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Boards: Pharmacology > Adrenergic Agents and other CV-Modifying Drugs > Flashcards

Adrenergic Agents and other CV-Modifying Drugs Flashcards

1
Q

Sympathomimetics

A

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)

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2
Q

Sympatholytics

A

decrease activation of SNS

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3
Q

Naturally-Occurring Catecholamines

A

Epi, NE, dopamine

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4
Q

Synthetic Catecholamines

A

dobutamine, dopexamine, isoproterenol (isoprenaline), phenylephrine

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5
Q

Direct agonists

A

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

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6
Q

MOA Indirect agonists

A

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

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7
Q

Mixed Agonists

A

Have both indirect, direct agonists effects ie ephedrine

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8
Q

Location a1 R

A

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

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9
Q

Location a2 R

A

throughout CNS, vascular endothelium, platelets

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10
Q

Location beta 1 R

A

Heart (70%)
Juxtaglomerular cells

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11
Q

Location beta 2 R

A

Heart (20%)

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

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12
Q

Location beta 3 R

A

Adipose tissues - agonism = lipolysis

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13
Q

Location dopamine 1 R

A

CNS, vascular SmM, kidney, sympathetic ganglia, others

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14
Q

Location of dopamine 2R

A

CNS, vascular SmM, kidney, sympathetic ganglia, others

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15
Q

MOA a1 R

A

Gq

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16
Q

MOA a2 R

A

Gi/o

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17
Q

MOA beta R

A

Gs

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18
Q

MOA D1

A

Gs

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19
Q

MOA D2

A

Gi/o

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20
Q

Agonist selectivity of a

A

PHE, EPI > NE&raquo_space;>isoproterenol

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21
Q

Agonist selectivity beta 1

A

Isoproterenol > epi =/> NE

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22
Q

Agonist selectivity beta 2

A

Iso > epi&raquo_space;> NE

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23
Q

Structure of catecholamines

A

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

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24
Q

Epinephrine

A

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

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25
Q

Epinephrine formulations/ROA

A

 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

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26
Q

How calculate different epinephrine solutions?

A

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

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27
Q

Epi CV Effects

A
  • 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
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28
Q

aR stimulation by epi

A

-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

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29
Q

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

A

 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

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30
Q

beta 2 R effets of epi

A

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

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31
Q

Beta 1 effects of epi

A

 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

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32
Q

Epinephrine in cats

A

(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

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33
Q

Does epinephrine induce tachyphylaxis?

A

No

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34
Q

Effects of super therapeutic doses of epi

A

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

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35
Q

Unwanted Cardiac Effects of Epi

A

 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

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36
Q

Proarrhythmogenic Effect of Epinephrine

A

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

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37
Q

Arrhythmogenic effects of halothane, epinephrine

A
  • 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
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38
Q

Resp Effects of Epi

A
  • 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
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39
Q

MAC sparing or increasing effect of epi?

A

None

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40
Q

GIT effects of epi

A

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

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41
Q

Metabolic Effects of epi

A
  • 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
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42
Q

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

A

13% increase in metabolic rate

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43
Q

Potassium effect of epi

A

 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

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44
Q

Renal effects of epi

A

 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

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45
Q

UG effects of epi

A

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

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46
Q

Ophthalmic effects of epi

A

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

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47
Q

Epinephrine’s effect on coag

A

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

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48
Q

Epinephrine’s PK

A

 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

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49
Q

Effects of chronic epinephrine secretion

A

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

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50
Q

Epinephrine Reversal

A

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

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51
Q

NE selectivity

A

Agonist at α1=α2, > β1 > (β2)

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52
Q

Clinical use of NE

A

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

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53
Q

NE

A

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

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54
Q

Structure of NE

A

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

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55
Q

CV Effects of NE

A

 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&raquo_space;> 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&raquo_space;> NE
 Venous VC: decreased venous capacitance, increased venous return –> increased SV, CO

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56
Q

NE Unwanted CV Effects

A

 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

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57
Q

Other Unwanted AEs of NE

A

 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

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58
Q

Effects of Chronic NE Release

A

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

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59
Q

NE Metabolic Effects

A

o Minimal metabolic effects

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60
Q

PK NE

A

 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

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61
Q

Dopamine R Selectivity

A

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

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62
Q

DA1

A

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

GPCR: Gs

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63
Q

DA2

A

: 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

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64
Q

Dose-dependent effects of dopamine

A

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

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65
Q

Formulations of dopamine

A

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

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66
Q

Clinical CV Uses of Dopamine

A
  • 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
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67
Q

CV Effects of Dopamine

A

 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

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68
Q

How discontinue a dopamine CRI

A

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

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69
Q

Dogs and dopamine

A

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

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70
Q

Cats and dopamine

A

> 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

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71
Q

Horses and Dopamine

A

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

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72
Q

Adverse CV Effects of Dopamine

A

 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)

