adrenergic pharmacology Flashcards
what is the molecular / chemical structure of catecholamines?
- aromatic amines
- catechol ring (phenol with 2 OHs)
- and ethylamine (CH3CH2NH2)
what catecholamines do alpha receptors favour?
noradrenaline > adrenaline > isoprenaline
what catecholamines do beta receptors favour?
isoprenaline > adrenaline > noradrenaline
state teh different catecholamines and their respectivites favourites
NA: a1, a2, b1
A: a1, a2, b1, b2
ISO: b1, b2
Dopamine: D1, D2, a1, b1
other than being receptor specific, the catecholamines can also eb controlled by concentration. where can we see this?
Adrenaline:
low doses (beta) high doses (alpha)
Dopamine:
low doses (dopamine), moderate doses (beta) high doses (alpha)
the higher the concentration, the more able to bind to receptor with lower affinity.
what is the precursor of noradrenaline, and where is it found, and where is synthesised into NA?
Tyrosine is the precursor.. Found in the body fluids, and taken up by adrenergic neurons. the synthesis is done in pre-synaptic sympathetic neurons.
tyrosine is transported with Na+ into the neuron via aromatic L-aa transporter
what are the steps of NA synthesis in the pre-synaptic sympathetic neurons
tyrosine enters, converted into L-DOPA (dihydroxyphenylalanine) by tyrosine hydroxylase (RLS), then into dopamine by DOPA decarboxylase, and enters vesicles by H+ pump VMAT (vesicular monoamine transporter). within the vesicle, the dopamine is converted into NA by dopamine-beta-decarboxylase.
ca2+ influx, and the vescile containing NA fuses with emmebrane and NA released into the pre-synaptic cleft.
what is the fate of NA after being released into the pre-synaptic cleft?
after the NA is released into the pre-synaptic cleft, there are 2 fates.
75% gets taken back up into the synapse, and this can either occur via Na+ transporter NET or by the a2 autoreceptors on the pre-synaptic membrane.
There, they can either be stored in NA vesicles by VMAT or converted to DOPGAL (dihydroxyl-phenyl-glycol-aldehyde) by MAO or into MHPG by COMT (catechol-O-methytransferases).
25% are captuered by non-neuronal cells in the vicininty to limit the spread, via EMT (extraneuronal monoamine transporter).
In the adrenal medulla, NA is converted into adrenaline (A) by PNMT (phenyethanolamine N-methyl transferase).
DOPGAL inhibits tyrosine hydroxylase.
In circulation, A and NA are degraded enzymatically, but at a much slower rate than ACh by AChE.
beta receptor desensitisation
via the phosphorylation of ser residues in the tails of the GPCRs by G-protein coupled receptor kinases (GRKs)
- **Phosphorylation allows for the binding of B-arrestin to the B-gamma subunits of the G-protein. The G-protein is uncoupled from the receptors, and cannot be reactivated. this reasults in a loss of response.
- Arrestin binding also initiates the internalisation of the receptors into an endosome, which also involves clathrin and AP2 adaptor proteins.
- In the endosome, the pH drops and in the presence of MAPK, beta arrestin and NA dissociate from the receptor.
- The receptor can be recylced, but will required PP2A and N-ethylmaleimide sensitive fusion (NSF) proteins to be present, dephosphorylating the receptor.
- If dephosphorylation does not occur, the receptor is tagged with ubiquitin and marks it for degradation
how can the drug interactions be classified as?
direct: binding directly to ther eceptor at the site same as the ligand
e.g. salbutamol (b2), clonidine (a2) and phenylephrine (a1)
indirect: affect the degradation or synthesis (uptake 1 analogues or inhibitors)
e.g. analogues: tyramine, amphetamine
inhibitors: cocaine, trycyclic antidpressants (aiming to prolong the efefct of NA)
mixed: can bidnd directly to the receptor (cos same structure) and also increase the NA release
e.g. ephedrine
what is the structure activity relationship for catecholamines?
the size of group on the N-atom in catecholamines affects it selectivity.
1. the bigger the group on the N-atom, the more selective it is for the beta receptor
e.g. salbutamol
- the addition of a methyl group makes it more selective to the alpha receptor.
- removal of the beta-OH decreases the interaction btwn the alpha and beta adrenoreceptors.
- removal of the catechol-O groups renders resistance the COMT, but still can bind to the recepotr
- removal of one or all of the OH groups of the ring abolishes the affinity for the receptor`
name an example of a alpha 1 agonist and antagonist
ag: phenylephrin
antag: prazosin
name an example of an alpha 2 agonist
ag: alpha-mehtyl=dopa and clonidine
name an example of a beta-1 agonist
dobutamine
name an example of a beta 2 agonist
salbutamol
what is dobutamine
b1 agonist
dopamine analgue
exists as 2 stereoisomers
(-) a1 agonist, weak b1 agonist
(+) a1 antagonist, strong b2 agonist
administered as racemix, b2 effects dominate
what is the PK of dobutamine
cannotbe admnistered orally or chronically
orally: will be degraded by first pass metabolism, digested and goes to the liver
chronically: desensitisation adn loss of receptor density (compensation to increased agonistic effect)
What are the effects of dobutamine and clinical therapies
increased heart rate and contractility
short term treatment of congestive heart failure and shock
what is salbutamol
beta 2 agonist
bronchodilation, smooth msucle relaxation
hence vasodilation and decreases BP
what is the beta 3 receptor agonist?
Mirabegron
what are the 3 main actions of beta blockers
- on the heart: decreases HR and contractility
- on kidney: decreases renin secretion, hence BP drops (anti-hypertensive)
- smooth muscle: relaxation, leading to vasodilation
What are the issues with rapid withdrawal of the beta antagonists:
Cells have been blockaded chronically, and this increasese their sensitivity to the agonists. This can be via the upregulation of gene expression coding for the adrenoreceptors, increased numbers of recepetors, such that there is an extreme response in the presence of natural ligand numbers. (Adaptation)
Causes rebound hypertension
Solution: gradual withdrawal, allows beta receptors to have time to readapt
what are the issues to take note of in patients who are taking beta blockers
In patients with abnormal myocardial function, the maintenance of cardiac function may be due to sympathetic drive
peripheral vascular disease (their legs cannot vasodilate)
asthmatic patients : bronchoconstriction is a NO NO
insulin-dependent diabetics: causes hypoglycaemia as it prevent glycogenolysis and may cause excercise induced hypoglycaemia and also masks the effects of a hypoglycaemic attack (HR increase and tremors)
what is propanolol and what are the effects of it
non-selective beta blocker
decreases heart rate and contractility
antiarryhthmic effects: decreases the slope of phase 4 in pacemaker cells (slower depol) and increased AV nodal delay, increasing the refractory period (longer repol)
antihypertensive effects: decreases renin release, HR decreases, CO reduced but there is no postural hypotension since a1 reflex intact
decreased renal perfusion, decreased Na excretion to counter the drop in volume
bad for asthmatics, on the B2, exacerbatin
