PHAR 300 Lecture Notes - Lecture 17: Therapeutic Index, Nmda Receptor, Passive Transport
7 Jun 2018
School
Department
Course
Professor
PHAR300
Pharmacodynamics
Drug action
-we look at the organ system, tissue, cell and then
subcellular target (sometimes, it is not quite as clear as we
would like it to be, especially in the brain for example,
where things are very complex)
-affects the normal function of individual cells
Example: antihypertensive drugs
-usually more than one way to solve the problem
-hypertension (high blood pressure) is extremely
dangerous, increases risk of heart attack and strokes very
seriously
-keeping a normal blood tension is essential, and we have a
variety of different mechanisms that are doing it
-as we understood more and more how blood pressure was
regulated (through the brain, the heart, the kidney…),
many different types of drugs treating hypertension were
developed, and also because people are different => these
different drugs act with different mechanisms
Selectivity
-selective effect (most desired effect because we want only
the target tissue to be affected and minimise side effects)
(e.g. iodide just targets the thyroid, very selective in its
effect because only the thyroid absorbs it)
-generalised effect (e.g. adrenaline: will raise the blood pressure, spread towards the entire body
and will affect many organs; epinerphine: treats allergies)
Few no -specific mechanisms for drugs (e.g. antacids don’t have a specific target, they just
neutralise acid in the stomach)
Sites of drug action:
-surface of the cell membrane or inside the cell (nucleus for example)
Drug receptor: macromolecular protein target to which endogenous ligand or exogenous agonist/
antagonist bind to give a cellular response
-we usually have endogenous ligands or molecules that bind to it and we can use exogenous
agonists or antagonists to bind to it and exert the desired effect (activate or plug it)
-receptor is in our body and we are targeting it with a drug to either activate it or block it
-linked to cellular response elements (ion channels, enzymes, second messengers…)
-can be identified by using a drug with a radioactive ligand bound to it, then isolate and sequence
the receptor and see exactly where the drug binds
-agonist drugs: will activate the receptor at the normal site where the natural ligand would
activate it -> molecular configuration allows them to bind to that particular location
1
-antagonist drugs: designed in such a way that they will be able to bind to the receptor and block
it, natural ligand can’t bind and activate the receptor
-allosteric sites: can activate or decrease the function of a receptor
-when something activates the receptor => intracellular signalling mechanisms where some drugs
can act on
Receptors
-many kinds on the cell membrane/ inside the cell
-receptor activated enzymes
-receptor activated ion channel
(neurotransmitters bind to these types of
receptors)
-tyrosine kinases (enzymes activated in
specific ways and involve phosphorylation)
-G protein coupled receptors (most common
receptors found in the body, lots of different
ones but share common basic structures)
-intracellular receptors (the drug first has to
cross the membrane and get into the cell)
-act in cell to cell communication
(neurottransmitters, hormones, cytokines…) -
autocrine, endocrine, paracrine, juxtacrine
-all these receptors can be targets for drugs
->1000
•Ion channels (e.g. nicotinic receptor)
-major targets for various types of drugs
-e.g. communication between neurons
-transmembrane-spanning proteins that open
to allow passage of specific ions
-3 stages: closed, opened, inactivated
-2 major types: voltage gated (closes and opens
when activated, e.g. on the axons of the
neurons, NMDA receptor where glutamate is
the normal agonist) or receptor operated
(ligand gated, at the synapsis e.g. nicotinic ACh
receptor, 5 subunits, 2 molecules of ACh needed to bind to the channel to open it up and allow
sodium to flow through it, different kinds of nicotinic receptors)
-affinity of drugs for ion channels varies depending on the stage of the ion channel
-some drugs can stimulate / block ion channels
-we were able to design different structures of drugs to bind only to certain types of nicotinic
receptors for example, to be more selective
-we can also modulate ion channels to increase or decrease their opening probability
•Carrier molecules
-change configuration and move things in and outside the cells
-passive transport (diffusion or facilitaed diffusion) and active transport (using ATP, require
energy) where drugs can act
2
Document Summary
We look at the organ system, tissue, cell and then subcellular target (sometimes, it is not quite as clear as we would like it to be, especially in the brain for example, where things are very complex) Affects the normal function of individual cells. Usually more than one way to solve the problem. Hypertension (high blood pressure) is extremely dangerous, increases risk of heart attack and strokes very seriously. Keeping a normal blood tension is essential, and we have a variety of different mechanisms that are doing it. Selective effect (most desired effect because we want only the target tissue to be affected and minimise side effects) (e. g. iodide just targets the thyroid, very selective in its effect because only the thyroid absorbs it) Generalised effect (e. g. adrenaline: will raise the blood pressure, spread towards the entire body and will affect many organs; epinerphine: treats allergies)