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73
Q

Other Unwanted Effects Assoc with DOP

A

 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

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74
Q

Resp Effects of DOP

A

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

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75
Q

Other Effects of DOP

A

 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

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76
Q

Onset, Absorption of DOP

A

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

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77
Q

Metabolism of DOP

A

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

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78
Q

Excretion of DOP

A

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

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79
Q

Dobutamine R Selectivity

A

β1> β2&raquo_space;»α1

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80
Q

Dobutamine

A

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

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81
Q

Main use of dobutamine

A

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

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82
Q

MOA Dobutamine

A

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

83
Q

Formulations of dobutamine

A

12.5-50mg/mL, sodium metabisulfite preservative

84
Q

Horses and Dobutamine (under halothane ax)

A
  • 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
85
Q

Dogs and Dobutamine (under isoflurane ax)

A
  • <10: limited effects on BP; increased CO, HR, SVR
  • Usefulness in improving hemodynamic function?
86
Q

Cats and dobutamine

A
  • <10: limited effects on BP; increased HR
  • decreased SVR DT beta2 – peripheral VD in SkM
87
Q

Other CV Effects of dobutamine

A

 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

88
Q

Potential Unwanted effects of dobutamine

A

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

89
Q

Resp Effects of Dobutamine

A

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

90
Q

PK Effects of Dobutamine

A

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

91
Q

Dopexamine Selectivity

A

β2&raquo_space;> β1, DA-1, DA-2

92
Q

Dopexamine Uses

A

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

93
Q

CV Effects of Dopexamine

A

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

94
Q

Dopexamine in Horses

A

(Halothane) - NOT RECOMMENDED

At high doses, tachycardia, arrhythmias, m twitching, poor recoveries from GA

95
Q

Dopexamine in Dogs

A

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

96
Q

Other Effects of Dopexamine

A

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

97
Q

PK Dopexamine

A

Short half life
Hepatic Metabolism via O-methylation, sulfation

98
Q

Isoproterenol Selectivity

A

B1=B2

VERY potent synthetic catecholamine
NO ALPHA EFFECTS

99
Q

ISOP use in People

A

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

100
Q

ISOP formulation

A

0.2mg/mL solution, light sensitive preservative sodium metabisulfite

101
Q

CV Effects of ISOP

A

 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

102
Q

ISOP and Dogs

A

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

103
Q

Unwanted CP Effects of ISOP

A

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

104
Q

Other effects of ISOP?

A

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

105
Q

PK Effects of ISOP

A

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

EXPENSIVE

106
Q

Other Positive Inotropes

A
  1. Calcium (esp LA)
  2. Digoxin
  3. Pimobendan
107
Q

Calcium

A

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

108
Q

Digoxin

A

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

109
Q

Digoxin - PSNS Effects

A

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

110
Q

Digoxin - positive inotropic effects

A

–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

111
Q

Digoxin - Arrhythmogenic Effects

A

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)

112
Q

SE of digoxin

A

 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

113
Q

Pimobendan

A

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

114
Q

Function of PDE-3 Inhibitor

A

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

115
Q

Pimobendan as Ca Sensitizer

A

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]

116
Q

Other Cardiac Effects of Pimobendan

A

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

117
Q

When to give pimobendan?

A

Always give morning of anesthesia

Contradicted in outflow tract obstructions (?)

118
Q

Other Effects of Pimobendan

A

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

119
Q

PK of Pimobendan

A
  • 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
120
Q

Metabolism of Pimobendan

A

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

121
Q

Phenylephrine selectivity

A

a1 ONLY

122
Q

Phenylephrine

A

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

123
Q

Uses of Phenylephrine

A

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

124
Q

Phenylephrine Formulations

A

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

125
Q

CV Effects

A

Dose-dependent increase in SVR and MAP, reflex reduction in heart rate
* CO minimally altered or falls DT increased afterload with bradycardia

Not Proarrhythmogenic

126
Q

Phenylephrine in Dogs

A
  • > 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
127
Q

Horses and Phenylephrine

A
  • 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
128
Q

Patients that Benefit from Phenylephrine?

A

If arrhythmogenic

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

129
Q

Phenylephrine in Cats

A
  • 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
130
Q

Other Effects of Phenylephrine

A

 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!)

