1. Dr Andrew Ferguson

2. 56 year old male with
cardiogenic shock after
AMI
66 year old male with
aortic dissection
78 year old male with
septic shock
42 year old female with
hypotension after
amlodipine OD
82 year old nil orally with
postoperative
hypertension
45 year old female after
subarachnoid
haemorrhage

3. 
How do you classify adrenergic receptors?

Describe the location and function of each

Tell me about agonists acting at the….receptor

4. Receptor
Location
Comment
a1
Vascular smooth muscle
Gq-coupled vasoconstriction
a2
Nervous system
Gi-coupled AC inhibition
b1
Platelets and heart
Gs-coupled platelet aggregation and positive
inotropy
b2
Bronchi, vascular smooth
muscle, uterus
Gs-coupled AC stimulation and cAMPmediated hyperpolarisation
b3
Adipose, heart
Gs-coupled – lipolysis
? mechanism of negative inotropy
D(A)1
CNS, peripheral (renal)
Gs-coupled AC stimulation vasodilation and
extrapyramidal effects
D(A)2
CNS, peripheral
Gi-coupled AC inhibition of pituitary hormone
and NA release

5. Gq:11
phospholipase C ->
inositol triphosphate IP3 ->
Increased Ca2+
DAG -> activates Protein
Kinase C
Gs
Adenylate cyclase ->
cAMP ->
protein kinase A ->
e.g. increased Ca2+ b1
Gi
Inhibits adenylate cyclase

6. 
GPCR
 Seven region transmembrane receptor
 Transmits stimulus across membrane
 Amplifies stimulus
▪ Single GPCR to multiple G-proteins
▪ G-protein to multiple second messengers
 Controlled by phosphorylation and binding of b-arrestin
 Agonist binding may induce phosphorylation -> tachyphylaxis

G-proteins
 3 subunits (a, b, g)
 a-GDP-bg -> a-GTP -> activates AC, PLC, or ion channel
 Gs activates AC, Gi inhibits AC, Gq activates PLC

8. Drug
Alpha-1
Alpha-2
Beta-1
Beta-2
DA-1
Adrenaline
++
++
+++
+++
0
Noradrenaline
+++
+++
++
+
0
Dobutamine
0
0
+++
+
0
Dopexamine
0
0
+
+++
++
Dopamine
+
0
++
++
++
Phenylephrine
++
0
0
0
0
Clonidine
0
+++
0
0
0
Salbutamol
0
0
+
+++
0
Effects of adrenaline are dose dependent with more b effect at lower doses

9. What are they?
 How do they work?

 Cardiac excitation-contraction coupling
 Receptor systems (adrenergic etc)
 Second messenger systems
 Ion channels
Typical agents
 Atypical agents


11. 
Classify inotropic agents

Describe how they increase contractility

Draw the catechol ring structure

12. Beta 1
agonists
Na+/K+ ATPase
antagonists
PDE
inhibitors
Calcium
sensitisers
2+
Ca

14. Figure 1. Simplified schematic of postulated intracellular actions of β-adrenergic agonists. βReceptor stimulation, through a stimulatory Gs-GTP unit, activates the adenyl cyclase
system, which results in increased concentrations of cAMP.
Overgaard C B , Džavík V Circulation 2008;118:1047-1056
Copyright © American Heart Association

15. Figure 2. Schematic representation of postulated mechanisms of intracellular action of α1adrenergic agonists. α1-Receptor stimulation activates a different regulatory G protein (Gq),
which acts through the phospholipase C system and the production of 1,2-d...
Overgaard C B , Džavík V Circulation 2008;118:1047-1056
Copyright © American Heart Association

16. Na-K-ATPase inhibition
 Increased calcium availability

 AC/cAMP via b-agonists, glucagon, PDEIII inhibition
 SERCA2 activation (sarcoplasmic reticulum)
 Ryanodine receptor stabilisation
Calcium sensitization
 Activation of cardiac myosin
 Metabolic substrate modification


21. Synthetic catecholamine
 Basically b1-agonist (minor b2) BUT






(-) and (+) stereo-isomers
(-) isomer is b-agonist and a1 agonist
(+) isomer is b-agonist and a1 antagonist
So no net effect on a receptors at low doses
At higher doses some a1 agonism limiting
degree of vasodilation

22. Active substance from Ma Huang plant
 Direct action on b-receptors
 Indirect action (Predominant)

 Taken up into presynaptic adrenergic terminals
 Displaces noradrenaline from vesicle binding sites
 Releases NA from adrenergic nerve terminals
 Stimulates a and b receptors


Tachyphylaxis early due to NA depletion
AVOID with MAOIs

23. 




