adrenergic pharmacology

Question 1

what is the molecular / chemical structure of catecholamines?

Answer 1

• aromatic amines
• catechol ring (phenol with 2 OHs)
• and ethylamine (CH3CH2NH2)

Question 2

what catecholamines do alpha receptors favour?

Answer 2

noradrenaline > adrenaline > isoprenaline

Question 3

what catecholamines do beta receptors favour?

Answer 3

isoprenaline > adrenaline > noradrenaline

Question 4

state teh different catecholamines and their respectivites favourites

Answer 4

NA: a1, a2, b1
A: a1, a2, b1, b2
ISO: b1, b2
Dopamine: D1, D2, a1, b1

Question 5

other than being receptor specific, the catecholamines can also eb controlled by concentration. where can we see this?

Answer 5

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.

Question 6

what is the precursor of noradrenaline, and where is it found, and where is synthesised into NA?

Answer 6

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

Question 7

what are the steps of NA synthesis in the pre-synaptic sympathetic neurons

Answer 7

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.

Question 8

what is the fate of NA after being released into the pre-synaptic cleft?

Answer 8

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.

Question 9

beta receptor desensitisation

Answer 9

via the phosphorylation of ser residues in the tails of the GPCRs by G-protein coupled receptor kinases (GRKs)

1. **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.
2. Arrestin binding also initiates the internalisation of the receptors into an endosome, which also involves clathrin and AP2 adaptor proteins.
3. In the endosome, the pH drops and in the presence of MAPK, beta arrestin and NA dissociate from the receptor.
4. The receptor can be recylced, but will required PP2A and N-ethylmaleimide sensitive fusion (NSF) proteins to be present, dephosphorylating the receptor.
5. If dephosphorylation does not occur, the receptor is tagged with ubiquitin and marks it for degradation

Question 10

how can the drug interactions be classified as?

Answer 10

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

Question 11

what is the structure activity relationship for catecholamines?

Answer 11

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

2. the addition of a methyl group makes it more selective to the alpha receptor.
3. removal of the beta-OH decreases the interaction btwn the alpha and beta adrenoreceptors.
4. removal of the catechol-O groups renders resistance the COMT, but still can bind to the recepotr
5. removal of one or all of the OH groups of the ring abolishes the affinity for the receptor`

Question 12

name an example of a alpha 1 agonist and antagonist

Answer 12

ag: phenylephrin
antag: prazosin

Question 13

name an example of an alpha 2 agonist

Answer 13

ag: alpha-mehtyl=dopa and clonidine

Question 14

name an example of a beta-1 agonist

Answer 14

dobutamine

Question 15

name an example of a beta 2 agonist

Answer 15

salbutamol

Question 16

what is dobutamine

Answer 16

b1 agonist
dopamine analgue
exists as 2 stereoisomers
(-) a1 agonist, weak b1 agonist
(+) a1 antagonist, strong b2 agonist

administered as racemix, b2 effects dominate

Question 17

what is the PK of dobutamine

Answer 17

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)

Question 18

What are the effects of dobutamine and clinical therapies

Answer 18

increased heart rate and contractility

short term treatment of congestive heart failure and shock

Question 19

what is salbutamol

Answer 19

beta 2 agonist

bronchodilation, smooth msucle relaxation
hence vasodilation and decreases BP

Question 20

what is the beta 3 receptor agonist?

Answer 20

Mirabegron

Question 21

what are the 3 main actions of beta blockers

Answer 21

1. on the heart: decreases HR and contractility
2. on kidney: decreases renin secretion, hence BP drops (anti-hypertensive)
3. smooth muscle: relaxation, leading to vasodilation

Question 22

What are the issues with rapid withdrawal of the beta antagonists:

Answer 22

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

Question 23

what are the issues to take note of in patients who are taking beta blockers

Answer 23

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)

Question 24

what is propanolol and what are the effects of it

Answer 24

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

Question 25

what is atenolol and what is its effects

Answer 25

cardio selective, B1 antag

no adverse B2 inhibitory effects
no hypoglycaemi effects

angina, hypertension, arrhythmia
does not cross the BBB, so less sedative effecst

Question 26

what is labetelol and what is it effects

Answer 26

Mixed 𝜶 / 𝞫 antagonist (reversible, non-selective)

