Test 5: CV Drugs pt. 1 Flashcards
What are Sympathomimetics?
-Any drug that acts on α, β, or Dopa receptors
-Positive inotropy, chronotropy, dromotropy
-Changes in vascular tone
-Effects of sympathetic stimulation (postganglionic) are mediated by norepi
-Epinephrine release from adrenal gland into the blood - target tissues
-Direct vs Indirect Agents
What is the difference between direct and indirect sympathomimetics?
Direct: Drug activates receptor on postsynaptic membrane.
-Administering Epi or NE
Indirect: Either displace catecholamines or Decrease the clearance of NE. Can inhibit reuptake or prevent metabolism. Can enhance release of NE
-MAOIs and COMT inhibitors
Mixed: Has some direct actions and some indirect.
-Ex: Ephedrine
What are the different G-Proteins involved with Adrenergic receptor stimulation?
Gs: Inc cAMP, Beta 2, Epinephrine
Gi: Dec cAMP, Alpha 2, Norepi/Epi
Gq: Inc IP3, Alpha 1, Norepi/Epi, Vasopressin, and Prostaglandins
What are the effects of Beta 1 Agonism in the heart?
Activates Adenylyl Cyclase to increase cAMP.
-Increase contractility
(positive inotropy)
-Increase relaxation rate
(positive lusitropy)
-Increase heart rate
(positive chronotropy)
-Increase conduction velocity
(positive dromotropy)
-Also increases Renin release by the Juxtaglomerular cells
What are the effects of Beta 2 Agonism?
Works on Smooth muscle, blood vessels, and liver.
-Bronchodilation
-Hepatic glycogenolysis
-Pancreatic release of glucagon
-Renin release by kidneys
What are the effects of Alpha 1 Agonism?
Located on the postsynaptic side.
-Involves IP3 pathway
-Constricts blood vessels
-Contracts smooth muscle (ureter, uterus, mydriasis)
-Glucose metabolism (gluconeogenesis)
What are the effects of Alpha 2 Agonism?
Located on the presynaptic side.
-Inhibits Adenylyl Cyclase, decreasing cAMP
-Inhibits release of NE
What are the basic uses for CV Drugs?
-Positive inotropy - ↑ CO
-Elevate MAP and SVR
-Treatment of bronchospasm
-Management of extreme allergic reaction/anaphylaxis
-Add to local anesthetic to slow absorption
-Tocolytics
In general, describe the basic concepts behind the use of CV Drugs.
1) They act on multiple receptors
2) Dose-dependent activation of receptor subtypes (Ex: Dopamine)
3) Direct & Reflex actions (Ex: Phenylephrine increases MAP (direct) but decreases HR (Reflex) ).
4) Drugs are not a substitute for volume (but can buy time during fluid resuscitation)
5) Choice of drug should be based on underlying etiology of HOTN
6) If 1st agent is ineffective, add a 2nd agent with a different MOA
7) Titrate to achieve end organ perfusion
8) Most are linear response pattern
9) Relatively short duration of action
-Bolus/titrate to effect and then wean off easily.
10) Frequently re-evaluate the need for drugs
What are the different Catecholamine drugs we administer?
Naturally occurring:
-Epinephrine
-Norepinephrine
-Dopamine
Synthetic:
-Isoproterenol
-Dobutamine
What are the non-catecholamine CV drugs we administer?
Synthetic:
-Ephedrine
-Phenylephrine
Describe the chemical structure of Sympathomimetics.
-All sympathomimetics originate from beta-phenylethylamine
-Hydroxyl (-OH) groups on the 3 and 4 position of the benzene ring
What is the metabolism & elimination of sympathomimetics?
-Primary method of inactivation is via rapid reuptake into the cell.
-MAO & COMT enzymes cause metabolism of the drugs, but are slower and affect less drug
-Lungs metabolize about 25% of NE, 20% of Dopa, and no Epi.
What are the routes of administration for the Catecholamines?
-Inactivated if given PO
-Epi: IV, SQ, or via ETT (but have to give 10x dose)
-Dopa, Dobutamine, and NE are given IV
What are the routes of administration for the synthetic non-catecholamines?
-May be given PO or via inhalation
-Phenylephrine administered IV, intranasal
-Ephedrine is IV and can be used IM in OB
What is Epinephrine?
