Adrenergic Agents and other CV-Modifying Drugs

Question 1

Sympathomimetics

Answer 1

stimulate or activate SNS
 Agonists at Dopamine R also sympathomimetics
o Can also be classified as having direct effects at R or indirect (cause release of NE)

Question 2

Sympatholytics

Answer 2

decrease activation of SNS

Question 3

Naturally-Occurring Catecholamines

Answer 3

Epi, NE, dopamine

Question 4

Synthetic Catecholamines

Answer 4

dobutamine, dopexamine, isoproterenol (isoprenaline), phenylephrine

Question 5

Direct agonists

Answer 5

endogenous (NE, EPI), sympathomimetic (Phenylephrine, dobutamine)

Question 6

MOA Indirect agonists

Answer 6

Increase endogenous catecholamines
o Reduce breakdown of catecholamines by blocking enzymes involved in NE/EPI metabolism (MAO inhibitor)
o Inhibiting physiological reuptake of NE from synaptic space (cocaine, tricyclic antidepressants)
o Enhancing release of catecholamines from postgang symp nerve terminal (tyramine

Question 7

Mixed Agonists

Answer 7

Have both indirect, direct agonists effects ie ephedrine

Question 8

Location a1 R

Answer 8

SmM: BV, bronchi, GI, uterus, urinary system
Pupillary dilator m
Splenic capsule

Question 9

Location a2 R

Answer 9

throughout CNS, vascular endothelium, platelets

Question 10

Location beta 1 R

Answer 10

Heart (70%)
Juxtaglomerular cells

Question 11

Location beta 2 R

Answer 11

Heart (20%)

SmM: BV, bronchi, GIT, uterus, urinary system
Liver

Question 12

Location beta 3 R

Answer 12

Adipose tissues - agonism = lipolysis

Question 13

Location dopamine 1 R

Answer 13

CNS, vascular SmM, kidney, sympathetic ganglia, others

Question 14

Location of dopamine 2R

Answer 14

CNS, vascular SmM, kidney, sympathetic ganglia, others

Question 15

MOA a1 R

Answer 15

Gq

Question 16

MOA a2 R

Answer 16

Gi/o

Question 17

MOA beta R

Answer 17

Gs

Question 18

MOA D1

Answer 18

Gs

Question 19

MOA D2

Answer 19

Gi/o

Question 20

Agonist selectivity of a

Answer 20

PHE, EPI > NE&raquo_space;>isoproterenol

Question 21

Agonist selectivity beta 1

Answer 21

Isoproterenol > epi =/> NE

Question 22

Agonist selectivity beta 2

Answer 22

Iso > epi&raquo_space;> NE

Question 23

Structure of catecholamines

Answer 23

o Benzene ring + various amide side chains at C1 position
o Catecholamine: when hydroxyl group present at C3, C4; catechol: 3,4-dihydroxybenzene

Question 24

Epinephrine

Answer 24

non-selective, direct agonist at β1=β2 > α1= α2

Question 25

Epinephrine formulations/ROA

Answer 25

 1mg/ml (1:1000) or 0.1mg/ml (1:10,000)  Protected from light – colored glass ampules or vials  Administered IV or IT during CPR (in humans available as inhaler)  Can be formulated with LA solutions 1:200,000 to 1:80,000 o Racemic mixture – L isomer active form

Question 26

How calculate different epinephrine solutions?

Answer 26

1gm into how many mL? 1gm into 1,000mL --> 1mg/mL = 1:1,000 0.1mg/mL = 1:10,000 (1g in 10,000mL) 0.01mg/mL = 1:100,000 0.005mg/mL (5mcg/mL) = 1:200,000

Question 27

Epi CV Effects

Answer 27

* Low doses – (0.01mg/kg): β1 and β2 effects predominant o β1 – increased CO, increased myocardial O2 consumption, coronary artery dilation, reduced threshold for arrhythmia  Increased HR, ctx, venous return o β2 – decrease in diastolic BP, SVR * High doses – (0.1mg/kg) α1 effects predominantly o α1 – marked rise in SVR

Question 28

aR stimulation by epi

Answer 28

-Higher doses * a1 R in cutaneous, splanchnic, renal vascular beds * a2 stimulation: VC * More sensitive to epi at higher doses * At higher doses, VC will dramatically increase afterload, may impede increased CO * Increased venous return DT venoconstriction: lots of a1 R in venous vasculature, increase BP/CI/SVR

Question 29

What determines epinephrine's effect on BF to a particular organ?

Answer 29

 Balance of b1/b2 R in vasculature of organ determines epinephrine’s overall effect on blood flow to that organ * Net effect of changes in peripheral vascular tone = preferential distribution of CO to SkM and increased SVR

Question 30

beta 2 R effets of epi

Answer 30

 b2: SkM dilation * More sensitive to epi at lower doses

Question 31

Beta 1 effects of epi

Answer 31

 a1: increase HR, increase myocardial contractility, increased CO, decreased DAP DT VD in SkM * Net effect = increased pulse pressure, mild change in MAP * Increased HR DT increased rate of spontaneous phase 4 depolarization, increased likelihood of dysrhythmias * Also increased venous return

Question 32

Epinephrine in cats

Answer 32

(0.125-2 mcg/kg/min) cause increase in PCV DT α1 splenic contraction * Increase in arterial oxygen content, HR, CI, SVI – predominance of beta effects at low CRI dises * >0.5mcg/kg/min = increased MAP o Increased BP, CI associated with increased lactate, progressive metabolic acidosis

Question 33

Does epinephrine induce tachyphylaxis?

