Pharmacology - Targets For Drug Action Flashcards
What’s : Pharmacology ? Toxicology ? Therapeutics ? (3)
Pharmacology : study of the way in which the function of living things is altered by chemical agents !
Toxicology : The study of toxic or harmful effects of chemicals , their mechanisms and conditions of occurrence
Therapeutics :The branch of medicine concerned with the use of drugs to treat a disease of its symptoms
Where do drugs come from ?
5
1) individual chemicals purified from cells and tissues (PLANTS)
2) ANIMALS
3) chemical synthesis
4) large scale production of recombinant human proteins ie : human insulin
5) antibodies to human proteins : Cytokines mediators
What are the molecular targets for drug Action?
3
1) Proteins :
- ions channels
- membrane proteins
- enzymes
- non-cellular proteins
- receptors
2) nucleic acids
3) miscellaneous targets ( metal ions and GI contents)
What’s an agonist drug ?
1
Chemical which binds to a receptor and causes a biological response !!
It mimics the natural chemical mediator
What’s an antagonist drug?
2
Inhibits the physiological effect of chemical mediator or agonist !
What’s a blocker drug?
What’s an allosteric modulator ?
What’s an inhibitor modulator ?
facilitator modulator ?
Can u give examples ?
(6)
1) blocker= beta blocker ie : Lidocaine which is a local anaesthetic, it blocks V-G Na+ channels so depolarisation doesn’t occur= no AP =No contraction !
2) Allosteric modulator = binds to allosteric site and these can be inhibiting like Amplodipine ( targets V-G ca2+ channels = less contraction in muscle = so vessel dilates , very useful in treating High BP and preventing Angina and hypertension.
3)Facilator modulators = binds to allosteric sight and increases function ie : Diazepam which causes GABA receptors CL- gate to be opened wider and for a longer time = HYPERPOLARIZATION so the cell Is less excitable ; this DECREASES neuronal activity in brain and relieves Anxiety / acts as a sedative !
Diazepam acts as a facilitator OF GABA which is a inhibitory neurotransmitter .
What is an inhibitor drug? (2)
-cl channel example
what’s a false substrate? (3)
Binds to channel and causes loss of function ie:
FUROSEMIDE =binds to the chloride transport channel, thus causing sodium, chloride, and potassium loss in urine. ( loop diuretic)
so REABSORBTION DECREASES= OFFLOADS FLUID!
False substrate : accumulation of unnatural compounds which compete with the natural substrate ie: AMPHETAMINE (ecstasy) which has a similar shape to noradrenaline, serotonin and dopamine. this can be a short term performance enhancer providing wakefulness, foes and euphoria.
what is a pro drug ? (2)
what is a an example of a non cellular target site?(2)
what is an example of a nucleic acid drug ?(2)
1- They require conversion by an enzyme in liver to become activated
ie : ACE inhibitor = perindoperil –> Perindoprilat ( which is activated form and can act on ACE inhibitor )
2- non cellular target site ie: antibodies and cytokines ie :
Heparin which act on glycoproteins in blood
3-CISPLATIN- cross links DNA , STOPS TRANSCRIPTION, replication and is used as an anticancer drug
How are receptors divided into categories ?
broad overview of pharmacological and molecular biology approach …
(4 )
There is a pharmacological approach which classifies the adrenoceptors, demonstrating that their are ALL different: they all have different potency , and different agonists and antagonists too !
-Receptors can also be classified according to the molecular biology approach which illustrates that they can be divided into 4 SUPER FAMILIES :
1) Ligand gated channels ie : acetylcholine
2) G-protein coupled receptors ie: muscarinic Ach receptor
3) Kinase linked receptor ie: RTK
4) Nuclear receptors which cause gene transcription
using the adrenoceptor family illustrate the general principles of receptor classification
give an example of a selective agonist
give an example of a selective antagonist
(6) case study of adrenoceptors
New research ? ( 2)
Adrenoceptor family –> Alpha and Beta adrenoceptors
1) Alpha Adrenoceptors : split into Alpha 1 and alpha 2
2)Beta is split into 3 : b1/b2/b3
they both have Selective agonists and selective antagonists
All receptors are DIFFERENT which enables selective drug use and they are ENCODED BY DIFFERENT GENES , HENCE they differ slightly in the binding sites ie :
3)Salbutamol (selective agonist )can identify the sub groups of the beta receptor - B2 . It has a higher potency in the airways where the B2 receptor is , compared to in the heart where there is B1 receptors .( causes bronchodialation)
4)selective antagonist : ATENOLOL(competitively reversible antagonist of the B1 adrenoceptor)
it causes a greater decline of adrenaline function in the HEART, ( B1 receptor ) compared to the airways (b2 receptors )
new research shows many more sub groups in the adrenceptor family meaning we can develop much more specific drugs ie: TAMSULOSIN which is a novel selective antagonist of the Alpha 1A adrenoceptor = it’s an alpha blocker which allows relaxation of smooth muscle ( remember noradrenaline constricts smooth muscle )- this improves urine flow !
what does each receptor need to be linked to ?