A natural catecholamine
-Manufactured, stored, and released from the Adrenal Medulla
-The prototype sympathomimetic
-Potent Alpha, with strong B1 and B2 action
-Vasoconstriction, + Inotropy, + Chronotropy, + Dromotropy, and also relaxes smooth muscle (bronchioles)
-Poor lipid solubility
What are clinical uses for Epinephrine?
-Allergic reactions
-Ventricular fibrillation/cardiopulmonary arrest
-Increase cardiac contractility
-Increased SVR
-+ inotropy when weaning from CPB
-↑ O2 delivery and ↑ CO in sepsis
-Additive in regional or neuraxial anesthetics
-Enhanced surgical field hemostasis (decreases bleeding)
How does Epi affect receptors at different doses?
1-2 mcg/min: Beta 2 effects. Still have alpha and beta 1, but effects seen are predominantly Beta 2. Will have decreased diastolic
3 - 10 mcg/min: Beta 1 effects. Increased systolic, heart rate, contractility, and cardiac output.
> 10 mcg/min: Alpha 1 and Beta. Vasoconstriction.
What are the clinical effects of Epinephrine?
-Skin and kidneys clamp down
-Muscles and airways dilate (airway will clamp down if on beta-blockade)
-GI tract slows
-Blood glucose increases
-Potassium decreases
-Leukocytes increase
-Coagulation accelerates
What are advantages to Epinephrine?
-No tachyphylaxis
-Powerful Inotrope
-Bronchodilator and Stabilizes mast cells (Primary tx for bronchospasm and anaphylaxis)
What are disadvantages to Epinephrine?
-Tachycardia and arrhythmias
-Vasoconstriction and Hypoperfusion
-Pulmonary HTN and RV failure
-Myocardial ischemia
-Hyperlactatemia (increases Lactate)
What is Norepinephrine?
An endogenous catecholamine.
-Immediate precursor of Epinephrine
-Primary physiologic post-ganglionic neurotransmitter
Effects:
-Beta 1 similar to Epi
-Little Beta 2 (less metabolic effect compared to Epi, don’t have increase in Lactate)
-Strong Alpha 1 (Arterial and venous vasoconstriction)
-SVR, SBP, DBP, and MAP increase
-Redistributes blood flow to central organs
Describe the synthesis and release of Norepi?
-Starts with Tyrosine which is converted to Dopamine which is converted to Norepinephrine.
-Calcium causes NE to be released at the nerve terminal
-Cocaine blocks NE reuptake, causing SNS surge.
1) The amino acid tyrosine is transported into the sympathetic nerve axon.
2) Tyrosine (Tyr) is converted to DOPA by tyrosine hydroxylase (rate-limiting step for NE synthesis).
3) DOPA is converted to dopamine (DA) by DOPA decarboxylase.
4) Dopamine is transported into vesicles then converted to norepinephrine (NE) by dopamine β-hydroxylase (DBH); transport into the vesicle can by blocked by the drug reserpine.
5) An action potential traveling down the axon depolarizes the membrane and causes calcium to enter the axon.
6) Increased intracellular calcium causes the vesicles to migrate to the axonal membrane and fuse with the membrane, which permits the NE to diffuse out of the vesicle into the extracellular (junctional) space. DBH, and depending on the nerve other secondary neurotransmitters (e.g., ATP), is released along with the NE.
7) The NE binds to the postjunctional receptor and stimulates the effector organ response.
What is the usual dosing for Epinephrine?
-SQ: 10mcg/kg
-IV bolus: 0.03-0.2mcg/kg
-IV infusion: 0.01-0.3 mcg/kg/min OR 2-10 mcg/min for adults.
What are advantages to the use of Norepinephrine?
-First line for hypotension in septic shock, vasoplegia
-Direct agonist
-Equipotent to Epi on B1 receptors
-Redistributes blood flow to central organs (can be good or bad)
-May be used after cardiac bypass
-Increases BP and CO
-Good for hypotension unresponsive to phenylephrine
What are disadvantages to the use of Norepinephrine?
-Arrhythmogenic potential
-Organ Ischemia: Renal splanchnic and peripheral vascular beds (can cause necrosis and GI issues)
-Caution with RV failure
-Pulmonary vasoconstriction
-Myocardial ischemia
-Skin necrosis with extravasation
What is the dosing for Norepinephrine?
-Starts at 2-4 mcg/min
-2 to 200 mcg/min as continuous infusion
What are the clinical uses for Dopamine?
-Hypotension caused by decreased CO or decreased SVR
-Temporary tx of hypovolemia
-Renal failure (controversial)
Why do some feel that Dopamine is renal-protective?
