Pharmacology Lecture 2 - Terms & Definitions

What is a receptor?

A drug receptor is a protein (95%) on the surface of cells or a macromolecule (5%, e.g., enzyme, DNA molecule etc.) within cells​

Any macromolecular tissue site where a drug may bind can be considereda binding site and if this site has some functional activity then it isa receptor​

They mediate the conversion of the signaling information into a cellular response or action

(In many cases, the receptor is named after a drug that has a strong binding power (i.e., high affinity) for the receptors and therefore activates the receptor (e.g., glutamate and GABA receptor etc.).​)

High affinity

binding and effects last a long time

Low affinity

binding quickly detaches and won’t have long effects

Cell membrane

This has a phospholipid bilayer, with the hydrophilic heads of the each of the phospholipid layers facing outwards and the lipophilic ends facing inwards

Embedded proteins throughout the span of this bilayer act as ion channels, receptors, G-proteins(secondary messengers), or enzymes

Some barriers to the distribution of drugs (CSF barrier, blood-brain barrier aka plasma membrane of inner ear, etc.) - ligands don’t easily pass through (ear is well protected from toxic chemicals)

True or False: Receptor is embedded in lipid bilayer (of cell membrane) to pass chemicals through​

True

True or False: Phospholipid bilayer is impermeable

True

In the case of a post synaptic response, two basic response types are generally identified:

1. Ionotropic

2. Metabotropic

Ionotropic receptors

(direct, quickly open once bonded) control individual membrane ionic channels such as Na, K, and Cl channels. The effects are local, immediate, and primarily on the membrane potential​

Metabotropic receptors

(indirect, second messenger molecules activate) gate ion channels indirectly and may have other wide ranging effects on the cell mediated by cellular signaling cascades

4 Receptor subtypes

1. Ligand-gated ion channels (ionotropic)

2. G protein-coupled receptors (metabotropic)

3. Kinase-linked receptors

4. Nuclear receptors

Ligand-gated ion channels

Sometimes called ionotropic receptors​

​They are involved mainly in fast synaptic transmission in milliseconds

Act quickly (ms) once binded (hyperpolarization/depolarization)​

( Examples include the nicotinic acetylcholine (nACh), GABA type A, glutamate (NMDA) and ATP (P2X) receptors)​

G protein-coupled receptor

Sometimes called metabotropic or seven-transmembrane domain (7-TDM) receptors

The G protein is a membrane protein comprising three subunits (α, β, γ), each subunit possessing different activity.

When receptor binding, the α subunit binds GTP, dissociates and is then free to activate an effector (e.g., membrane enzyme). Activation of the effector is terminated when the bound GTP molecule is hydrolyzed, which allows the α subunit recombined with βγ.

There are several types of G protein, which interact with different receptors and control different effectors (e.g., enzyme, ion channels).

Binds to receptor then receptor activates second receptor which then activates target – takes seconds not ms!​

​(Example include muscarinic acetylcholine (mACh), adrenoceptors, neuropeptide, ATP (P2Y), chemokine receptors)​​

Kinase-linked receptors

Large and heterogenous membrane receptors with a large extracellular ligand-binding domain connected via a single trans-membrane helix to the intracellular domain that typically contains a protein tyrosine kinase (i.e., enzyme)​

​Receptors incorporate tyrosine kinase in their intracellular domain.​

​‘Kinase cascade’ mechanism includes protein phosphorylation, gene transcription, protein synthesis and cellular effects (e.g., cell growth, inflammation).

Connected to inside cell –once binded, activate ____ which activates further steps (cellular effects) ​​

​(Example include insulin, a few hormone receptors, growth factors and cytokine receptors)

Nuclear receptors

Nuclear receptor ligands are many and varied including steroid drugs, thyroid hormone, Vitamin A and D, and various lipids.

Class I NRs: Present in the cytoplasm inside of cells, forming homodimers and migrate to the nucleus (e.g., steroid hormones)​

Class II NRs: Present in the nucleus, forming heterodimers (e.g., lipids, fatty acids)

Receptor binding initiates changes in gene transcription (interacting with DNA) and ‘Kinase cascade’ mechanism includes protein phosphorylation, gene transcription, protein synthesis and cellular effects (e.g., cell growth, inflammation).

