positive inotropes, vasopressors, and vasodilators
TRANSCRIPT
Dr Andrew Ferguson
56 year old male with cardiogenic shock after
AMI
42 year old female with hypotension after
amlodipine OD
82 year old nil orally with postoperative hypertension
66 year old male with aortic dissection
78 year old male with septic shock
45 year old female after subarachnoid haemorrhage
How do you classify adrenergic receptors?
Describe the location and function of each
Tell me about agonists acting at the….receptor
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 cAMP-mediated 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
Gq:11phospholipase C ->
inositol triphosphate IP3 ->Increased Ca2+
DAG -> activates Protein Kinase C
GiInhibits adenylate cyclase
GsAdenylate cyclase ->
cAMP -> protein kinase A ->
e.g. increased Ca2+ b1
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
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
What are they?
How do they work?
Cardiac excitation-contraction coupling
Receptor systems (adrenergic etc)
Second messenger systems
Ion channels
Typical agents
Atypical agents
Classify inotropic agents
Describe how they increase contractility
Draw the catechol ring structure
Beta 1 agonists
Na+/K+ -ATPase
antagonists
PDE inhibitors
Calcium sensitisers
Ca2+
Figure 1. Simplified schematic of postulated intracellular actions of β-adrenergic agonists. β-
Receptor 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
Figure 2. Schematic representation of postulated mechanisms of intracellular action of α1-
adrenergic 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
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
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
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
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
a1 PARTIAL agonist (but an impressive one!)
Usually described as agonist
Minor b-agonism at VERY high doses
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
Figure 3. A, Endogenous catecholamine synthesis pathway.
Overgaard C B , Džavík V Circulation 2008;118:1047-1056
Copyright © American Heart Association
Rate limiting
Granulated vesicles
Adrenal medulla
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
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
Journal of Internal MedicineVolume 264, Issue 3, pages 224-236, 8 AUG 2008 DOI: 10.1111/j.1365-2796.2008.01981.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2008.01981.x/full#f3
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
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%
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
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
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