Positive inotropes, vasopressors, and vasodilators

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Positive inotropes, vasopressors, and vasodilators

  1. 1. Dr Andrew Ferguson
  2. 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. 3.  How do you classify adrenergic receptors?  Describe the location and function of each  Tell me about agonists acting at the….receptor
  4. 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. 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. 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
  7. 7. 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
  8. 8. What are they?  How do they work?   Cardiac excitation-contraction coupling  Receptor systems (adrenergic etc)  Second messenger systems  Ion channels Typical agents  Atypical agents 
  9. 9.  Classify inotropic agents  Describe how they increase contractility  Draw the catechol ring structure
  10. 10. Beta 1 agonists Na+/K+ ATPase antagonists PDE inhibitors Calcium sensitisers 2+ Ca
  11. 11. 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
  12. 12. 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
  13. 13. 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 
  14. 14. 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
  15. 15. 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
  16. 16.      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
  17. 17.  a1 PARTIAL agonist (but an impressive one!)  Usually described as agonist  Minor b-agonism at VERY high doses
  18. 18.      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
  19. 19. 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
  20. 20.  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
  21. 21.  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
  22. 22. 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
  23. 23.              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
  24. 24.        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%
  25. 25.      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
  26. 26.    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
  27. 27. 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     

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