Pharmacology Flashcards
What is an agonist?
A drug that binds to a receptor o produce a cellular/biological response
What is an antagonist?
A drug that blocks the actions of an agonists
What is efficacy?
The ability of an agonist to ellicit a response
What is affinity?
The strength of association between ligand and receptor
Longer the against stays on the receptor the higher the affinity
What shape is the relationship between concentration and response of a drug?
Sigmoidal
What happens to curve in presence of competitive antagonist?
SHIFTED PARALLEL TO THE RIGHT
Slope remains the same shape
Max remains the same
EC50 is increased
What happens to the curve in presence of non competitive antagonist?
POSITION OF CURVE STAYS THE SAMENESS
Slope is decreased
Max response is decreased
EC50 is unchanged
Examples of regulatory proteins that drugs bind to?
Enzymes Carrier molecules Ion channels Receptors (DNA or RNA)
What is the distribution of a drug?
The process by which it leaves the circulation and enters the tissues
What is the metabolism of a drug?
Process by which tissue enzymes (principally in the liver) catalyse the chemical conversion of a drug to a more polar form that is easily excreted from the body
How do drugs get from the stomach & intestines to the liver?
Portal circulation
What physiochemical factors affect drug absorption?
Solubility
Chemical stBilty
Lipid to water partition coefficient
Degree of ionisation
Do acidic drugs become more or less ionised in a acidic environment?
Less
What factors affect GI absorption of drugs?
GI motility pH at the absorption site Blood flow to the stomach & intestines (increased by food) Way in which capsule is manufactured Physics chemical interactions
Downsides of taking medication orally?
Inactivation of some drugs by acids/enzymes
Variable absorption
First pass metabolism
GI irritation
How do you calculate the volume of distribution of a drug?
Vd = dose(mass) / plasma concentration
What is the somatic afferent nervous system?
Nerves that supply skin, joints & muscles
Send info to CNS
What is the somatic efferent nervous system?
Includes neurons that leave spinal cord and enervate muscle (voluntary contraction)
What is the enteric nervous system?
In walls of GI tract
Involves nerves of the myenteric plexus and submucosa plexus
“Little brain of the gut”
Functions of the ANS
Contraction and relaxation of vascular and visceral smooth muscle
All exocrine and certain endocrine secretions
The heart beat
Aspects of metabolism
Training allows degree of control of some ANS functionsn(e,g, urination/deflection)
What is a ganglion?
A collection of nerve cell bodies that lies outside the CNS.nthey lie in different positions depending on whether they’re sympathetic or parasympathetic
What neurotransmitters does the sympathetic system use?
Acetylcholine = preganglionic Noradrenaline = postganglionic
Difference between pre and para vertebral ganglia?
Paravertebral = close to spinal cord Prevertebral = further away from spinal cord
Why is adrenal gland the exception in ganglions?
Pre ganglionic innervation but transmitter is Ach
What neurotransmitter does parasympathetic system use?
Acetyl choline
Where are parasympathetic ganglia found?
Mainly in the target organs
Difference between efferent and afferent signals?
Efferent = away from the CNS Afferent = towards the CNS
What cranial nerves are involved in the parasympathetic outflow?
3, 7, 9 & 10
Sympathetic actions on the heart
Increases HR
Increases force of contraction
Parasympathetic actions on the heart
Decreases HR
Sympathetic actions on the lungs
Relaxes bronchi (via release of adrenaline) Decreases mucus production (decreased airway resistance)
Parasympathetic actions on the lung
Constricts bronchi
Stimulates mucus production (increased airway resistance)
Sympathetic actions on the intestines
Reduces motility
Contradicts sphincters
Parasympathetic actions on the intestines
Increases motility
Relaxes sphincters
Mechanism of cholinergic transmission
1- Uptake of choline via transporter
2- Synthesis of ACh via choline acetyltransferase (CAT)
3 - Storage of ACh via transporter (concentrates)
4 - Depolazization by action potential
5 - Ca2+ influx through voltage-activated Ca2+ channels
6 - Ca2+- induced release of ACh (exocytosis)
7 - Activation of ACh receptors (nicotinic or muscarinic) causing cellular response
8 - Degradation of ACh to choline and acetate by acetylcholinesterase (AChE) – terminates transmission
9 - Reuptake and reuse of choline
Two types of signal in cholinergic transmission
Electrical signal from transmitted gated ion channels
Biochemical signal from G protein coupled receptor
Why activates G-protein-coupled muscarinic acetylcholine receptors in parasympathetic division
ACh
What drug block ganglionic transmission no what is its mechanism of action
Hexamethonium
Open channel block - form of non competitive antagonism
Examples of G protein coupled receptor
Muscarinic ACh receptor
Is signalling via G-proteins fast or slow when compared to transmitter gated ion channels?
