Module 1 - Pharmacodynamics Flashcards
2 & 3: List the 6 cellular locations of drug targets
Cell surface targets: transporters, receptors, ion channels
Intracellular targets: enzymes, nuclear receptors, protein synthesis
2 & 3: Name the FOUR main kinds of regulatory proteins commonly involved as primary drug targets.
Receptors - the sensing elements in the system of chemical communications that coordinate the function of all the different cells in the body.
Enzymes - many drugs are targeted on enzymes.
Carrier molecules (transporters) - the transport of ions and small organic molecules across cell membranes generally requires a carrier protein, because the permeating molecules are often too polar (insufficiently lipid-soluble) to penetrate lipid membranes on their own.
Ion Channels - known as LIGAND-GATED ION CHANNELS, incorporates a receptor and open only when the receptor is occupied by an agonist.
2 & 3: Where do drugs that hyrophillic (water soluble) act on?
Act at the cell surface.
2 & 3: Where do drugs that are lipid permeable (fat soluble) act on?
Cross the membrane to inhibit an enzyme or regulate gene expression.
2 & 3: Drugs need to get into 4 different places
Hydrophillic (cell surface)
Lipid permeable (cross the membrane to inhibit an enzyme or regulate gene expression).
Mimic endogenous compounds to hijack cellular systems.
Drugs that act in the CNS have to cross the Blood Brain Barrier.
2 & 3: G-Protein-Couple Receptors (GPCRs)
Are the largest and most diverse group of membrane receptors in eukaryotes.
These cell surface receptors act like an inbox for messages in the form of light energy, peptides, lipids, sugars and proteins.
Approximately 50% of drugs act of GPCRs. There are about 3000 types of GPCRs/ 10% of human gene is coding GPCR - therefore they play many roles
2 & 3: Structure of GPCRs
Their characteristic structure comprises seven transmembrane alpha-helices, often linked as dimeric structures.
The G-protein is a membrane protein comprising three subunits (alpha, beta, gamma)
- Ligand bonds to GPCR.
- GPCR undergoes conformational change.
- alpha subunit exchanges GPP for GTP.
- alpha subunit dissociates and regulates target proteins.
- Target protein relay signal via 2nd messenger.
- GTP hydrolyzed to GPP.
2 & 3: Types of Receptor (3)
Agonist, antagonist, modulators
2 & 3: Agonist
A chemical that binds to a receptor and activates the receptor to produce a biological response; CAUSES AN ACTION.
Agonists can be endogenous (from the body) or exogenous (not from the body)
E.g. Acetylcholine
2 & 3: Antagonist
A substance that acts against and BLOCKS an action.
2 & 3: Modulators (receptor)
A substance which indirectly influences (modulates) the effects of an agonist or inverse agonist at a target protein.
2 & 3: Types of Enzymes (2)
Inhibitors, false substrates
2 & 3: Inhibitors
Molecule that binds to an enzyme and decreases its activity; the normal reaction can’t take place.
2 & 3: False substrates (enzyme)
Molecule binds to an enzyme an abnormal metabolite is produced.
2 & 3: Types of Carrier molecules (transporters) (2)
Blockers, false substrates
2 & 3: Blockers (carrier molecules)
Blocks transporter from working; plugs it up
2 & 3: False substrates (carrier molecules)
Drugs undergo chemical transformation to form an abnormal product that subverts the normal metabolic pathway.
2 & 3: Types of Ion Channels (2)
Blockers, modulators
2 & 3: Blockers (ion channels)
Stop the ions flowing in or out of the cell.
2 & 3: Modulators (ion channels)
Change the way the channel is activated or inactivated (make it open more or less).
2 & 3: What was the first GPCR to be fully characterised?
The beta-adrenoceptor agonist.
2 & 3: What does Noradrenaline activate?
Activates beta and alpha adrenergic receptors
2 & 3: What does Salbutamol activate?
Selectivity for beta2 adrenergic receptors; can bind to beta-adrenergic but can’t bind to the alpha-adrenergic receptors (SELECTIVE AGONIST)
2 & 3: Explain the activation of beta-adrenergic receptors
- Agonist binds to receptor, which induces a change in receptor assoication with the alpha subunit of the G-protein
- GDP is release and is replaced with high energy GTP.
- The activated alpha subunit and the beta-gamma subunits dissociate
- Alpha, beta-gamma modulate the activity of intracellular enzymes or ion channels.
2 & 3: What are Ion Channels?
They are pore-forming membrane proteins whose functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane.
They are present in the membrane of ALL cells
A Na+ channel block will stop the influx of Na+ ions
2 & 3: Examples of enzyme and reversible inhibitor of that?
Cyclooxygenase (COX)
Aspirin is an irreversible inhibitor of cyclooxygenase; low doses of aspirin is used to irreversibly inhibit COX in platelets, which stops platelets from clotting blood; you are more likely to bleed when taking aspirin, because it stops blood clotting.
2 & 3: Comparison between Indomethacin, Paracetamol and Aspirin
Indomethacin - very potent COX inhibitor (about 10x the potency of aspiring); significant risks include cardiovascular and GI toxicity.
Aspirin - an irreversible COX inhibitor; prrolonged inhibition of COX in platelets, can be used to prevent clotting, can cause excessive GI bleeding.
Paracetamol - has similar pharmacological effects as aspiring, with less side effects BUT we don’t know how it works (people use this to commit suicide, which can take about 2 weeks to do)
2 & 3: What transporters do antidepressants block?
Serotonin, dopamine and noradrenaline transporters
2 & 3: What transporters do cocaine block?
