphine=100 mg of pethidine, morphine is more potent, its potency is 10 times that of pethidine.
  • Drug efficacy mentions the ability of a drug to provoke a response when it binds to a receptor e.g. Morphine yields a degree of analgesia not attainable with any dose of aspirin, this means Morphine is efficacious more than that of aspirin.

Drug potency and efficacy curves:                                       

  • The Drug B is equally efficacious but less potent than drug A
  • Drug C is less efficacious and less potent than drug A. and less efficacious but equally potent as drug B
  • Drug D is potent more than drug A, B, & C, but equally efficacious as drug C and less than that of drugs A&B.

Slope and Variability:

The slope shows the effect of an increase in dose. Variability is the productivity of different data for different people:

Therapeutic index;

The therapeutic index use for judging drug safety. The therapeutic index is the ratio of Ld50 to Ed50

  • Ed50 – Median effective dose at which 50% of individuals exhibit a specific effect
  • Ld50 – Median lethal dose required to produce death in 50% of individuals

Advantages of plotting log dose-response curves

  • Display wide range of drug doses on graph
  • Easy to make a comparison between agonist and antagonist

Limitations

The idea of a linear dose-response relationship, thresholds, and all-or-nothing responses might not apply to non-linear situations. A threshold model or linear no-threshold model might be more suitable.

Usually, Dose-response relationships depend on the exposure time and exposure route (e.g., inhalation, dietary intake); calculating the response after a different exposure time or for a different route leads to a dissimilar relationship and probably different conclusions on the effects of the stressor into account.

This limitation cause by the complex biological systems and the habitually unknown biological processes functioning between the external exposure and the adverse cellular or tissue response.

Threshold:

It is a dose such that there are no adverse effects of exposure to chemicals below this dose level.

Reviewed by:
Dr. Muhammad Adnan Asghar (Ph.D.)

Chinese Academy of Sciences Fuzhou, Fujian