Drugs and the Peripheral nervous system L11 Flashcards
where is noradrenaline released
released by postganglionic fibres and the sympathetic nervous system
how is noradrenaline synthesised
enzyme tyrosine hydroxylase converts tyrosine into DOPA
enzyme DOPA carboxylase converts DOPA to dopamine
enzyme dopamine B-hydroxylase converts dopamine to noradrenaline
how is NA stored
in vesicles
how is NA released
exocytosis
what types of receptors does NA interact with
Alpha or Beta Noradrenergic receptors
how is NA action terminated
it is reuptook by transporter and either
1. recycled into vesicles
2. broken down by monoamine oxidase into amines
describe alpha 1,2 noradrenergic receptors
- where are they found
- what type of receptors are they
- what kind of response do they have
- located on effector tissue of sympathetic nervous system
- G protein or metabotropic
- slow response
describe beta 1,2 and 3 noradrenergic receptors
- where are they found
- what type of receptors are they
- what kind of response do they have
- located on effector tissue of sympathetic nervous system
- G protein or metabotropic
- slow response
what parts of sympathetic nervous system will A1 receptors effect
- Pupils dilate(radial muscle contracts)
- Blood vessels to visceral organs & skin constrict
- Brain activity general alertness
what parts of sympathetic nervous system will A2 receptors effect
A2 receptors found on presynaptic neurone not effector tissue
- acts as a negative feedback system
- when NA (ACh or other neurotransmitters) binds to them, they inhibit release of further NA dampening down effect of sympathetic NS
what are A2 auto-receptors and heteroreceptors
- autoreceptors
- only sensitive to the neurotransmitters or hormones released by the neuron on which the autoreceptor sits - heteroreceptor
- receptor regulating the synthesis and/or the release of mediators other than its own ligand
what part of the sympathetic nervous system do B1 receptors effect
- Heart rate increases (and force of contraction)
what part of the sympathetic nervous system do B2 receptors effect
- Airways in lungs dilate (bronchodilation)
- Lens of eye adjust for far vision (ciliary muscle relax)
- Blood vessels to limb muscles dilate
what part of the sympathetic nervous system do B3 receptors effect
- Increase lipolysis (breakdown of triglycerides to fatty acids)
give 5 examples of noradrenergic agonists
- adrenaline
- clonidine
- dobutamine
- salbutamol
- Clenbuterol
describe agonist effects of adrenaline
acts on all the noradrenergic receptors
destroyed in gut so has to be injection
- when given locally, it can prolong and isolate local anaesthesia
- mediates vasoconstriction when bound to A1
- when given intramusically, can treat anaphylactic shock
- mediates cardiac stimulation when bound to B1
- mediated bronchiol smooth muscle relaxation when bound to B2
describe agonist effects of Clonidine
acts on A2 receptors
- it decrease NA release dampen down overall sympathetic system so is used to treat hypertension
- involve a central effect (nucleus tractus solitarius) which results in decrease sympathetic outflow.
- Also used to treat withdrawal symptoms in morphine withdrawal (inhibits central NA release which drives withdrawal symptoms)
describe agonist effects of dobutamine
acts on B1 receptor
- increased cardiac rate and force so used to treat heart failure
describe agonist effects of salbutamol
acts on B2 receptors
Used to treat asthma.
beta 2 – mediated bronchiol smooth muscle relaxation:
describe agonist effects of Clenbuterol
acts on B2 and 3 receptors
B2: bronchodilation- treat asthma
B3: lipolysis/increased metabolism- Increases muscle bulk in athletes/body builders/livestock
give examples of Noradrenergic antagonists
- prazosin
- Tamsulson
- Propranolol
- Atenolol
- Timolol
describe antagonist effects of prazosin
acts on A1 receptors
- A1 – antagonism: vasodilation and decreased vascular resistance treat hypertension
- Side effects: orthostatic or postural hypotension due to some loss in sympathetic reflex
describe antagonist effects of Tamsulson
acts on A1
- A1 – antagonism: relaxation of smooth muscle in bladder neck, ease of urinary flow treats urination problems in prostate hyperplasia
- Side effects: orthostatic or postural hypotension due to some loss in sympathetic reflex
describe antagonist effects of propanol
acts on B1 and 2
B1: Used to treat hypertension and angina
Blocking B1 receptors decreases cardiac output and also decreases oxygen demand.
B2: blocking B2 receptors causes bronchoconstriction. Therefore contra-indicative in asthmatics .
describe antagonist effects of Atenolol
acts on B1
- Used to treat hypertension and angina
Blocking B1 decreases cardiac output and also decreases oxygen demand.
- Side effect: can cause rebound hypertension/ angina on abrupt withdrawal probably due to B1 receptor supersensitivity
describe antagonist effects of Timolol
acts on B2 receptors
- Used to treat glaucoma, antagonism of B2– receptors cause ciliary contraction, and decreased intraocular pressure
where are Potential sites of drug action on NA neurotransmission
Synthesis
Storage
Release
Receptors
Uptake
Metabolism
how can synthesis of NA be targeted
- give a false substrate such as methlyDOPA
- DOPA carboxylase converts this to MeDA which is converted to MeNA
- this outcompetes normally NA synthesis. as it uses the same enzymes, less enzyme available to
how can synthesis of NA be targeted
what is it used to treat
- give a false substrate such as methlyDOPA
- DOPA carboxylase converts this to MeDA which is converted to MeNA
- this outcompetes normally NA synthesis. as it uses the same enzymes, less enzyme available to synthesise NA so less is made so sympathetic system is inhibited
- Used in the treatment of hypertension
how can storage be targeted
what is it used to treat
Reserpine disrupts storage of NA in synaptic vesicles
- Overall decrease in NA neurotransmission
Used to treat hypertension
how can release be targeted
what is it used to treat
NA release is subject to autoinhibitory control via presynaptic A2 -autoreceptor
clonidine (A2-agonist) causes inhibition of NA release
Overall decrease in NA neurotransmission
Used to treat hypertension
how can uptake be targeted
what is it used to treat
NA uptake can be blocked by NA reuptake inhibitors
This will prolong the action of NA in the synapse
- desipramine tricyclic antidepressants
- reboxetine selective noradrenaline reuptake inhibitors
- treat depression
how can metabolism be targeted
what is it used to treat
After reuptake NA is metabolised by the enzymes monoamine oxidase (MAO), and catecholamine transferase (COMT)
- By blocking these enzymes the amount of NA available for release is increased.
- tranylcypramine blocks MAO and allows more NA to be recycled so increases NA neurotransmission.
what else does monoamine oxidase (MAO), and catecholamine transferase (COMT) block
block the metabolism of dietary amines (e.g. commonly found in cheese, marmite) and amines found in popular cold remedies.
- Accumulation of dietary amines can have a sympathomimetic effect and result in hypertension