It inhibits aldosterone, causing natriuresis.
-Increases UOP
-Increases RBF
How is Dopamine eliminated?
Redistribution
Reuptake by nerve terminals
MAO and COMT enzymes
What are the advantages of Dopamine?
-Dose-dependent effects: 2-20 mcg/kg/min
-Easily titratable
-CO increased with β1 stimulation
-HR, BP and SVR increased due to NE release
-Increased urine output
-Rapid metabolism
What are the disadvantages of Dopamine?
-Inhibits insulin- Hyperglycemia
-Tachyarrhythmias
-Less inotropic effect than epi
-Increased MvO2 and Myocardial ischemia
How does Dopamine effect different receptors at different doses?
1-3 mcg/min:
-Dopamine 1 (D1): Post-synaptic. Dilates renal, coronary, cerebral, and mesenteric
-Dopamine 2 (D2): Pre-synaptic. Inhibits NE release, can cause N/V
3-10 mcg/min: Beta 1 (heart). Increases CO and increases stroke volume.
> 10 mcg/min: Alpha 1 (periphery). Increases SVR (profound vasoconstriction)
What is Renal Dose Dopamine?
Low-dose dopamine.
-Increased diuresis and urine output, but no protection of renal function
-No decrease in kidney injury or prevention of renal replacement in clinical trials
-Multiple adverse effects
-Use for this purpose NOT recommended
What is Dobutamine?
A synthetic catecholamine.
-Chemically modified isoproterenol
-Selective β1, very weak β2, mild α1,
-Results = strong inotropy; moderate chronotropy, some vasoconstriction
-Rapid metabolism (t½ ~ 2 minutes)
-Continuous infusion at 2-20 mcg/kg/min
What are the advantages to Dobutamine?
-Less tachycardia than Isupprel or Dopamine
-Afterload reduction
-Increased SBP
What are the disadvantages to Dobutamine?
-Dose related increase in HR
-Possible coronary steal due to inc HR
-Nonselective vasodilator
-Tachyphylaxis >72 hrs
-Mild Hypokalemia
What are the effects of Dobutamine?
-CO increases as infusion rate increases
-Atrial filling pressures decrease (offloading heart a little bit)
-SA node effect is less than with isoproterenol (lower HR increase)
-Lower ischemia risk
-Coronary arteries dilate (due to beta effects)
-SVR may decrease
-May be used in combination with vasodilators in heart failure
What is Isoproterenol?
-Synthesized from Dopamine
-Very potent B1 and B2 activator
-Devoid of Alpha Activity
-Minimal or no nerve ending uptake
-Rapid COMT metabolism
-EXPENSIVE
What are the effects of Isoproterenol?
-Increase HR and CO
-No alpha effects = no vasoconstriction
-NOT a PRESSOR
What are the uses of Isoproterenol?
-Bradycardia (not 1st line)
-Pulmonary HTN (not 1st line): Drops PVR in pulmonary HTN (Avoid with stenosis)
-Beta Blocker Overdose (increases HR)
-EP lab to induce arrhythmias
-Post cardiac transplant (pts are denervated and don’t have intrinsic rate)
-Useful in third degree heart block pending pacemaker (Inc HR without affecting BP)
What is the dose of Isoproterenol?
1-5 mcg/min infusion
What are cautions to the use of Isoproterenol?
-No vasoconstriction: Useless in shock
-Dysrhythmogenic and extends ischemic areas
-Unpredictable BP results in setting of increased CO and no vasoconstriction
-Inc CO and inc HR, but no vasoconstriction. BP can increase or decrease.
Describe the metabolism/Removal of Norepinephrine?
-Most (~90%) of the NE is transported back into the nerve terminal by a neuronal reuptake transport system. This transporter is blocked by cocaine; therefore, cocaine increases junctional NE concentrations by blocking its reuptake and subsequent metabolism. (This is a major mechanism by which cocaine stimulates cardiac function and raises blood pressure.)
-Some of the junctional NE diffuses into capillaries and is carried out of the tissue by the circulation. Therefore, high levels of sympathetic activation in the body increase the plasma concentration of NE and its metabolites.
-Some of the junctional NE is metabolized within the extracellular space before reaching the capillaries.
-A small amount of NE (~5%) is taken up by the postjunctional tissue (termed “extraneuronal uptake”) and metabolized.
How are the clinical effects of Norepi ended?
-Redistribution, neural uptake, and metabolism
-MAO and COMT
