PHARM; Lecture 1, 2 and 3 - Intro to ANS, Mechanism of Drug action (I & II) Flashcards
What are the principal target organs of the sympathetic NS?
Eye, Salivary glands, trachea/bronchioles, skin, heart, GI, Liver, adipose, kidney, ureters and bladder, blood vessels
What are the principal target organs of the Parasympathetic NS?
Eye, Salivary glands, trachea/bronchioles, heart, GI, ureters and bladder
FITB for the action of ANS on target organs
x
What transmitters are released from pre and post ganglionic fibres in sympathetic NS?
x
What transmitters are released from pre and post ganglionic fibres in parasympathetic NS?
x
What is the difference between the PSNS and SNS in terms of response?
SNS is very coordinated with a lot of divergence due to short pre-ganglionic fibres VS PSNS is discrete, localised and with little divergence
What is the difference in the innervation of the somatic NS compared to the ANS?
Somatic has a motor neurone which releases ACh then leads onto the effector skeletal muscle
What are the membrane bound receptors for ACh?
Muscarinic and Nicotinic
What kind of receptor are the nicotinic ones?
Ionotropic, and is stimulated by nicotine/acetylcholine
Where are nicotinic receptor situated?
All autonomic ganglia
What are muscarinic receptors and where are they situated?
G-protein coupled and located at all effector organs innervated by post-ganglionic PSNS fibres
What are muscarinic receptors stimulated by?
Muscarine and ACh
Which of the following effects would be observed after blockade of nicotinic acetylcholine receptors in an individual at rest? 1) Bronchoconstriction 2) Increased sweat production 3) Constipation 4) Increased urinary frequency 5) Short-sightedness
Constipation
What are the types of muscarinic receptors?
M1, M2, M3, M4, M5
What is the function of M1 receptor?
Neural - forebrain; learning and memory
What is the function of M2 receptor?
Cardiac - brain; inhibitory autoreceptors
What is the function of M3 receptor?
Exocrine and smooth muscle - Hypothalamus; food intake
What is the function of M4, M5?
M4: periphery; prejunctional nerve endings (inhibitory). M5: Striatal DA release
What are the different types of muscarinic?
x
What are the types of adrenoceptors?
Alpha 1, 2 and beta 1, 2
Where are adrenoceptors located?
All effector organs innervated by postganglionic sympathetic fibres
What are adrenoceptors and what stimulates them?
G-protein coupled and stimulated by NA/Adrenaline
Blockade of which of the following receptor sub-types would induce both an increased heart rate and a reduction in sweat production during exercise? 1) Muscarinic receptors 2) α1 adrenoceptors 3) α2 adrenoceptors 4) β1 adrenoceptors 5) β2 adrenoceptors
Muscarinic receptor
How is ACh synthesised, released and metabolised?
1) Binding of Acetyl CoA + Choline to form ACh. 2) ACh is placed in vesicles. 3) Ca2+ moves in via VSCC, so vesicle moves to membrane 4) ACh is exocytosed into the synaptic space. 5&6) ACh moves in synapse and attaches with receptor. 7) Acetylcholine esterase breaks down ACh into choline and acetate. 8) Choline is taken up and is used back up.
How is NA synthesised, released and metabolised?
x
Blockade of which of the following targets would cause the most significant rise in synaptic noradrenaline concentrations? 1) Tyrosine hydroxylase 2) DOPA decarboxylase 3) Uptake 1 transport protein 4) Monoamine oxidase 5) Cathecol-O-methyl transferase
Uptake 1 transport protein
What is pharmacokinetics?
What the body does to the drugs
What is pharmacodynamics?
What the drugs do to the body
What is a drug?
A chemical substance that interacts with a biological system to produce a physiological effect
What are the 4 drug target sites?
Receptors, ion channels, transport systems, enzymes - NB: ALL ARE PROTEINS
What are the receptors for drug target sites and what are they activated by?
Proteins within cell membranes, 4 types -> activated by NT/hormones
What is an agonist?
A molecule that stimulates the receptor causing the original action
What is an antagonist?
A molecule that blocks the receptor
How do ion channels allow drugs to target?
Has selective pores and allows transfer of ions down electrochemical gradients
How many types of ion channels and what are they?
2 -> Voltage sensitive (VSCC) and receptor-linked (nAChR)
What are some examples of receptor drugs?
ACh (agonist), atropine (antagonist)
What are some examples of ion channels drugs?
Local anaesthetics, Ca channel blockers
What are the transport system drug targets?
Transport against conc grad; with specificity for certain species
What are some examples for transport system receptors?
Na/K ATPase and Na uptake 1
What are some drug examples for transport systems?
Tricyclic anti-depressants, cardiac glycosides
What are enzymes that are acted upon by drugs and how do they interact with drugs?
Catalytic proteins interacting by: enzyme inhibitors, false substrates (form false substrates), prodrugs
What is an example of an enzyme inhibitor drug?
Anticholinesterases
What is an example of a false substrate drug?
Methyldopa -> Produces fake NA which causes a decreased interaction
What is an example of a prodrug drug?