Answer 33

No

Question 34

Effects of super therapeutic doses of epi

Answer 34

acute heart failure, pulmonary edema, arrhythmias, hypertension, myocardial infarction

Question 35

Unwanted Cardiac Effects of Epi

Answer 35

 Proarrhythmogenic – **decrease in threshold for vfib, increased incidence of VPC, dropped beats, VT, tachycardia**  Increased MVO2 with increased LV preload, increased contractility, increased afterload, tachycardia Also local tissue necrosis with extravasation

Question 36

Proarrhythmogenic Effect of Epinephrine

Answer 36

decrease in threshold for vfib, increased incidence of VPC, dropped beats, VT, tachycardia * MOA: activation of β1, α1 on myocardial cells, activation of cardiac cholinergic reflexes * Increased rate of spontaneous phase 4 depolarization, increased conduction velocity, decreased refractory period in AV node/Bundle of His/Purkinje cells/ventricular m cells * Increased automaticity of latent PMs Dose of epi required to induce arrhythmias higher with ACP

Question 37

Arrhythmogenic effects of halothane, epinephrine

Answer 37

* Halothane sensitizes myocardium to catecholamine-induced arrhythmias in dogs, cats, horses, pigs – similar MOA o Also propofol, thiopental o Iso, sevo do not sensitize to any great extent o Threshold for halothane + epi not altered by xylazine in horses, ketamine decreases dose of epi in halo-ax dogs, cats

Question 38

Resp Effects of Epi

Answer 38

* Bronchodilation - β2 – small increase in minute volume o B2 stimulation: increases cAMP, decreased release of vasoactive mediators assoc with asthma o No BD effects in presence of beta blockade – see BC DT alpha R * PVR increased at higher dose rates - α1

Question 39

MAC sparing or increasing effect of epi?

Answer 39

None

Question 40

GIT effects of epi

Answer 40

Relaxation of gastric SmM Hepatosplanchnic VC – greater impairment of splanchnic circulation than NE or DOP

Question 41

Metabolic Effects of epi

Answer 41

* Increased basal metabolic rate, slight increase in body temp * Increased plasma glucose concentration o Inhibition of insulin secretion via α2, β2 – inhibition of peripheral glucose uptake o Glycogenolysis in liver, muscle via α1, β2 – activation of hepatic phosphorylase enzyme o Lipolysis via β2, β3 – activation of triglyceride lipase, accelerates breakdown to TG to form FFA, glycerol o Gluconeogenesis via α1, β2

Question 42

What is the increase in metabolic rate per 1*C?

Answer 42

13% increase in metabolic rate

Question 43

Potassium effect of epi

Answer 43

 Serum K increase and then decrease (β2 effect) DT uptake by cells * a2 effect: activation of Na-K ATPase pump, transfer of K into cells, decrease K levels

Question 44

Renal effects of epi

Answer 44

 Release of renin from kidney via β1, β2 in kidney (renal blood flow decreased DT VC) * Epi 2-10x more potent renal VC than NE

Question 45

UG effects of epi

Answer 45

 beta R relax detrusor m of bladder, alpha R contracts trigone, sphincter m

Question 46

Ophthalmic effects of epi

Answer 46

mydriasis, exophthalmos (ctx of orbital m, likely a1)

Question 47

Epinephrine's effect on coag

Answer 47

 Accelerates coagulation, potent inducer of platelet aggregation, increases factor V activity

Question 48

Epinephrine's PK

Answer 48

 Very short half life – rapid metabolism by mitochondrial monoamine oxidase, catechol-O-methyltransferase within liver, kidney, circulation to inactive metabolites (3-methyloxy-4-hydroxymandelic acid and metanephrine) * Conjugated with glucuronic acid or sulfates, excreted in urine o Can block or attenuate effects via prior admin of beta or a R antag

Question 49

Effects of chronic epinephrine secretion

Answer 49

 Decreased plasma volume DT loss of protein-free fluid in ECF  Arterial wall damage  Local myocardial necrosis

Question 50

Epinephrine Reversal

Answer 50

alpha adrenergic blocking agents can reverse alpha agonist effects of epi  BP decreases IRT epi in presence of phenoxybenzamine  beta2 R stimulation NOT blocked: VD in vascular beds, further decrease in BP

Question 51

NE selectivity

Answer 51

Agonist at α1=α2, > β1 > (β2)

Question 52

Clinical use of NE

Answer 52

o α effects dominate at clinically used dose rates – treat hypotension especially when caused by reduction in SVR (VD) DT sepsis, admin of volatile anesthetics  Also for patients with decreased SVR after CPB  Ensure appropriate volume resuscitation

Question 53

NE

Answer 53

o Endogenous NT synthetized/stored in postganglionic sympathetic nerve endings  Released with SNS stimulation o Immediate precursor to epi

Question 54

Structure of NE

Answer 54

 Absence of methyl group on nitrogen atom vs epi  Formulation: 1mg/ml solution bitartrate salt

Question 55

CV Effects of NE

Answer 55

 Low dose rates (0.02mcg/kg/min): β1 effects, increased HR/CO, decreased SVR  Higher dose rates (0.5-1.5mcg/kg/min), dose dependent increase in SAP, DAP, MAP, CO, SVR, PVR, coronary VD (improved coronary BF) * INCREASE SVR, DAP, MAP, SAP >>> epi * KB: Equal potency at B1 vs epi * Tachycardia less likely vs epi * Effective at improving CV function, preserving splanchnic circulation in iso-hypotensive foals (0.3), alpacas (1.0)  Minimal HR change: BRR from VC counteracted by 1 effects * Epinephrine’s increased chronotropic effect >>> NE  Venous VC: decreased venous capacitance, increased venous return --> increased SV, CO

Question 56

NE Unwanted CV Effects

Answer 56

 Very high doses: increases SVR, decreased CO, increased O2 demand DT to increased afterload * Use as positive inotrope limited by significant VC, increased peripheral resistance and afterload by decrease CO, increase LV work  Caution with R CHF: increase venous return, PAP (pulmonary vascular a1)  Arrhythmogenic effects of NE similar to epinephrine * KB: less than epi * Tachycardia