Dopamine and Serotonin transporters
2 & 3: Tamoxifen
Estrogen receptor antagonist.
Discovered to be useful for treating Estrogen receptor positive breast cancer, as it prevents estrogen dependent stimulation of breast cancer cell growth.
Tamoxifen binds to the estrogen receptors, and then they can no longer bind to DNA so can’t assist in gene regulation.
4: Define Affinity
The tenacity with which a drug binds to its receptor (gets the drug bound to the receptor); indicates the potency of the drug.
Generally as affinity increases so too does binding specificity. We are interested in drugs with high affinity; because we want it to bind to a specific target. High affinity means it will bind at a low concentration.
It is indicated by the dissociation constant KD
4: Define Efficacy
An inherent property of an agonist that determines its ability to produce its biological effect (determines what happens once the drug is bound).
4: Define Selectivity
Selective is a drug that acts on a particular target and not another.
4: Define Specific
Specific is a drug that has a particular effect and not another.
4: List the 4 binding forces between agonist and receptor
Electrostatic (charge); H-bonding; Van der Waals, Hydrophobic
4: Law of Mass Action
The principle that the rate of a chemical reaction is proportional to the concentrations of the reacting substances.
Assumes binding is reversible
4: What is the dissociation constant?
It is the inverse of an association constant.
Indicates affinity of any molecule that binds; the lower the KD the greater the affinity of that drug.
4: When a linear horizontal scale is used you get a?
Rectangular hyperbola
4: When concentration is on a log scale you get a?
Sigmoidal curve
4: Hills-Langmiur Equation
This equation is useful for determining the degree of cooperativity of the ligand(s) binding to the enzyme or receptor
5: Define competitive antagonist
They reversibly bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor. The Agonists and antagonists ‘compete’ for the same binding site on the receptor. Effect of antagonist can be seen only when an agonist is present.
No change in reactivity/slope of concentration-effect curve.
No change in the maximum (i.e. the agonist can compete and therefore displace antagonist)
5: KB
KB is the dissociation constant for an antagonist
5: Schild Plot and competitive antagonist
The presence of a competitive antagonist will shift an agonism dose-response curve to the right.
A Schild plot for a competitive antagonist will have a slope equal to 1, and the X-intercept and Y-intercept will each equal the dissociation constant of the antagonist.
5: Define non-competitive antagonist
Describes two distinct phenomena: one in which the antagonist binds to the active site of the receptor, and one in which the antagonist binds to an allosteric site of the receptor.
Non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist.
Results in a right-ward shift in the dose-response curve.
5: What does the slope equal if the antagonism is competitive or not competitive?
If competitive antagonism, slope = 1
If non-competitive antagonism, slope doesn’t equal 1
5: Antagonist IC50 (potency)
To determine potency of an antagonist (IC50) one firstly maximally activates the receptor to an agonist and then measures concentration of antagonist to reduce the response by half.
6: What is the sympathetic system responsible for?
Fight or flight.
ACh ganglia; noradrenaline terminal; exceptions sweat glands ACH; runs quite close to the spin; has longer post ganglia fibres.
Noradrenaline acts on blood vessels
ACh (muscarine) acts on sweat glands
ACh (nicotine) acts on the adrenal medulla
6: What is the parasympathetic system responsible for?
Rest and digest.
Slowing down the heart rate; ACh ganglia; ACh; it has a short post ganglia nerve fibre.
ACh (muscarine) acts on salivary glands
Define physiological antagonism and give example
Physiological antagonism describes the behaviour of a substance that produces effects opposite to those of another substance using a mechanism that does not involve binding to the same receptor.
Example: the heart
Describe how the heart is an example of a physiological antagonism
The push - increase heart rate
Noradrenaline binds to beta1-adrenoceptors on pace maker cells and myocytes causing the Gs subunit of the receptor to activate adenylate cyclase, resulting in increased cAMP, which leads to increased calcium for contraction and increased heart rate.
The pull - decreased heart rate
ACh binds to the muscarinic-2 ACh receptors in the heart, where they act to slow the heart rate down by slowing the speed of depolarisation. They also reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). M2ACh receptors in part do this because the G-protein they activate inhibits adenyly cylcase; then enzyme that beta adrenoceptors activate.
Describe how the lung is an example of a physiological antagonism
The push - narrowing of airways (contraction of airway smooth muscle)
G alpha q activating phospholipase C (metabolises plasma membrane) to generate the second messengers inositol triposphate and diacylglycerol. The second messengers in smooth muscle lead to increase cytosolic free calcium which promotes contraction.
The pull - dilation of narrowed airways (relaxation of airway smooth muscle)
Adrenaline - beta 2 adrenoceptor; noradrenaline approximately 20x more potent than NA at these receptors.
Define receptor desensitisation
Desensitisation is the phenomenon whereby the effect of a drug gradually diminishes when it is given continuously or repeatedly
What are the main mechanisms of receptor densensitisation? (3)
- Loss of coupling - the receptor can no longer activate second messenger cascades
- Translocation of receptors - is a slower process and can take hours
- Exhaustion of receptors - for example, the repeated use of amphetamines results in the depletion of amines from the nerve terminal
Define biased agonism or functional selectivity
Is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor
Define orthosteric ligand
Orthosteric ligand refers to the primary, unmodulated binding site (on a receptor).
Binds to a site distinct from allosteric.
Define allosteric ligand
An allosteric modulator refers to a drug which indirectly influences the effects of an agonist or inverse agonist at a receptor.
Binds to a site distinct from orthosteric.
