positive inotropes, vasopressors, and vasodilators

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