Question 57

Other Unwanted AEs of NE

Answer 57

 Extravasation: tissue necrosis * Ideally admin via central line  Intense VC in SkM, liver, kidneys, skin – decreases total blood flow, can lead to metabolic acidosis  Organ ischemia: excessive VC will decrease perfusion of renal, splanchnic, peripheral vascular beds – end-organ hypoperfusion, ischemia  Renal arteriolar VC --> oliguria, renal failure

Question 58

Effects of Chronic NE Release

Answer 58

Similar to epi  Precapillary VC  Loss of protein-free fluid into ECF

Question 59

NE Metabolic Effects

Answer 59

o Minimal metabolic effects

Question 60

PK NE

Answer 60

 Metabolized similarly to epinephrine, short half life * Reuptake into adrenergic nerve endings  Unlike epinephrine – 25% extracted as it passes through lung * In lung, deactivated by monoamine oxidase, catechol-O-methyltransferase in endothelial cells of pulmonary microvasculature

Question 61

Dopamine R Selectivity

Answer 61

Effects, receptors dose dependent; DA-1=DA-2 > β1 > β2 > α1, a2

Question 62

DA1

Answer 62

postsynaptic, activation (mediated via AC) elicits VD in renal, mesenteric, coronary, cerebral vascular beds, inhibition of Na-K ATPase pumps GPCR: Gs

Question 63

DA2

Answer 63

: presynaptic, inhibit AC activity, release NE in ANS ganglia, adrenergic nerves (renal, mesenteric vessels) = VD * Also in pituitary gland, emetic center (medulla), kidney * Nausea, vomiting likely DT D2 R stimulation Gi/o

Question 64

Dose-dependent effects of dopamine

Answer 64

o 1-2mcg/kg/min effects on DA-1/DA-2 predominate o 2-10mcg/kg/min effects on β1, β2 o >10mcg/kg/min effects on α1 o Also stimulates release of NE from presynaptic storage sites for endogenous SNS stim

Question 65

Formulations of dopamine

Answer 65

 40mg/mL dopamine HCl sln, preservative sodium metabisulfite  Dopamine HCl 100mL dextrose 5%, 0.8-6.4mg/mL

Question 66

Clinical CV Uses of Dopamine

Answer 66

* Increase CO in patients with decreased contractility, decreased SBP, decreased urine output * Increases myocardial contractility, RBF, GFR, excretion of Na, urine output * Positive chronotrope, dromotrope, inotrope, lusitrope (1) * Increases SVR, preload, LV afterload * Increases PVR

Question 67

CV Effects of Dopamine

Answer 67

 β1 – increase in myocardial contractility, HR, CO, coronary BF * Can increase myocardial O2 consumption  α1 (>10mcg/kg/min) – increased SVR, PVR, venous return, PCV DT splenic contraction; tachycardia can still occur

Question 68

How discontinue a dopamine CRI

Answer 68

 Decrease dose in stepwise manner DT decrease in CO/MAP after cessation

Question 69

Dogs and dopamine

Answer 69

isoflurane, 3-20mcg/kg/min – dose-dependent increase in CI, BP * >7mcg/kg/min: increase HR, SVR * < 7, insufficient to support hemodynamic variables * > 10, marked increase in SVR/ decrease in SV, increase myocardial work with increase afterload

Question 70

Cats and dopamine

Answer 70

>10 needed to maintain MAP >70 with isoflurane * Wiese et all studied HCM cats with dopamine: 2.5-10 increased HR, BP, CO DO2 (better than phenylephrine?) o 6/6: VPCs – negative impact on MVO2, despite increased DO2

Question 71

Horses and Dopamine

Answer 71

– 5mcg/kg/min increases myocardial contractility, CO with little effect on BP (decreased smooth muscle tone by stim of DA-1 and DA-2)

Question 72

Adverse CV Effects of Dopamine

Answer 72

 Proarrhythmic at >10mcg/kg/min  Predispose to myocardial infarction by precipitating tachycardia, increased contractility, increased afterload, coronary artery spasm  Attenuate response of carotid body to hypoxemia, hypercapnia  Caution in patients with PH, RV dysfunction (avoid in R CHF)

Question 73

Other Unwanted Effects Assoc with DOP

Answer 73

 Can increase IOP  Extravasation: localized vasoconstriction * Tx phentolamine  Disrupts metabolic, immunologic functions – effects on hormonal, lymphocyte function  GI mucosal ischemia: translocation of bacteria/bacterial toxics  MODS  D2 R on enteric nervous system: interfere with GI motility

Question 74

Resp Effects of DOP

Answer 74

 No inhibition of HPV  May decrease PVR in patients with COPD  Improves resp m contraction  Increases lung edema clearance  Inhibition of bronchoconstriction

Question 75

Other Effects of DOP

Answer 75

 Increased renal blood flow, increased urine output – DT increased CO * +inhibition of prox tubular Na resorption * Not DT renal arterial dilation like previously thought * D1/D2 R in proximal tubules, thick ascending LoH, cortical collecting ducts – inhibit NaK ATPase activity, increases Na excretion (natriuresis, diuresis)  VD mesenteric dilation via D1 R activation

Question 76

Onset, Absorption of DOP

Answer 76

 Short half life, ~3min – requires CRI  Slower onset, up to 5 min  No PO absorption

Question 77

Metabolism of DOP

Answer 77

 Metabolized by monoamine oxidase, catechol-O-methyltransferase in liver, kidney, and plasma

Question 78

Excretion of DOP

Answer 78

 Excreted in urine as sulfate and glucuronide conjugates  25% converted to NE in sympathetic nerve terminals

Question 79

Dobutamine R Selectivity

Answer 79

β1> β2 >>>>α1

Question 80

Dobutamine

Answer 80

o Direct-acting synthetic catecholamine, derivative of isoproterenol  50:50 racemic mixture of two stereoisomers  (-) enantiomer = potent a1 agonist, weak B1/B2  (+) enantiomer = competitive antagonist at a1, potent B1/B2 agonist

