Mechanistic Basis of Drug action: Cellular Mechanism

What is Pharmacological Intervention

is the restoration of normal cellular functioning

Name some of the Cellular Mechanisms

1. Rapidly Acting Mechanism

2. Slower mechanisms

3. Host defense response

What process includes rapidly acting mechanism

Excitation- excitable cells are those which are activated by changes

in membrane potential e.g. nerve cells and cardiac cells

• Contraction (smooth/skeletal muscle and cardiac muscle)

• Secretion (chemical mediators)

What is the role of calcium in cells

Calcium is a major regulator of cell function

Where would calcium be stored in resting cells

Endoplasmic reticulum

Sarcoplasmic Reticulum

Mitochondria

Concentration gradient favors calcium entry into the cells.Outline the three mechanisms that regulate calcium

Control of Ca2+ entry

Control of Ca2+ extrusion

Exchange of Ca2+ between the cytosol and intracellular stores

What are the four main routes by which calcium enters the cell

Voltage gated calcium channels- Ca2+ enters the cell when the membrane is depolarized

Ligand gated calcium channels

Store operated calcium channels

Na+-Ca2+ exchange

How is calcium released from cells

Release of calcium from ER and SR

The inositol trisphosphate receptor (IP3R) is activated

by inositol trisphosphate (IP3 ) and is the main

mechanism by which activation of Gaq-coupled receptors

cause an increase in [Ca2+]i

• Ryanodine receptors (RyR) located in the SR in muscle

cells and on the ER in some non-muscle cells

o critical for Ca2+ release from intracellular stores during

excitation-contraction coupling;

§ cardiac muscle

§ skeletal muscle

How do drugs exert their therapeutic effect in muscle cells

Many drugs exert their therapeutic effect by affecting the contractile machinery of muscle cells

Contraction is mediated by an increase in [Ca2+]i in all

muscle types

• In skeletal and cardiac muscle the increase in [Ca2+]i is

achieved mainly by depolarisation

• In smooth muscle this increase in [Ca2+]i is achieved by IP3-

mediated release from calcium stores

• Clinical example: beta-2 receptor agonists (e.g. salbutamol)

for the treatment of asthma; results in the relaxation of the

smooth muscle of the airways (mediated via a decrease in

[Ca2+]i)

How do drugs work in the treatment of asthma

Beta-2-receptor agonists( e.g. salbutamol) for the treatment of asthma which results in the relaxation of the smooth muscle of the airways.

What are the examples of chemical mediators and what are their roles

Neurotransmitters

Hormones

Inflammatory mediators

agents that alter intracellular calcium concentrations can therefore exert a therapeutic effect through alteration of chemical mediator release.

How is the mediator released

by exocytosis

or by diffusion