131
Q

Methoxamine

A

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

132
Q

B2 R Agonists:

A

clenbuterol , albuterol (salbutamol), terbutaline

Uses: management of bronchospasm, hypoxemia in horses

133
Q

Clenbuterol Uses

A

illegally to increase muscle mass, reduce fat composition of production animals

Clenbuterol: COPD in horses

Delay parturition in cattle via uterine relaxation (clenbuterol inj)

134
Q

Limitations of Administration of Inhalation Beta 2 Agonists

A

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

135
Q

CV Effects of Beta 2 Agonists

A

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

136
Q

Other Effects of Beta 2 Agonists

A

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

137
Q

Clenbuterol IV for Tx Hypoxemia in Horses

A

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

138
Q

Albuterol IN for Tx Hypoxemia in Horses

A

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

use is supported

139
Q

Bronchospasm in Cats

A

Face mask or terbutaline for BAL or bronchoscopy

140
Q

Ephedrine

A

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

141
Q

Limitations of Ephedrine

A

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

142
Q

Other Effects of Ephedrine

A

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

143
Q

Resp Effects of Ephedrine

A

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

144
Q

CV Effects Ephedrine

A

Increase CO, HR, BP, coronary BF, MVO2

145
Q

Metabolism of Ephedrine

A

rapid N-demethylation to norephedrine in dogs, ponies

Norephedrine = active metabolite

146
Q

Metaraminol

A

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

147
Q

Vasopressin

A

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

148
Q

Uses of Vasopressin

A

 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

149
Q

Desmopressin

A

VP Analogue

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

150
Q

Uses of Desmopressin

A

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

151
Q

Prazosin

A

Highly selective a1 antagonist
Sympatholytic, quinazoline derivative

Primarily for management of functional UO in cats, dogs

152
Q

CV Effects Prazosin

A

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

153
Q

SE Prazosn

A

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

154
Q

PK in Dogs

A

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

155
Q

Other Uses of Prazosin

A

+/- use for tx of pheochromocytoma

Prazosin + B blocker = refractory hypotension during regional ax DT blunted a, b responses

156
Q

Phentolamine

A

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

157
Q

MOA Phentolamine

A

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

158
Q

Phenoxybenzamine

A

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

159
Q

Main use of Phenoxybenzamine

A

 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

160
Q

SE Phenoxybenzamine

A

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

161
Q

Consequence of chronic beta blocker use?

A

increases # of betaadrenergic R

Myocardium: 75% B1, 20% B2

162
Q

Beta Blockers - Dose Response Curve

A

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

163
Q

MOA Beta Blockers

A

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

164
Q

Potential AEs of Beta Blockers

A

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

165
Q

How Do Beta Blockers Control HR/CO?

A

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

166
Q

High Doses of Beta Blockers

A

(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

167
Q

B1 Selective

A

> P: atenolol, esmolol, metoprolol

168
Q

Non B Selective

A

pindolol, propranolol, sotalol

169
Q

Atenolol

A

Prescribed to delay onset of adverse sequelae in cats with HCM or management of ventricular arrhythmias (cats and dogs)

Beta 1 R antag - PO

170
Q

Esmolol

A

 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

171
Q

Metabolism of Esmolol

A

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

172
Q

Metoprolol

A

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

173
Q

Pindolol

A

Non-selective Beta antagonist

Intrinsic sympathomimetic, membrane-stabilizing properties

Also a serotonin receptor antagonist, may potentiate analgesia provided by tramadol in dogs

174
Q

Propanolol

A

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

175
Q

Sotalol

A

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

176
Q

Nitroglycerin

A

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

177
Q

MOA Nitroglycerin

A

Nitroglycerin generates NO = stimulation of cGMP, vasodilation

Requires presence of thio-containing compounds, nitrate group biotransformed to NO via glutathione-dependent pathways

178
Q

Sodium Nitroprusside

A

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

179
Q

Effects of SNP

A

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

180
Q

Coronary Steal Assoc with SNP

A
  • 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
181
Q

SNP - Words of Wisdom

A

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

182
Q

Other Effects of SNP

A

Cyanide Toxicity

183
Q

Cyanine Toxicity

A

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

184
Q

Cyanine Toxicity CS

A

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

185
Q

Tx Cyanine Toxicity

A

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

186
Q

Hydralazine

A

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

187
Q

NO

A

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”

188
Q

iNO MOA

A

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

189
Q

iNO Pulmonary Vasodilation

A

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

190
Q

Toxicity Assoc with iNO

A

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

191
Q

Silo-Fillers Disease

A

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

192
Q

Fenoldopam

A

Dopamine type 1 R agonist: systemic arterial VD through increased cAMP

Increases RBF, urine output – increases splanchnic BF DT lots of DA1 R

193
Q

SE Effects Fenoldopam

A

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

194
Q

PDE 3

A

positive inotropy on intracellular Ca movement

195
Q

PDE 5

A

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

196
Q

Sildenafil

A

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

197
Q

Amrinone

A

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

198
Q

SE Amrinone

A
  • 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
199
Q

Milrinone

A

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

200
Q

Labetalol

A

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

201
Q

Carvedilol

A

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

202
Q

Role of Na Channel Blockers for Arrhythmia Management

A

Fast Na channels determine speed of AP = how fast membrane depolarizes

Related to conduction velocity: if slow Na channels, slow conduction velocity

203
Q

Prolongation of the refractory Period

A

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

204
Q

Delay of Depolarizing PM potentials

A

Ca channel blockers

reduce PM firing rate

Reduce conduction velocity through AV node

Boards: Pharmacology (9 decks)

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