Lipid-soluble (easily passes through bilayer/membrane) takes hours

Ligand-activated bc soluble, to nucleus then target ​​

​(Example include estrogen, steroid, thyroid hormones, Vitamin A & D)​​​

Two methods of transportation of drugs

1. passive diffusion

2. active transportation

chart slide12 review -write out and quiz self using slide 10

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Simple passive diffusion

-Water soluble or small lipid drugs can move across the plasma membrane through aqueous channels/pores or the membrane bilayers.(more concentrated to less concentrated area until equilibrium)​

-Simple diffusion is governed by Fick’s law of diffusion​

-Aqueous diffusion occurs through aqueous pores that are found in most cell membranes, water-soluble drugs can pass along the concentration gradient, but protein-bound drugs cannot permeate through pores.​

-Lipid diffusion occurs directly across the cell membrane and lipid-soluble drugs pass along the concentration gradient.​

Tonicity

how an extracellular solution can change the volume of a cell by affecting osmosis

Osmosis

spontaneous net movement or diffusion of solvent molecules through a membrane

Isotonic

Equal solute and water, no net movement of water (e.g., 0.9% NaCl)​

“same strength”

Hypertonic

Greater osmotic potential in comparison to normal saline

“more strength”

more solutes and less solvent (more concentrated)​

Hypotonic

Lower osmotic potential in comparison to normal saline

“less strength”

Fewer solutes and more solvent (less concentrated)​

Through what process does steroids get into the inner ear neuroepithelium?

simple passive diffusion

Normal saline (0.9%NaCl)

Physiologically equivalent to the body’s fluids

It is close to the natural levels found in human blood and extracellular fluids; its salt concentration is similar to that of the body’s cells and fluids (KEEP THEM STABLE = Isotonic).

​-It is widely used in medical settings for hydration, as a vehicle for medications.​

1% solution is 1 gram of solute in ___mL of solvent

100

Milliequivalents (mEq)

These units are obtained by multiplying the molar concentration of the substance by its charge or valence. Hence, normal saline(0.9% NaCl) is 155 mmoles/liter. In solution these are 155 mEq of Na+ and 155 mEq ofCl-. The units allow one to “keep track” of the electrical charge of complex solution. For most solutions, electrical neutrality holds (i.e., there are an equal mEq of charge for both positive and negative ion species). ​

Mole

A fundamental unit used to measure/express the amount of a substance. One mole of any substance contains exactly 6.022 X 1023 particles (=Avogadro’s number); a specific quantity of a substance, representing participles (atoms, molecules, and, ions, etc.)​

Molarity (M)

A measure of the concentration of a solute in a solution. It is defined as the number of moles of solute dissolved in one liter of solution.

M = moles of solute/liters of solution (=solvent)​

​a concentration of a substance by relating the number of moles to the volume of the solution​

Molality (m)

number of molesof solute per kilogram of solvent(mol/kg).​

-m = moles of solute/mass of solution (=solvent) in kilograms​

-Molality is useful when solution volume may change with temperature because it is based on mass rather than volume (e.g., boiling point elevation, freezing point depression).​

a concentration in terms of mol/kg

Osmolarity

concentration ofosmotically active particles in asolution (Osm/L).​

-Expressed in units of osmoles perliter (osmol/L) = molarity (M) x number of particles per formula unit in solution​

-1 M of glucose ≈ 1 Osm/L; 1 MNaCl ≈ 2 Osm/L; 1 M CaCl2 ≈ 3Osm/L, contributing to the osmotic pressure.

a concentration of osmotically active particles in a solution in terms of osmoles/L​

Osmolality

concentration of osmotically active particles per kilogram of solvent (Osm/kg). ​

-The unit of measurement is the osmole (in milli) and it measures the number of particles in a kilogram of solvent (mOsmol/kg). ​

-Osmolality is more accurate as it does not change with temperature.

osmolarity is about volume (L) vs. osmolality is about weight (kg)​

Meaning of molarity, unit

Moles of solute / liter of solution, M, mM = mmol/L

Meaning of Molality, unit

Moles of solute / kg of solvent, mol/kg, mmol/kg

Meaning of Osmolarity, units

Osmoles of particles / liter of solution, Osm/L, mOsm/L

Meaning of Osmolality, units

Osmoles of particles / kg of solvent, Osm/kg, mOsm/kg

when using kg not affected by temp? T or F

true?

Active Transport

Some drugs use a carrier protein by using energy (e.g., ATP) and can be transported against a concentration gradient.

The drug molecule cross the membrane from a region of lower concentration to a region of higher concentration, against the concentration gradient. ​​

Review last diagram on slide 23!

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