Question 81

Main use of dobutamine

Answer 81

o Improves CO in patients with heart dz (CHF, DCM, PH), tx BP in LA  Potent β adrenergic agonist to myocardial ctx, moderate peripheral VD  L-isomer stimulates α1 receptors at higher doses

Question 82

MOA Dobutamine

Answer 82

o Primarily to augment reduced myocardial function  MOA: GPCRS  stimulation of AC, increased production of cAMP  activation of protein kinase --> phosphorylation of proteins (L type VG Ca channels) --> positive chronotropic, inotropic, dromotrophic effects  Increased Ca release from SR --> increased contractility * KB: Increased CO via increased SV: B1 (a1R) * b2 decrease afterload o LJ: 0.5-5mcg/kg/min – Primarily β1, increased SAP, DAP, MAP, no increase in ctx or CO; PCV increased o Higher doses (5-10mcg/kg/min), +β2, α1 – increased SVR/HR, inotropic/chronotropic effects

Question 83

Formulations of dobutamine

Answer 83

12.5-50mg/mL, sodium metabisulfite preservative

Question 84

Horses and Dobutamine (under halothane ax)

Answer 84

* Low dose infusion (0.5): increase SAP, DAP, MAP without increasing CO, myocardial contractility; increased PCV * 4-5: increased ABP, CO with minimal effects on HR, SVR * 10: increased SVR, HR with increased CO DT positive inotropic, chronotropic effects * Ponies ax'd with halo: More consistent effect in increasing IM BF

Question 85

Dogs and Dobutamine (under isoflurane ax)

Answer 85

* <10: limited effects on BP; increased CO, HR, SVR * Usefulness in improving hemodynamic function?

Question 86

Cats and dobutamine

Answer 86

* <10: limited effects on BP; increased HR * decreased SVR DT beta2 – peripheral VD in SkM

Question 87

Other CV Effects of dobutamine

Answer 87

 Weak effects on vascular tone, peripheral VD  Stimulates SA node automaticity, AV nodal/ventricular conduction * Chronotropic effects less than dopamine, isop but more than epi

Question 88

Potential Unwanted effects of dobutamine

Answer 88

 **Arrhythmogenic** potentia, higher doses (>10mcg/kg/min) * Ventricular arrhythmias less likely than with DOP, ISOP  Will increase MVO2, but will also increase CO  No direction action on NE release or DA-1/2 receptors  **Tachyphylaxis** may occur as it acts on β receptors  **eosinophilic myocarditis, peripheral eosinophilia**

Question 89

Resp Effects of Dobutamine

Answer 89

 **Inhibits HPV, lower PAP/PVR**  Potential to worsen VQ mismatch

Question 90

PK Effects of Dobutamine

Answer 90

 Short half life  Primarily metabolized via catechol-O-methyltransferase in liver to inactive metabolites that are conjugated and excreted in urine

Question 91

Dopexamine Selectivity

Answer 91

β2 >>> β1, DA-1, DA-2

Question 92

Dopexamine Uses

Answer 92

o Inhibits neuronal uptake of endogenous catecholamines o Human medicine: Used to improve CO, mesenteric perfusion – potential protection of hepatosplanchnic and renal BF – evidence lacking

Question 93

CV Effects of Dopexamine

Answer 93

--Cardiac β2 – positive inotropic effect, drop of systemic BP (vasodilation particularly in SkM) --> promotes increased CO

Question 94

Dopexamine in Horses

Answer 94

(Halothane) - NOT RECOMMENDED At high doses, tachycardia, arrhythmias, m twitching, poor recoveries from GA

Question 95

Dopexamine in Dogs

Answer 95

Increase CO, HR in dose-dependent manner Lower arrhythmogenic potential vs DOP

Question 96

Other Effects of Dopexamine

Answer 96

--BD --Increased GI, RBF DT increased CO, reduced regional vascular resistance --Increased UO

Question 97

PK Dopexamine

Answer 97

Short half life Hepatic Metabolism via O-methylation, sulfation

Question 98

Isoproterenol Selectivity

Answer 98

B1=B2 **VERY** potent synthetic catecholamine **NO ALPHA EFFECTS**

Question 99

ISOP use in People

Answer 99

Increase HR, myocardial contractility – promote arrhythmias during EP studies (humans)  Low doses: test dose to detect IV needle placement during epidural in children

Question 100

ISOP formulation

Answer 100

0.2mg/mL solution, light sensitive preservative sodium metabisulfite

Question 101

CV Effects of ISOP

Answer 101

 Increased HR < contractility, CO via beta1  β2 generally reduce SVR, MAP falls  Higher rates = DO2 compromised (from elevated HR, reduced coronary filling time) while decreased systemic BP --> reduced coronary perfusion

Question 102

ISOP and Dogs

Answer 102

 Dogs, very low dose infusion (0.1, isoflurane): increase CO, HR while increasing myocardial BF – maintained adequate myocardial oxygenation

Question 103

Unwanted CP Effects of ISOP

Answer 103

 **Discouraged for low blood volume patient** dependent on intense compensatory VC for coronary perfusion pressure  **Pro-arrhythmogenic** DT ion channel kinetics, promotion of intracellular Ca accumulation * General trend to tachycardia  **Systemic hypoxemia** DT potent BD effects - increased anatomic deadspace, VQ mismatching * **Increased CNS stimulation DT hypoxemia– arousal during GA**

Question 104

Other effects of ISOP?