Slow
Structure of G protein
Peripheral membranes protein
3 polypeptide subunits
(a, B & y - B & y always join together - “beta gamma complex”)
Guanine nucleotide binding site in alpha subunit
Can hold GTP & GDP
How to G-protein coupled receptors work when they are not signalling?
Receptor is unoccupied
Alpha subunit binds GDP
Th effector is not modulated
How do G-protein coupled receptors work to turn on the signal?
Agonist activates receptor
G protein couple with receptor causing a conformational change - reducing the affinity of the binding site for GDP
GDP dissociates from, and GTP binds to the alpha subunit
(Guanine nucleotide exchange)
G-protein loses affinity for “beta gamma complex” therefore it dissociates into different a & By subunits
G protein alpha subunits combines with and modifies activity of effector (effector is modulated)
What happens of the agonist dissociates from the receptor
Signalling still persists
How is the signal turned off in G-protein coupled receptor signalling?
Alpha subunit acts as enzyme to hydrolyse GTP to GDP and Pi.
This turns the signal off
G-protein regains its affinity for By subunit and alpha subunit recombined with the By subunit completing the G protein cycle
Which alpha sub unit couples with M1 receptors?
Gq
Example of where M1 receptors found and what do they do?
M1 receptors in stomach cause acid secretion
Which subunit do M2 couple with?
Gi (inhibitors)
Example of where M2 receptors are found and what they do?
On the SA node - thus can decrease the rate of cardiac contraction when stimulated by parasympathetic neurones
Which alpha subunit do M3 receptors couple to?
Gq
In general what do U1 and U2 do?
Reuptake of NA in adrenoceptors
What does U1 do?
NA can either be repackaged into vesicles or it can be degraded to inactive metabolites by MAO enzyme. MAO is the target of some anti-depressive drugs.
Therapeutic importance of U2
Noradrenaline broken down by COMT
What receptor does Gs couple with?
Beta-1 - sympathetic stimulation of the heart is dependent on beta-1 receptors and stimulation of adenylyl cyclase
Beta-2 - vascular smooth muscle that supplies skeletal muscle - when adrenaline is release during exercise it binds to B-2 adrenoreceptors in muscle. Increasing the perfusion of blood vessels in muscle
Summary of how Gs and B1 work?
B1 and Gs bind
Stimulate adenylyl cyclase
Increase heart rate and force
Summary of how B2 and Gs work?
B2 and Gs bind
Stimulation of adenylyl cyclase
Relaxation of bronchial and vascular smooth muscle
What does Gq bind to?
Alpha-1 - when noradrenaline is released from a post ganglionic nerve for most types of vascular smooth muscle it causes contraction
Summary of how Gq and A1 work?
Gq and A1 bind
Stimulation of phospholipase c
Contraction of vascular smooth muscle
What does Gi bind to?
Alpha-2
Summary of how GI and A2 work?
A2 and Gi bind
Inhibition of adenylyl cyclase
Inhibition of NA release
What happens in presynaptic heteroreceptors?
In organs supplied by both sympathetic and parasympathetic nervous systems they communication and mutual antagonism occurs
Sympathetic down regulates the activity of the paradympathetic
What happens in presynaptic autoreceptors?
ACh released - limits Ca influx - limits ACh release (negative feedback)
NA released - binds to a2 - less Ca in - less NA release (neg feedback)
What is the action of cocaine on the ANS?
Similar structure to NA
Binds to U1 and prevents uptake of NA
Higher conc of NA in synaptic cleft
Leads to more stimulation of post-synaptic neurone
Peripheral actions cause vasoconstriction (a1 stimulation)
causes cardiac arrhythmias (B1 stimulation)
Actions of amphetamine on the ANS
Resembles NA
Inhibits MAO enzymes
Amphetamine is imported into the vesicle
Displaces NA into the cytoplasm
Conc of NA builds up in the synapse cleft causing incredd eerie ocelots stimulation
Peripheral actions cause vasoconstriction (a1 stimulation) cardiac arrhythmias (B1 stimulation)
Actions of prazosin on the ANS?
Selective, competitive antagonist of a1 (vascular smooth muscle)
Does not block a2, B1 or B2
Vasodilator used as anti-hypertensive agent
Causes relaxation of vascular smooth muscle - vasodilator
Actions of atenolol on the ANS?