3
1-SIGNAL TRANSDUCTION PATHWAY :
- Ion influx
- enzyme activity
- gene expression
Outline the SUPERFAMILY 1 CASE STUDY - nicotinic acetylcholine receptor
(6)
competitive reversible antagonist examples
Competitive irreversible antagonist examples
=>AGONIST called Nicotine
=>ligand gated ion channels
1) competitive REVERSIBLE ANTAGONIST: Tubocuraine, vecuronium = neuromuscular blocking agents, they bind to orthosteric site competing with acetylcholine/nicotine. They prevent skeletal muscle contraction during surgery! It is used to treat muscle spasm
2) Competitive IRREVERSIBLE ANTAGONIST: Alpha Bungarotoxin from (Bungaras multicinctus= Indian snake )
It binds to the orthosteric site irreversibly causing muscle paralysis, respiratory failure, death!
what are the subtypes of the nicotinic cholinoreceptors
(3)
overview
-17 lego blocks are available! each is encoded by different gene .
-Each receptor is made of 5 subunits = PENTAMETERS=HETERO OR HOMOPENTAMETERS
The subunit composition determines the the physiological and pharmacological properties of the the receptor : affinity to agonist etc .
outline the GABA a receptor case study SUPERFAMILY 1 and the chloride channel ?
(3)
- GABA is an inhibitory neurotransmitter found in CNS
-Facilitator modulator - diazepam (valium) , which enhances GABA. activity by making CL- gate open more readily and for longer , increasing the period of hyperpolarization ( decreasing the neuronal activity )
this is why diazepam is used as a sedative !
Outline the G-protein mediated receptor (GPMR) case study (SUPERFAMILY 2 ):
MUSCARINIC ACETYLCHOLINE RECEPTOR FAMILY (Parasympathetic Ns)
-what is the agonist? what does it do?
-what is the antagonist?
-How does the competitive antagonist work?
(4)
Remember that the G-protein isn’t part of the RECEPTOR, it’s just attached!
GPCR - Heterotrimeric (remember it contains alpha, beta, gamma subunits)
-high affinity for acetylcholine :
agonist =muscarine
-slows down heart rate, bronchoconstriction, peristalsis ( parasympathetic rest and digest)
ANTAGONISTS A: Atropine (atropa belladona)
Atropine is a competitive reversible inhibitor that blocks the muscarine/acetylcholine binding site! - hence suppressing the actions of the parasympathetic system!
- atropine treats bradycardia , speeding up HR
what are the factors that affect size and response to a receptor antagonist ?
3 main factors
(6)
1-Concentration of drug ( which depends on dose, administration , distribute, metabolisms and excretion )
2-Characteristics of the agonist receptor ie : affinity and intrinsic efficacy (ability to activate a response within the cell )
3-Characteristics of tissue : nature of receptor-response to the SINGAL TRANSDUCTION MECHANISM and total number of receptors present !
what’s fractional occupancy ? (3)
what effects It ?
1- fraction of receptors occupied by agonist and it depends on :
-agonist concentration =Xa
-strength of bonding (Affinity ) =Ka
FO equation : agonist concentration / (agonist concentration+ka equ constant )
A high Ka would mean a lower fractional occupancy ! (because the denominator would be larger )
how do we tend to measure ka? (1)
measure the circuit marker and downstream response ie : contraction of muscle !
Whats EC50?
3
Effective concentration to produce 50% of maximum response possible on stimulation of that receptor !
A higher EC50 means a lower Potency , because It means you would require a larger concentration of the drug to produce the same effect !
look at graph in notes ! log concentration response curve
what are the receptor -response coupling mechanisms?
(4)
-4 subtypes
1-chemical gating and ion channels
2-activation of G-proteins
3-Direct activation of enzymes
4-Regulation of gene transcription
what is the equation that links all the points which affect the response of receptor agonist ? (3)
R= N of receptors x transducer function x intrinsic efficacy x agonist concentration / (agonist concentration +ka)
Give an example of a reversible ANTAGONIST DRUG ?
outline the major properties !
( properties on graph
intrinsic efficacy , max response , type of bonding )
(5)
Competative reversible inhibitor =ATENOLOL B-blocker (which stops the effects of noradrenaline causing vasodilation and slows down the heart ) = good for managing angina and managing hypertension !
1-Intrinsic efficacy is ZERO ( doesn’t cause a response in cell - it just blocks noradrenaline and adrenaline )
2- reversible means it has weak bonds such as : ionic bonds , H-bonds , VDWs
3-causes a RHS shift on the log response curve and can be overcome by increasing agonist concentration !
4-MAX response is still achievable !
Give an example of Competitive Irreversible Antagonists
graph shift?
max response?
(3)
- bonded with covalent bonds and are usually toxins or poisons
-ie: CLOPIDOGREL or alpha-bungarotoxin ( less used clinically, used to inhibit thrombus formation )
1- graph doesn’t shift
The 2-Max response can’t be reached, so it is lowered!
Give an example of a NON competitive Antagonist
(2)
2 examples
They can be reversible or irreversible
example 1: Binds to allosteric site causing conformation change in orthosteric site , hence agonist and chemical mediator can’t fit into the orthosteric site ie:Palonsetron . prevents vomitting!)
example 2: Interference downstream in signal transduction pathway ie :local Anaesthetic - Lidocaine which blocks the V-G na+ channels to prevent Depolarisation , AP hence muscle contraction !