Answer 104

 **Increases splanchnic, renal BF**  β receptor – **increase in BG, free fatty acid concentrations, decrease in serum K DT shift of K into cells**

Question 105

PK Effects of ISOP

Answer 105

 Short half life  Metabolized by catechol-O-methyltransferase in liver  Unchanged or conjugated sulfates excreted in urine EXPENSIVE

Question 106

Other Positive Inotropes

Answer 106

1. Calcium (esp LA) 2. Digoxin 3. Pimobendan

Question 107

Calcium

Answer 107

Fxn: + inotrope Tx hypotension in LA, raises threshold potential for AP during tx for hyperkalemia iCa affects pH, albumin, can be proarrhythmogenic (hypercalcemia, parathyroidectomy)

Question 108

Digoxin

Answer 108

Foxglove plant, glycosides * Structure: steroid-type nucleus – attached to unsaturated lactone ring at carbon-17 * Sugar molecules attached at C3: influence water solubility, cell penetrability, DOA

Question 109

Digoxin - PSNS Effects

Answer 109

Parasympathetic effect on sinus node, AV node, atrial tissue - slows conduction through AV node, increases vagal tone to ventricle (slows ventricular response rate) * Used for treatment of SVT, CHF * Prolongs refractory period

Question 110

Digoxin - positive inotropic effects

Answer 110

--More pronounced in hypo dynamic, failing heart; less inotropic effects than dobutamine --activation of Na-Ca exchanger/inhibition of Na-K ATPase --++Na-Ca exchanger: Na out, Ca in - increases amount of intracellular Ca, increased delivery of Ca to contractile proteins -Inhibition of Na-K ATPase prevents Na ions from being pumped out in exchange for K so can be exchanged out for Ca

Question 111

Digoxin - Arrhythmogenic Effects

Answer 111

inhibition of Na-K ATPase, resulting depletion of inward rectifying K currents that reduces resting membrane potential to less negative value (No pumping of K in)

Question 112

SE of digoxin

Answer 112

 SE: nausea, loss of appetite, vomiting, diarrhea  Cats particularly sensitive, also used in horses in combination with quinidine for treatment of afib  No increase in MVO2 in patients with heart failure

Question 113

Pimobendan

Answer 113

Positive inotrope, inodilator – sensitizes cardiac contractile apparatus to intracellular Ca * Potential to increase intracellular [Ca], increase MvO2 o Cardiac effect reportedly minimal at pharmacological doses, major advantage relative to other inotropic PDE-I (milrinone) PDE-3 inhibitor

Question 114

Function of PDE-3 Inhibitor

Answer 114

increases cardiac contractility via increasing cAMP within myocyte * cAMP: positive effect on myocardial ctx * Relaxes vascular SmM, bronchial SmM – helpful in cases of CHF  Prolongs development of CHF in MMVD dogs by 14mo

Question 115

Pimobendan as Ca Sensitizer

Answer 115

enhance SR response to calcium without potential for SE of adding Ca to myocyte * Binds to Ca binding site on Troponin C * Increases contractility * Enhances systolic function w/o increase MvO2 or pro arrhythmogenic o Vs agents that solely increase intracellular Ca or [cyclic AMP]

Question 116

Other Cardiac Effects of Pimobendan

Answer 116

**positive lusitrophy** * PDE III inhibition in cardiac myocytes: increases intracellular CMP, facilitating phosphorylation of receptors on SR * Diastolic reuptake of calcium enhanced, speed of relaxation increased

Question 117

When to give pimobendan?

Answer 117

Always give morning of anesthesia Contradicted in outflow tract obstructions (?)

Question 118

Other Effects of Pimobendan

Answer 118

 Antithrombotic effects in dogs at supraclinical doses  Alterations of proinflammatory cytokines

Question 119

PK of Pimobendan

Answer 119

* Rapid absorption, peak plasma levels within one hour PO * Elimination half-life ~ one hour or less * Administered > 1hr prior to feeding until steady state reached, reduced in presence of food * Heavily protein bound: 90-95%, water insoluble

Question 120

Metabolism of Pimobendan

Answer 120

demethylation in liver to more potent metabolite, UDCG-212 * Metabolite = more potent inhibitor of PDEIII, longer half life

Question 121

Phenylephrine selectivity

Answer 121

a1 ONLY

Question 122

Phenylephrine

Answer 122

o Direct acting sympathomimetic amine with potent α1 effects “vasopressor”, no β effects  Indirect release of NE  a1 stimulation at much lower doses than a2 stimulation  Minimal CNS stimulation

Question 123

Uses of Phenylephrine

Answer 123

 Increase SVR --> increase ABP  Topical administration to mucosal surfaces: localized VC, reduce edema/hemorrhage  Horses: medical management of nephrosplenic entrapment, splenic ctx

Question 124

Phenylephrine Formulations

Answer 124

Formulations: 10mg/mL with hydrochloride salt  Nasal decongestants, topical ophthalmic preparations

Question 125

CV Effects

Answer 125

Dose-dependent increase in SVR and MAP, reflex reduction in heart rate * CO minimally altered or falls DT increased afterload with bradycardia **Not Proarrhythmogenic**

Question 126

Phenylephrine in Dogs

Answer 126

* >0.4mcg/kg/min needed to increase MAP significantly in conscious dogs * Reduction in HR at lowest dose, 0.008mcg/kg/min – vagally-induced reflex bradycardia * At least 0.14 needed to manage hypotension caused by halo + ACP

Question 127

Horses and Phenylephrine

Answer 127

* Hemodynamic effects wane rapidly with cessation of CRI * **SVR, PVR increased; limited effect on CO** * 0.25-2: **no improvement in SkM BF (halothane)** * **Severe hemorrhage in older horses** when used for correction of nephrosplenic entrapment – attributed to secondary hypertension by increased SVR * **Avoid use to tx hypotension DT myocardial depression**

Question 128

Patients that Benefit from Phenylephrine?

Answer 128

If arrhythmogenic Coronary artery dz, AS - increase coronary perfusion pressure without chronotropic YEs

Question 129

Phenylephrine in Cats

Answer 129

* Healthy cats (iso), 0.125-2: MAP increase, no change in HR (blunted BRR), no change in CO, oxygen delivery increased with no change in global oxygen consumption * Cats with HCM, 0.25-1: MAP increase, no change in HR, no change in CO, oxygen delivery increased with no change in global oxygen consumption

Question 130

Other Effects of Phenylephrine

Answer 130

 Reduced HBF, RBF - a1 VC  Reduced uterine blood flow, potential adverse effects on fetal DO2, LJ: avoid * SS: compare to studies where best for C sections? * KB: less fetal acidosis than ephedrine  Topical eye drops: increase BP (JANICE!)