𝜶1 antagonist: vasodilation, BP drops
𝞫1 antagonist: decreases HR and renin release, BP drops
𝞫2 partial agonist: makes it “safe” for asthmatic (causes bronchodilation) and diabetic patients (no hypoglycaemic effect)

𝞫1 blockade → no sympathetic reflex tachycardia

Therapeutic uses: hypertension, angina, arrhythmia

Question 27

what are the beta blockers (3) and type them

Answer 27

propanolol: non selective beta
atenolol: cardio B1 selective
labetolol: mixed a/b antagonist, reversible , non-selective

Question 28

what are the type of dopamine receptors and what are their actions

Answer 28

D1: Gs, increased cAMP
on smooth muscle
dilation of renal blood vessels

D2: Gi, decreased cAMP
on presynaptic
autoinhibitory , decreased dopamine release

Question 29

therapeutic uses of dopamine

Answer 29

1. cardiogenic
2. hypovolemic shock
   congestic heart failure (short term only)

Question 30

Effects of dopmaine

Answer 30

postiive inotropic effect (beta 1), increasing cardiac contractility

renal vasodilation, increasing urinaary output and relief of oedemia

Question 31

side effects of dopamine

Answer 31

vasoconstriction with risk of hypertension
arrythmia
increased HR, irregular ,sinus tachy

Question 32

what are the 4 targets of indirect drugs

Answer 32

1. syntehsis
2. storage
3. metabolism
4. uptake

Question 33

what are some of the indriect drugs affecting synthesis

Answer 33

1lpha-methyl-dopa
carbidopa

Question 34

how does alpha methyl dopa work to prevent synthesis?

Answer 34

• not deaminated by MAO
• diplaces NA from the vesicles
• released in the same way as NA
• binds to alpha 2 (autoinhibitory)
• inhibiting further release
• used for treating gestational diabetes but no longer administered due to its safety profile

Question 35

how does carbidopa work?

Answer 35

inhibits dopa decarboxylase. preventing the conversion of L-DOPA inot dopamine in the peripheral tissue.

unmetabolised L-DOPA is able to cross the BBB and gets metabolised by the dopa decarboxylase in the brain. Carbidopa cannot pass into the brain. this increases dopamine levels in tthe brain.

Clinical use: parkinson’s, administere with L-dopa

decreases the adverse effects of systemic dopamine accumulation

Question 36

what are the different types of uptakes

Answer 36

uptake 1: via NET, on presynaptic neurons, removes the neurotranmitter from the synaptic cleft

uptake 2: via EMT, on postsynaptic neurons on peripheral cells to prevenet lateral diffusion.

Question 37

what are the other methods of termination of NT action?

Answer 37

1. MAO
   switches off catecholamines by breaking them down in the cell. there are 2 types A for serotonin, tyramine and NA, B for tyramine and dopamine.

MAOi prolongs the effects by inhibiting its breakdown. e..g tricylic depressants

2. COMT
   catalyses transmitter breakdown and is widespread throughout the body, with particularly high levels in the liver.
3. Diffusion
   away from the synapse

Question 38

what is one drug that affects storage

Answer 38

Resperine

Question 39

what does respirine do?

Answer 39

irreversibly inhibits the VMAT, preventing uptake and storage of catecholamines, and vesicles are depleted.

Effect: reduce AP-mediated vesicle exocytosis o f NA, the vesicles still fuse but less NA released into the synaptic celft.

Indirecyl leading to arteriolar vasodilation and reduced cardiac output

Question 40

drugs that affect reuptake

Answer 40

tricyclic antidepressants and cocaine

Question 41

what do the triclycic antidepressants and cocaine do? (same?)

Answer 41

inhibits NET (uptake 1)

prolong shte physiological effect of NA, accumulation of NA in synaptic cleft

peripheral sympathomimetics effects due to enhanced effects of transmitters, leading to tachycardia and increased BP

Cocaine
CNS effects: able to penetrate the BBB, inhibits dopamine uptake, causing euphoria and excitement

Question 42

drugs affecting metabolism

Answer 42

MAO i - selegiline

highest MAO in the GIT, liver, brain

potentiates the effect of NA,