HOMEOSTASIS Sean Oosterholt

Homeostasis (from Greek: ὅμοιος homoios, "similar" and στάσις stasis, "standing still")

the property of a system in which variables are regulated so that internal

conditions remain stable and relatively constant.

Homeostasis

• Negative feedback

– Thermostat, cruise control

• A lot of biological homeostatic processes

– Temperature

– Energy

– Blood composition

• (Calcium, Iron, Copper , Zinc , Sugar, Fats, Osmoregulation,

Pressure, Acid-base, Volume, Hemostasis)

• Diseases often involve a disturbance of

homeostasis

Homeostatic control

• Stimulus- produces a change to a

variable (the factor being regulated).

• Receptor- detects the change. The

receptor monitors the environment and

responds to change (stimuli).

• Input- information travels to the control

center. The control center determines the

appropriate response and course of

action.

• Output- information sent from the control

center travels down to the effector.

• Response- a response from the effector

balances out the original stimulus to

maintain homeostasis.

Glucose Homeostasis

Glucose-Insulin model

Glucose-Insulin model

+

+

+

- -

Clockwise hysteresis loop

Tolerance

• Many biological systems are under homeostatic

control, they tend to return to a baseline state

when influenced by a drug.

Tolerance

Tolerance can be through different mechanisms:

– Change in receptors

– Translocation of receptors

– Exhaustion of mediators

– Increased metabolic degradation of the drug

– Physiological adaptation

– Active extrusion of drug from cells

Receptor tolerance

CHANGE IN RECEPTORS

Among receptors directly coupled to ion channels,

desensitisation is often rapid and pronounced.

Example: At the neuromuscular junction, the

desensitised state is caused by a conformational

change in the receptor, resulting in tight binding of

the agonist molecule without the opening of the

ionic channel.

TRANSLOCATION OF RECEPTORS

Prolonged exposure to agonists often results in a gradual

decrease in the number of receptors expressed on the cell

surface, as a result of internalisation of the receptors.

Exapmple: ß-adrenoceptors. In studies on cell cultures, the

number of ß-adrenoceptors can fall to about 10% of normal in 8 h

in the presence of a low concentration of isoprenaline, and

recovery takes several days

Acute tolerance to the EEG effect of

benzodiazepines

Harald Ihmsen, et al. 2003

EXHAUSTION OF MEDIATORS

In some cases, desensitisation is associated with

depletion of an essential intermediate substance.

Drugs such as amphetamine, which acts by

releasing amines from nerve terminals show

tolerance because the amine stores become

depleted.

ALTERED DRUG METABOLISM Autoinduction of Rifampin

The change in amount of enzyme in the enzyme

pool over time was expressed as follows:

Rifampin plasma concentrations drive the enzyme

pool, which in turn affects the clearance:

PHYSIOLOGICAL ADAPTATION Morphine tolerance

Heinzen and Pollack, 2004

Pharmacokinetics Tolerance mechanism