Question 131

Methoxamine

Answer 131

a1 agonist - longer DOA vs phenylephrine Direct VC of arterioles, little effect on capacitance vessels

Question 132

B2 R Agonists:

Answer 132

clenbuterol , albuterol (salbutamol), terbutaline Uses: management of bronchospasm, hypoxemia in horses

Question 133

Clenbuterol Uses

Answer 133

illegally to increase muscle mass, reduce fat composition of production animals Clenbuterol: COPD in horses Delay parturition in cattle via uterine relaxation (clenbuterol inj)

Question 134

Limitations of Administration of Inhalation Beta 2 Agonists

Answer 134

12% of drug delivered to lungs – ETT decreases that 12% by an additional 50-70%

Question 135

CV Effects of Beta 2 Agonists

Answer 135

High doses: +B1 effects – tachycardia Low doses: predominantly B2 effects, VD/decreased BP Proarrhythmogenic * Shorten refractory period of AV node, slow ventricular conduction, shorten refractory period of ventricular myocardium * Effects more pronounced during hypoxemia or hypokalemia

Question 136

Other Effects of Beta 2 Agonists

Answer 136

 Relaxation of bronchial SmM  Stimulate Na/K ATPase pump – increase K+ uptake by cells, hypokalemia  Increased BG

Question 137

Clenbuterol IV for Tx Hypoxemia in Horses

Answer 137

IV not recommended for tx of hypoxemia in anesthetized horses: potentiates hypoxemia Potentiation MOA: increased shunt fraction (BD, reduction in HPV) AEs: profuse sweating, increased oxygen consumption

Question 138

Albuterol IN for Tx Hypoxemia in Horses

Answer 138

improvement of PaO2 * Predominant MOA: sympathomimetic effect on hemodynamic function use is supported

Question 139

Bronchospasm in Cats

Answer 139

Face mask or terbutaline for BAL or bronchoscopy

Question 140

Ephedrine

Answer 140

Direct, indirect sympathomimetic actions via a1, a2 > b1, b2  Also inhibits action of monoamine oxidase on NE  Direct: stimulation of adrenergic R  Indirect: release of endogenous NE

Question 141

Limitations of Ephedrine

Answer 141

o Tachyphylaxis with repeat doses DT depletion of NE stores therefore reduction in magnitude of indirect sympathomimetic effects

Question 142

Other Effects of Ephedrine

Answer 142

 Antiemetic effects IM  Mydriasis  CNS stimulation  No hyperglycemia

Question 143

Resp Effects of Ephedrine

Answer 143

bronchodilation (b2)  Chronic oral medication to tx bronchial asthma PO, 1hr onset time

Question 144

CV Effects Ephedrine

Answer 144

Increase CO, HR, BP, coronary BF, MVO2

Question 145

Metabolism of Ephedrine

Answer 145

rapid N-demethylation to norephedrine in dogs, ponies Norephedrine = active metabolite

Question 146

Metaraminol

Answer 146

o Synthetic amine: direct, indirect sympathomimetic effects that predominate a with some beta activity o Increase BP through increase in SVR, CO often falls

Question 147

Vasopressin

Answer 147

V1a receptors of vascular smooth muscle * Gi/o GPCR * No V1 R in pulmonary vasculature, no pulmonary VC V1b also has activity (on anterior pituitary) V2 = renal collecting duct * Gs GPCR * Stimulate aquaporin channels in kidney to resorb H2O, increase blood vol

Question 148

Uses of Vasopressin

Answer 148

 May reduce risk of myocardial ischemia compared with epinephrine due to lack of beta 1 adrenergic receptor activity  Coronary VC  Another advantage over epi = V1 receptors, unlike a1adrenergic receptors, remain responsive in an acidic environment  No benefit to use over epi in research during CPR

Question 149

Desmopressin

Answer 149

VP Analogue Used to treat central diabetes insipidus, management of coagulopathy - reduced vascular effects

Question 150

Uses of Desmopressin

Answer 150

Perioperative management of von Willebrand disease, management of central diabetes insipidus

Question 151

Prazosin

Answer 151

Highly selective a1 antagonist Sympatholytic, quinazoline derivative Primarily for management of functional UO in cats, dogs

Question 152

CV Effects Prazosin

Answer 152

VD arteries, veins – reduces SVR Decrease in BP: predominantly DAP Little to no reflex tachycardia DT reduction in central thoracic sympathetic outflow No renin increase DC 12-24hrs prior to GA

Question 153

SE Prazosn

Answer 153

 Vertigo  Fluid retention  Orthostatic hypotension  Lethargy  Increased urination  NSAIDS: may interfere with antihypertensive effects

Question 154

PK in Dogs

Answer 154

Well absorbed from GIT, low bioavailable in dogs following PO, 38% * DT hepatic extraction, presystemic metabolism of drug * Elimination time 3h, prolonged with CHF IV: extensive rapid tissue distribution, short DOA Major liver hepatic pathways: demethylation, amide hydrolysis, O-glucuronidation

Question 155

Other Uses of Prazosin

Answer 155

+/- use for tx of pheochromocytoma Prazosin + B blocker = refractory hypotension during regional ax DT blunted a, b responses

Question 156

Phentolamine

Answer 156

Sympatholytic, competitive non-selective alpha receptor blocker with 3 times greater affinity for a1>a2 o Ax: Management of hypertensive crises DT excessive administration of sympathomimetics, pheochromocytoma Human dentistry: reverse effects of LA admin

Question 157

MOA Phentolamine

Answer 157

VD, hypotension via postjunctional a1, a2 R blockade  Blockade of presynaptic 2 R: facilitates NE release – tachycardia, increased CO (opposite effects of dexmedetomidine)  Decreases PAP