Selective, competitive antagonist if B1
Dos not block B2, a1 or a2
Used as anti angina, and anti-hypertensive agent
Actions of salbutamol on the ANS
Selective B2 agonist
Does not activate B1, a1 or a2
Bronchodilator used in asthma
Actions of atropine on the ANS
Competitive antagonist of muscarinic ACh receptors
Does not block nicotinic ACh receptors
Blocks all muscarinic ACh receptors with equal affinity (1,2,3)
Exerts widespread blockade on parasympathetic division of the ANS
Used to reverse bradycardia after an MI
What is the half life of a drug?
The time taken for the conc to fall by 50%
Inversely related to the elimination constant
What is clearance?
The theoretical volume of a fluid (e.g. plasma) from which a drug is totally removed in unit time
Which alpha sub unit couples with M1 receptors?
Gq
Example of where M1 receptors found and what do they do?
M1 receptors in stomach cause acid secretion
Which subunit do M2 couple with?
Gi (inhibitors)
Example of where M2 receptors are found and what they do?
On the SA node - thus can decrease the rate of cardiac contraction when stimulated by parasympathetic neurones
Which alpha subunit do M3 receptors couple to?
Gq
In general what do U1 and U2 do?
Reuptake of NA in adrenoceptors
What does U1 do?
NA can either be repackaged into vesicles or it can be degraded to inactive metabolites by MAO enzyme. MAO is the target of some anti-depressive drugs.
Therapeutic importance of U2
Noradrenaline broken down by COMT
What receptor does Gs couple with?
Beta-1 - sympathetic stimulation of the heart is dependent on beta-1 receptors and stimulation of adenylyl cyclase
Beta-2 - vascular smooth muscle that supplies skeletal muscle - when adrenaline is release during exercise it binds to B-2 adrenoreceptors in muscle. Increasing the perfusion of blood vessels in muscle
Summary of how Gs and B1 work?
B1 and Gs bind
Stimulate adenylyl cyclase
Increase heart rate and force
Summary of how B2 and Gs work?
B2 and Gs bind
Stimulation of adenylyl cyclase
Relaxation of bronchial and vascular smooth muscle
What does Gq bind to?
Alpha-1 - when noradrenaline is released from a post ganglionic nerve for most types of vascular smooth muscle it causes contraction
Summary of how Gq and A1 work?
Gq and A1 bind
Stimulation of phospholipase c
Contraction of vascular smooth muscle
What does Gi bind to?
Alpha-2
Summary of how GI and A2 work?
A2 and Gi bind
Inhibition of adenylyl cyclase
Inhibition of NA release
What happens in presynaptic heteroreceptors?
In organs supplied by both sympathetic and parasympathetic nervous systems they communication and mutual antagonism occurs
Sympathetic down regulates the activity of the paradympathetic
What happens in presynaptic autoreceptors?
ACh released - limits Ca influx - limits ACh release (negative feedback)
NA released - binds to a2 - less Ca in - less NA release (neg feedback)
What is the action of cocaine on the ANS?
Similar structure to NA
Binds to U1 and prevents uptake of NA
Higher conc of NA in synaptic cleft
Leads to more stimulation of post-synaptic neurone
Peripheral actions cause vasoconstriction (a1 stimulation)
causes cardiac arrhythmias (B1 stimulation)
Actions of amphetamine on the ANS
Resembles NA
Inhibits MAO enzymes
Amphetamine is imported into the vesicle
Displaces NA into the cytoplasm
Conc of NA builds up in the synapse cleft causing incredd eerie ocelots stimulation
Peripheral actions cause vasoconstriction (a1 stimulation) cardiac arrhythmias (B1 stimulation)
Actions of prazosin on the ANS?
Selective, competitive antagonist of a1 (vascular smooth muscle)
Does not block a2, B1 or B2
Vasodilator used as anti-hypertensive agent
Causes relaxation of vascular smooth muscle - vasodilator
Actions of atenolol on the ANS?
Selective, competitive antagonist if B1
Dos not block B2, a1 or a2
Used as anti angina, and anti-hypertensive agent
Actions of salbutamol on the ANS
Selective B2 agonist
Does not activate B1, a1 or a2
Bronchodilator used in asthma
Actions of atropine on the ANS
Competitive antagonist of muscarinic ACh receptors
Does not block nicotinic ACh receptors
Blocks all muscarinic ACh receptors with equal affinity (1,2,3)
Exerts widespread blockade on parasympathetic division of the ANS
Used to reverse bradycardia after an MI
What is the half life of a drug?
The time taken for the conc to fall by 50%
Inversely related to the elimination constant
What is clearance?
The theoretical volume of a fluid (e.g. plasma) from which a drug is totally removed in unit time
