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.
