VL 5: Pharmacodynamics

• Most drugs exert their effects by interacting with receptors present on the cell surface or in the cell

• The drug–receptor complex initiates molecular and biochemical alterations in the effector cells by a process called signal transduction

• Cells have different types of receptors, each of which is specific for a particular ligand (naturally occurring molecule or a structurally similar drug molecule)

Examples of cellular receptors:

Histamine, Opioid, Serotonin (5-HT), Dopamine, Adrenergic, Muscarinic,

Nicotinic, Steroid, etc…

- Receptors exist in at least two states, inactive and active states that are in reversible equilibrium with one another.

- Ligand binding initiates a series of reactions that ultimately result in a specific intracellular response.

• Many drugs act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels

• The natural ligands of such receptors are primarily synaptic transmitters (e.g., acetylcholine (Ach), GABA, and glutamate)

• These receptors transmit the signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane

Example:

Ach causes the opening of the ion channel in the nicotinic

acetylcholine receptor (nAChR), which allows Na+ to flow down its

concentration gradient into cells, producing a localized excitatory

potential (depolarization). The time elapsed between the binding of

ACh and the cellular response can often be measured in milliseconds

• Voltage-gated ion channels do not bind neurotransmitters directly but are controlled by membrane potential

• These channels are also important drug targets

Example:

Verapamil and diltiazem inhibit voltage-gated calcium channels that are present in the heart and in vascular smooth muscle, producing antiarrhythmic effects and reducing blood pressure without mimicking or antagonizing any known endogenous transmitter

• Most abundant type of receptors, and their activation or blocking account for the actions of most commonly used therapeutic agents.

• Comprise a single α helical peptide that has seven membrane-spanning regions.

• The extracellular domain of this receptor usually contains the ligand-binding area.

• The intracellular side of these receptors is linked to a G protein (Gs, Gi,Gq, etc..).

• G protein consists of three subunits, an α subunit that binds to GTP and a βγ subunit.

• Binding of the ligand to the extracellular region of the receptor activates the G protein so that GTP replaces GDP on the α subunit.

• Dissociation of the G protein occurs, and both the α-GTP subunit and the βγ subunit subsequently interact with other cellular effectors, usually an enzyme, a protein, or an ion channel.

• These effectors then activate second messengers that are responsible for translating the ligand binding into a cellular response.

Examples of second messengers:

Cyclic adenosine monophosphate (cAMP): Involved in regulation of protein phosphorylation. Inositol-1,4,5-trisphosphate (IP3): Involved in the regulation of the activity of several intracellular proteins by controlling free Ca2+ level in the cells. Diacelyglycerol (DAG): activates several enzymes such as protein kinase C (PKC)

• Stimulation of these receptors results in responses that last several seconds to minutes.

• Important processes mediated by G protein–coupled receptors include neurotransmission, olfaction, and vision.

• Polypeptides consisting of an extracellular ligand-binding domain and a cytoplasmic enzyme domain, which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase.

• The two domains are connected by a hydrophobic segment that crosses the lipid bilayer of the plasma membrane.

• Mediates the first steps in signaling by insulin and several growth factors including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β).

• The receptor tyrosine kinase signaling pathway begins with binding of ligand to the extracellular domain. The resulting change in receptor conformation causes two receptor molecules to bind to one another (dimerize), which in turn brings together the tyrosine kinase domains, which become enzymatically active.

• The activated receptor autophosphorylates and then phosphorylates tyrosine residues on different target signaling proteins. (Duration of response: minutes/hours)

• A single type of activated receptor induces a cascade of events resulting in multiplication of the initial signal.

• Receptor is entirely intracellular (ligand must diffuse into the cell to interact with the receptor).

• Primary targets of these ligand-receptor complexes are transcription factors (activation or inactivation of these factors regulates the processes of DNA transcription and translation into proteins).

• Other targets of intracellular ligands include structural proteins, enzymes, RNA, and ribosomes.

Example:

Steroid hormones bind with their intracellular inactive receptor leading to dissociation of bound proteins to the receptor and receptor activation.

The activated ligand–receptor complex translocates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression.

• Cellular responses are observed after a lag period (30 mins to several hours) until new proteins are synthesized. Duration of the response persist for hours or days due to the slow turnover of the newly synthesized enzymes and proteins.

1. Signal amplification:

   • Ability of receptors to amplify signal intensity and

     duration.

   • Common feature of receptors that respond to

     hormones, neurotransmitters, and peptides (G protein-

     or enzyme-linked receptors)

   • A single ligand-receptor complex can interact with

     multiple G proteins, thereby multiplying the original

     signal

   • The activated G proteins persist for a longer duration

     than the original ligand-receptor complex

   • Further amplification of the initial signal is mediated by

     the interaction between G proteins and their respective

     intracellular targets

Spare receptors

• In biological systems exhibiting signal amplification only a fraction of the total available receptors are needed to be occupied by a specific ligand to elicit a maximal response.

  The remaining unoccupied receptors are called spare receptors.

Examples:

• Insulin receptors have approx. 99% spare receptors, ensuring efficient glucose uptake.

• Heart : Only 5-10% of β-adrenoceptors in the heart are spare, reflecting limited functional reserve, especially in heart failure.

1. Receptor Desensitization and Down-Regulation:

• Repeated or continuous stimulation of a receptor may lead to changes in its responsiveness due to molecular changes in the receptors

• Drug Tolerance (or Tachyphylaxis): Occurs when repeated

  administration of a drug results in a diminished effect

• Drug tolerance may be due to

a) Receptor desensitization:

Receptors remain on the cell surface but become

unresponsive to ligands.

b) Receptor down-regulation:

Persistent receptor stimulation causes receptors to undergo

endocytosis.

These receptors may be recycled to the cell surface, restoring

sensitivity, or processed and degraded, decreasing the total

number of receptors available on the cell surface.