Direct action on a-receptors
Indirect a- and b-agonist action through NA
and adrenaline release
Isomer (again)!
l-isomer is responsible for presynaptic effects
AVOID with MAOIs

24. 
a1 PARTIAL agonist (but an impressive one!)

Usually described as agonist

Minor b-agonism at VERY high doses

25. 




Hepatic and renal metabolism
Renal excretion (t 1/2 10-20 mins)
V1 receptor (G protein) -> vasoconstriction
V2 receptor (AC) -> increased water
permeability in collecting ducts
Minimal impact on PVR
 good in pulmonary hypertension

27. Figure 3. A, Endogenous catecholamine synthesis pathway.
Rate limiting
Granulated vesicles
Adrenal medulla
Overgaard C B , Džavík V Circulation 2008;118:1047-1056
Copyright © American Heart Association

28. 
Neural control
 Sympathetic and parasympathetic NS

Circulating humoral factors e.g.
 Adrenaline
 Vasopressin

Local regulatory factors e.g.
 Arachidonic acid metabolites
 Serotonin, Adenosine, Histamine
 NO and HNO, Endothelins
 pH etc etc

29. 
Calcium-based
 Calcium entry (L-type calcium channels)
 Calcium storage in, and release from, the SR

Vasoconstrictors
 G-protein -> PLC -> IP3 and DAG -> Ca2+


Ryanodine receptor activation by [Ca]I
Vasodilators acting via cGMP
 cGMP phosphorylates phospholamban
 Increases SERCA activity and Ca2+ uptake to SR

32. Journal of Internal Medicine
Volume 264, Issue 3, pages 224-236, 8 AUG 2008 DOI: 10.1111/j.1365-2796.2008.01981.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2008.01981.x/full#f3

33. 












Alpha-adrenoceptor antagonists (alpha-blockers)
Angiotensin converting enzyme (ACE) inhibitors
Angiotensin receptor blockers (ARBs)
Beta2-adrenoceptor agonists (β2-agonists)
Calcium-channel blockers (CCBs)
Centrally acting sympatholytics
Direct acting vasodilators
Endothelin receptor antagonists
Ganglion blockers
Nitrodilators
Phosphodiesterase inhibitors
Potassium-channel openers
Renin inhibitors

36. 






Precursor
Converted to methylnoradrenaline
Stimulates central presynaptic a2 receptors
Inhibits dopa decarboxylase
Depletes/replaces NA in storage vesicles
Not broken down by MAO
Positive Coombs test in 10-20%

37. 




K+ channel opener -> hyperpolarisation
? Increases NO production
Arteriolar dilation, minimal venous
Slow onset even after iv use (up to 20 mins)
Acetylated
 rapid (30%) v slow (50%) acetylators


Aplastic anaemia and lupus-like syndrome
Vasodilatory effect reduced by NSAIDs

38. 


Direct (spontaneous) NO donor
Dilates arterioles and veins
Interacts with Hb to produce
 cyanometHb
 cyanide ions





CN- + thiosulphate = thiocyanate (by liver rhodanese)
Cyanide toxicity is treated with sodium nitrite and
thiosulphate, and hydroxycobalamin (Vit B12a)
Thiocyanate only toxic at extreme doses usually with
renal impairment
Increases cerebral blood VOLUME & ICP, not FLOW
May induce coronary steal

39. Metabolism yields nitric oxide via nitrite
Main effect on venous capacitance vessels
Also large coronary artery dilator
No coronary steal
Pulmonary = systemic vasodilation which is
beneficial in pulmonary hypertension
 Rapid development of tolerance




