1.3 Pharmacodynamics Flashcards
Receptors are proteins that are usually membrane bound. Any exceptions?
Steroid receptors found in the nucleus.
[drug target sites- ion channels]
e.g injecting local anaesthetic close to a nociceptive neurone (pain conducting neurons) blocks voltage-sensitive sodium channels in the area, preventing action potentials along pain fibres toward CNS
What are the 2 main types of ion channels?
- Voltage-sensitive (e.g. voltage-sensitive calcium channels VSCC): open via a change in membrane potential
- receptor linked e.g. nAchR, receptor is linked to cation channels and when this channel is stimulated, it allows the flow of cations into the cell
[drug target sites- transport systems]
- Systems that transport substances against their concentration gradient (e.g. glucose, ions, neurotransmitters including dopamine, noradrenaline and glutamate)
- e.g. In depression, the noradrenaline system is not working optimally. Tricyclic antidepressants (TCAs) such as ______ which combines with and slows down ___________, allowing noradrenaline to remain in the synaptic cleft for a longer duration, enhancing the action of noradrenaline in the synapse and therefore used in treatment of clinical depression
amitriptyline; noradrenaline uptake 1 system
[drug target sites- enzymes]
Drug proteins may interact with enzymes via 3 mechanisms
- Act as enzyme inhibitors to slow down action of enzyme e.g. anticholinesterases inhibitors (neostigmine)
- Act as false substrates and creates a false transmitter e.g. _______ prevents generation of noradrenaline and is used as an antihypertensive. Methylnoradrenaline has a different effect on noradrenaline receptors and has a vasodilatory effect.
- Prodrugs that become activated e.g. _______ is activated by enzymes in the liver to trichloroethanol, which is sleep-inducing
methyldopa; chloral hydrate
[drug target sites- non spevcific]
- Drugs that do not fit into the 4 categories of protein-drug interaction but at according to their physiochemical properties
- E.g. antacids are basic in nature and relieve indigestion by combining with gastric acid to form salt and water
- E.g. __________(laxatives) draw water into the gut contents of the small intestine, expanding the contents of the gut, thereby softening faeces and promoting gut voiding
osmotic purgatives
[receptor types- ionotropic]
- location
- effector
- coupling
- speed of response
- cell membrane
- ion channel
- direct
- fast (in msecs)
[receptor types - G protein]
- location
- effector
- coupling
- speed of response
- examples
- cell membrane
- enzyme/ channel
- G protein
- slower (secs)
- mAChr, b1 adrenoceptors (located in heart tissue)
[receptor type- kinase linked]
- location
- effector
- coupling
- speed of response
- cell membrane
- enzyme
- direct/ in direct
- slower (in min)
[receptor type- nuclear]
- location
- effector
- coupling
- speed of response
- examples
- intracellular
- gene transcription
- via DNA
- slowest (in hours)
- steroid, thyroid receptors
Transmembrane ligand-gated ion channels: The extracellular portion of ligand-gated ion channels usually contains the _______. This site regulates the shape of the pore through which ions can flow across cell membranes. The channel is usually closed until the receptor is activated by an agonist, which opens the channel briefly for a few milliseconds. Depending on the ion conducted through these channels, these receptors mediate diverse functions, including neurotransmission, and cardiac or muscle contraction.
- For example, stimulation of the nicotinic receptor by acetylcholine results in __________, generating an action potential in a neuron or contraction in skeletal muscle.
- On the other hand, agonist stimulation of the γ-aminobutyric acid (GABA) receptor increases ________ and hyperpolarization of neurons. Voltage-gated ion channels may also possess ligand-binding sites that can regulate channel function.
ligand-binding sitesodium; influx and potassium outflux;
chloride influx
Transmembrane G protein–coupled receptors: The extracellular domain of this receptor contains the ligand-binding area, and the intracellular domain interacts (when activated) with a G protein or effector molecule. There are many kinds of G proteins (for example, Gs, Gi, and Gq), but they all are composed of three protein subunits. The α subunit binds _________, and the β and γ subunits anchor the G protein in the cell membrane. Binding of an agonist to the receptor increases GTP binding to the α subunit, causing dissociation of the α-GTP complex from the βγ complex. These two complexes can then interact with other cellular effectors, usually an enzyme, a protein, or an ion channel, that are responsible for further actions within the cell. Sometimes, the activated effectors produce second messengers that further activate other effectors in the cell, causing a signal cascade effect
guanosine triphosphate (GTP)
[Transmembrane G protein coupled receptor]
A common effector, activated by Gs and inhibited by Gi, is _________, which produces the second messenger cyclic adenosine monophosphate (cAMP). Gq activates _______, generating two other second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). DAG and cAMP activate different ______ within the cell, leading to a myriad of physiological effects. IP3 regulates intracellular free ______, as well as some protein kinases.
adenylyl cyclase; phospholipase C
protein kinases; calcium concentrations
Enzyme-linked receptors: This family of receptors consists of a protein that may form dimers or multisubunit complexes. When activated, these receptors undergo conformational changes resulting in increased cytosolic enzyme activity, depending on their structure and function. This response lasts on the order of minutes to hours. The most common enzyme-linked receptors (____________) possess tyrosine kinase activity as part of their structure. The activated receptor phosphorylates tyrosine residues on itself and then other specific proteins. Phosphorylation can substantially modify the structure of the target protein, thereby acting as a molecular switch.
epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others
[enzyme linked receptor- insulin]
For example, when the peptide hormone insulin binds to two of its receptor subunits, their intrinsic tyrosine kinase activity causes __________ of the receptor itself. In turn, the phosphorylated receptor phosphorylates other peptides or proteins that subsequently activate other important cellular signals. This cascade of activations results in a multiplication of the initial signal, much like that with G protein–coupled receptors.
autophosphorylation
Intracellular receptors: In order to move across the target cell membrane, the ligand must have sufficient ______. The primary targets of these ligand–receptor complexes are transcription factors in the cell nucleus. Binding of the ligand with its receptor generally activates the receptor via dissociation from a variety of binding proteins. The activated ligand–receptor complex then translocates to the nucleus, where it often dimerizes before binding to transcription factors that regulate gene expression. The activation or inactivation of these factors causes the transcription of DNA into RNA and translation of RNA into an array of proteins. The time course of activation and response of these receptors is on the order of hours to days.
lipid solubility