Chloralhydrate -> triichloroethanol
What is an example of an unwanted effect from paracetamol?
It saturates metabolising enzymes, so is metabolised via other pathways producing toxic metabolites
What kind of drugs aren’t part of the 4 drug target sites?
Non-specific drugs
How do non-specific drugs work?
Changing their physiochemical properties, e.g. by changing their active site
Give an example of a non-specific drug?
Antacids (neutralise acids not targeting the active site of the cells) and osmotic purgatives
What are the different drug-receptor interactions?
Agonist, antagonist, potency, full and partial agonist, selectivity and structure-activity relationship
What is an example of an agonist?
ACh, nicotine
What is an example antagonist?
Atropine, hexamethonium
What does the potency of a drug depend on?
Efficacy and affinity
What is the efficacy of the drug?
Ability to produce a change in the receptor -> the intrinsic activity/ conformational change of receptor
What is the affinity of a drug?
How the drug seeks to bind to the receptor
What is a full agonist?
The drug causes the maximum response
What is a partial agonist?
The drug can’t cause the maximum response due to less than max efficacy -> antagonist activity
How can the activity/selectivity of a drug change?
By changing the structure of the drug
What are the different types of structure-activity relationship?
Lock and key; agonist-> antagonist; pharmacokinetics
How does an agonist interact with the receptor?
x
What does the dose-response curve look like for a full agonist vs a partial agonist (log vs non-log)?
x
What is the affinity/efficacy of antagonists?
They have affinity but no efficacy
What are the 2 types of receptor antagonists?
Competitive and irreversible
What are competitive antagonists?
Act on the same site as the agonist; is surmountable by increasing the concentration of the agonist; shifts the D-R curve to the right
Give some examples of competitive antagonists.
Atropine, propanolol
What are irreversible antagonists?
Bind tightly to same site OR to different site than agonist; it is insurmountable -> forms tight covalent bonds or e.g. in ion channels
Give an example of an irreversible antagonist
Hexamethonium
How does the log D-R curve shift with competitive and irreversible agonists?
x
C
D
What are the different types of drug antagonism?
Receptor blockade, physiological antagonism, chemical antagonism, pharmacokinetic antagonism
What is receptor blockade antagonism?
Either competitive or irreversible -> has a use-dependency
What is a use-dependency and give an example of such drugs?
Of ion channel blockers -> i.e. the more active the cell the faster the drug will block the ion channels. Eg: local anaesthetics
What is physiological antagonism?
Each drug acts on a different receptor causing opposite effects on the same tissue
Give an example of physiological antagonism
Noradrenaline causes vasoconstriction, increasing TPR and BP BUT Histamine increases dilatation which decreases TPR and BP -> Antagonise but act on different receptors
What is chemical antagonism?
The rarest form of antagonism, occurs during interaction in solution
Give an example of chemical antagonism
Dimercaprol -> attaches to heavy metals and forms complexes which can be toxic; acts as a chelating agent
What is pharmacokinetic antagonism?
Works as an antagonist, decresing the concentration of active drug at site of action
Give an example of a pharmacokinetic antagonist
Barbiturates affect other drugs by decreasing their absorption, increasing their metabolism and excretion (NB: clinically important reaction)
What is drug tolerance?
A gradual decrease in responsiveness to drug with repeated administration
What is the main drug that is tolerated quickly?
Benzodiazepines
What are some reasons for increased drug tolerance?
Pharmacokinetic factors, loss of receptors, change in receptors, exhaustion of mediator stores, physiological adaptation
How do pharmacokinetic factors affect drug tolerance and give an example?
Can increase rate of metabolism of drugs -> barbiturates, alcohol
How does loss of receptors affect drug tolerance and give an example?
Receptors are lost from cell surface via endocytosis -> down-regulated due to over stimulation. E.g. beta-adrenoceptors
How does a change in receptors affect drug tolerance and give an example?
Receptors become desensitised due to a conformational change -> drug will still have affinity to receptor but the efficacy has lowered. E.g. nAChR at NMJ
How does the exhaustion of mediator stores affect drug tolerance and give an example?
For example, when amphetamine is used, it causes enhanced release of NA and after a few doses of Amph, the NA stores become depleted and the response is no longer the same
How does physiological adaptation affect drug tolerance?
Homeostatic responses in the body change -> the tolerance is to the drug side effects
How many types of receptor families are there and what is each family?
1) Ion channel-linked. 2) G-protein coupled. 3) Kinase-linked. 4) Intracellular steroid type
What are the characteristics of ion channel-linked receptors and give an example?
Fast responses (milliseconds) -> nAChR, GABAa
What are the characteristics of G-protein coupled receptors and give an example?
Slower responses (seconds) -> beta1 adrenoceptors in heart
What are the characteristics of kinase-linked type and give an example?
Quite slower respones (mins) -> insulin/growth factors
What are the characteristics of intracellular steroid type receptors and give an example?
Very slow (hrs) as they regulate DNA transcription -> steroids, thyroid hormones
Summarise the location, effector, coupling and examples of the 4 main types of receptors
x
Where are the binding domains for each of the 4 types of receptors?
x
C
x
E