Question 158

Phenoxybenzamine

Answer 158

Sympatholytic, long acting, non selective alpha blocker (a1>a2) Effects mediated by reactive intermediate, forms a covalent bond, alkylates a R = irreversible block  Inhibits neuronal, extraneuronal uptake of catecholamines

Question 159

Main use of Phenoxybenzamine

Answer 159

 Aids in reversing chronic VC DT increased circulating epi, NE  Facilitate expansion of IV volume  Admin 20d prior to adrenalectomy = decreased mortality vs untreated controls in dogs Downside: long duration of action can lead to persistent hypotension under GA  Can dc 48hr prior to sx  Epinephrine reversal

Question 160

SE Phenoxybenzamine

Answer 160

o Does not prevent arrhythmias, +/- concurrent beta blockade to control arrhythmias, reduce tachycardias in people o Reduction in CNS sympathetic outflow as a result of adrenergic blockade  mild sedation Urinary, bile excretion

Question 161

Consequence of chronic beta blocker use?

Answer 161

increases # of betaadrenergic R Myocardium: 75% B1, 20% B2

Question 162

Beta Blockers - Dose Response Curve

Answer 162

RIGHT displacement of dose response curve DT competitive inhibition  At high enough doses, agonists can still exert full effect

Question 163

MOA Beta Blockers

Answer 163

Class II MOA: decrease heart rate by reducing automaticity in SA node, prolonging conduction in AV node  Decreased HR – lengthens diastole, improve coronary perfusion, increase regional MvO2, improves balance btw myocardial oxygen supply, demand

Question 164

Potential AEs of Beta Blockers

Answer 164

 Prolonged systolic ejection time  Dilation of ventricles  Increase in coronary vascular resistance  (due to antagonism of coronary vasodilatory B 2 receptors)

Question 165

How Do Beta Blockers Control HR/CO?

Answer 165

through reduction of HR, CO via inhibition of renin-angiotensin system due to blockade of Beta 1 receptors at juxtaglomerular apparatus  Reduced circulating angiotensin II ameliorates vasoconstriction that also drives secretion of aldosterone

Question 166

High Doses of Beta Blockers

Answer 166

(irrespective of Beta 1 selectivity) = bronchospasm via blockade of 2 R in bronchioles (opposing tonic sympathetically mediated bronchodilation) Will also see increased or decreased BG

Question 167

B1 Selective

Answer 167

>P: atenolol, esmolol, metoprolol

Question 168

Non B Selective

Answer 168

pindolol, propranolol, sotalol

Question 169

Atenolol

Answer 169

Prescribed to delay onset of adverse sequelae in cats with HCM or management of ventricular arrhythmias (cats and dogs) Beta 1 R antag - PO

Question 170

Esmolol

Answer 170

 High B1 selectivity  No intrinsic sympathomimetic activity, no membrane stabilizing properties  Very lipophilic: rapid onset, offset with IV use Beta blocker of choice under GA for tachycardia, hypertension, acute SVT associated with SNS activity

Question 171

Metabolism of Esmolol

Answer 171

 Rapidly metabolized by red blood cell esterases to essentially inactive metabolite (long half life) and methanol

Question 172

Metoprolol

Answer 172

Relatively selective for B1 receptor, no intrinsic sympathomimetic activity Rapidly absorbed from gut, very high first-pass metabolism * Oral bioavailability ~50% across species HL 2hr, urinary excretion

Question 173

Pindolol

Answer 173

Non-selective Beta antagonist Intrinsic sympathomimetic, membrane-stabilizing properties Also a serotonin receptor antagonist, may potentiate analgesia provided by tramadol in dogs

Question 174

Propanolol

Answer 174

Non-selective beta adrenergic antagonist without intrinsic sympathomimetic activity Racemic mixture * S- isomer = most of therapeutic cardiac effects of drug * R-isomer = prevents peripheral conversion of thyroxine (T4) to T3 Vet med = control HR, hypertension before thyroidectomy of cats with hyperthyroidism

Question 175

Sotalol

Answer 175

Non selective B adrenergic antagonist without intrinsic sympathomimetic activity Class III antiarrhythmic, potassium channel -blocking effects Use: PO treatment of vtach * Boxer dogs with familial ventricular arrhythmias: decrease VPCs Excreted unchanged in urine – renal impairment will significantly reduce clearance

Question 176

Nitroglycerin

Answer 176

Venodilator: organic nitrate that acts principally on **venous capacitance vessels, large coronary arteries** to produce **peripheral blood pooling, decrease cardiac ventricular wall tension**

Question 177

MOA Nitroglycerin

Answer 177

Nitroglycerin generates NO = stimulation of cGMP, vasodilation Requires presence of thio-containing compounds, nitrate group biotransformed to NO via glutathione-dependent pathways

Question 178

Sodium Nitroprusside

Answer 178

Direct acting, nonselective peripheral VD – relaxation of arterial/venous SmM Elicits arterial, venous dilation via liberation of potent endogenous vasodilator nitric oxide (NO) - Cyanide ions also produced as a by-product  Lacks significant effects on non-vascular SmM, CaM

Question 179

Effects of SNP

Answer 179

BRR-mediated response to SNP-induced decrease in SBP: tachycardia, increased contractility, may oppose decreased BP induced by SNP Decreased venous return, increased peripheral SNS output = decreased impedance to LV ejection, decreases afterload, increases CO LV failure: SNP decreases SVR, PVR, RAP

Question 180

Coronary Steal Assoc with SNP

Answer 180

* SNP dilates resistance vessels in non-ischemic myocardium * Diversion of BF away from ischemic areas where collateral blood vessels already maximally dilated * Decreased DAP may also contribute to MI vi decreased CPP, assoc CBF

Question 181

SNP - Words of Wisdom

Answer 181

 Can cause inadvertent hypotension or reflex tachycardia  Very potent: requires careful titration, ideally monitor via direct ABP

Question 182

Other Effects of SNP

Answer 182

Cyanide Toxicity

Question 183

Cyanine Toxicity

Answer 183

Cyanide ions produced with NO from SNP metabolized by liver to thiocyanate, then excreted in kidneys If overdose or hepatic or renal insufficiency = risk of cyanide, thiocyanate toxicity * When sulfur donors, Methgb exhausted, CN radicals accumulate * Tissue anoxia, anaerobic metabolism, lactic acidosis

Question 184

Cyanine Toxicity CS

Answer 184

Tachycardia, hyperventilation, metabolic acidosis (cyanide binds cytochrome oxidase, thereby inhibiting aerobic metabolism), seizures * Mixed venous PO2 will increase in presence of cyanide toxicity (tissues cannot uptake oxygen) Metabolic acidosis o Lactate >10mM = blood cyanide >40uM (anaerobic metabolism) Decreased cerebral oxygen use, increased cerebral O2 content – CNS dysfunction

Question 185

Tx Cyanine Toxicity

Answer 185

DC SNP, place on 100% oxygen despite normal saturation Give NaHCO3 to correct metabolic acidosis: 0.3 x BW (kg) x BE **Sodium thiosulfate** 6mg/kg/hr IV (dogs) – acts as sulfur donor to convert cyanide to thiocyanate **Sodium nitrate** – converts Hgb to MetHgb, converts cyanide to cyanometHgb **Hydroxycobalamin (vitamin B12a)** binds to cyanide to form cyanocobalamin (vitamin B12) **Methylene blue** will convert MetHgb to Hgb

Question 186

Hydralazine

Answer 186

o Direct systemic arterial VD: hyperpolarizes SmM, activates guanylate cyclase to produce vasorelaxation o Arterial vasodilation causes reflex SNS stimulation = increase in HR, contractility

Question 187

NO

Answer 187

Administered via inhalation (iNO) – leads to relaxation of pulmonary arterial vasculature o Synthetized in endothelial cells from L-arginine by NO-synthase = “Endothelial-derived relaxing factor”

Question 188

iNO MOA

Answer 188

Large role in vascular tone (deficiency in hypertension) NO binds to iron of heme-based proteins : avidly bound, inactivated by Hgb: t1/2 <5s under normal conditions o Why iNO only affects pulmonary vasculature, not peripheral Nitrovasodilators work via generation of NO t/o vasculature

Question 189

iNO Pulmonary Vasodilation

Answer 189

iNO – pulmonary arterial VD proportional to degree of pulmonary VC * Less effect on PVR if pulmonary vascular tone not increased ie PH that is not primary * Can improve oxygenation by decreasing VQ mismatch

Question 190

Toxicity Assoc with iNO

Answer 190

iNO can increase metHgb: life-threatening rebound arterial hypoxemia, pulmonary hypertension may accompany discontinuation of NO * Must wean patients off slowly

Question 191

Silo-Fillers Disease

Answer 191

NO --> oxidation > NO2 > pulmonary toxin * “Silo-filler’s Disease:” chemical pneumonitis, alveolar damage, acute hemorrhagic pulmonary edema * May be NO + O2 product

Question 192

Fenoldopam

Answer 192

Dopamine type 1 R agonist: systemic arterial VD through increased cAMP Increases RBF, urine output – increases splanchnic BF DT lots of DA1 R

Question 193

SE Effects Fenoldopam

Answer 193

Can get BRR-mediated increase in HR, plasma catecholamine concentrations  Also increases ICP

Question 194

PDE 3

Answer 194

positive inotropy on intracellular Ca movement

Question 195

PDE 5

Answer 195

selectively inhibit breakdown of cGMP, esp in vascular SmM * High levels of PDE5 in lungs – effective pulmonary vasodilators, esp for PH * Peripheral (systemic) vascular effects modest – more significant when combined with other drugs

Question 196

Sildenafil

Answer 196

Orally active PDE 5 inhibitor - prevent degradation of cGMP-specific PDE 5, resulting in relaxation of pulmonary vascular SmM

Question 197

Amrinone

Answer 197

Selective PDEIII inhibitor – dose-dependent positive inotropic, VD effects * Results in increased CO, decreased LV EDP Increases cardiac index, increases LV stroke index Decreases LV ejection fraction, PWP, PAP, RAP, SVR  Minimal effect on HR

Question 198

SE Amrinone

Answer 198

* Hypotension (VD) esp with rapid bolus, give slower or give VPs * Dose-related thrombocytopenia with chronic PO therapy DT inhibited platelet aggregation * Rare dysrhythmogenic properties: increased Ca will promote arrhythmias o Also increased AV nodal conduction, decreased atrial refractoriness * GI signs, hepatic dysfunction

Question 199

Milrinone

Answer 199

acute LV dysfunction, may potentiate effects of adrenergic agents, increase inotropy in chronic CHF (downregulation of B1 R)  SE: hypotension with fast IV bolus, can increase morbidity, mortality in severe CHF * May cause arrhythmias, fewer effects on platelets

Question 200

Labetalol

Answer 200

o Parenteral, PO antihypertensive – selective a1, nonselective B antagonist effects o Does not work at presynaptic a2 – released NE can further release catecholamines o CV: decreases systolic BP, CO unchanged o Clinically used for hypertensive emergencies o SE: orthostatic hypotension, bronchospasm, CHF, bradycardia, heart block, fluid retention

Question 201

Carvedilol

Answer 201

o Non-selective B antagonist with a1 blocking activity o Used in mild to moderate CHF DT ischemia or cardiomyopathy; also to tx essential (primary) hypertension

Question 202

Role of Na Channel Blockers for Arrhythmia Management

Answer 202

Fast Na channels determine speed of AP = how fast membrane depolarizes Related to conduction velocity: if slow Na channels, slow conduction velocity

Question 203

Prolongation of the refractory Period

Answer 203

-Prolong AP = prolongation of ERP -K channel blockers, delay depolarization

Question 204

Delay of Depolarizing PM potentials

Answer 204

Ca channel blockers reduce PM firing rate Reduce conduction velocity through AV node