Adrenergic Agents and other CV-Modifying Drugs Flashcards
Sympathomimetics
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)
Sympatholytics
decrease activation of SNS
Naturally-Occurring Catecholamines
Epi, NE, dopamine
Synthetic Catecholamines
dobutamine, dopexamine, isoproterenol (isoprenaline), phenylephrine
Direct agonists
endogenous (NE, EPI), sympathomimetic (Phenylephrine, dobutamine)
MOA Indirect agonists
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
Mixed Agonists
Have both indirect, direct agonists effects ie ephedrine
Location a1 R
SmM: BV, bronchi, GI, uterus, urinary system
Pupillary dilator m
Splenic capsule
Location a2 R
throughout CNS, vascular endothelium, platelets
Location beta 1 R
Heart (70%)
Juxtaglomerular cells
Location beta 2 R
Heart (20%)
SmM: BV, bronchi, GIT, uterus, urinary system
Liver
Location beta 3 R
Adipose tissues - agonism = lipolysis
Location dopamine 1 R
CNS, vascular SmM, kidney, sympathetic ganglia, others
Location of dopamine 2R
CNS, vascular SmM, kidney, sympathetic ganglia, others
MOA a1 R
Gq
MOA a2 R
Gi/o
MOA beta R
Gs
MOA D1
Gs
MOA D2
Gi/o
Agonist selectivity of a
PHE, EPI > NE»_space;>isoproterenol
Agonist selectivity beta 1
Isoproterenol > epi =/> NE
Agonist selectivity beta 2
Iso > epi»_space;> NE
Structure of catecholamines
o Benzene ring + various amide side chains at C1 position
o Catecholamine: when hydroxyl group present at C3, C4; catechol: 3,4-dihydroxybenzene
Epinephrine
non-selective, direct agonist at β1=β2 > α1= α2
Epinephrine formulations/ROA
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
How calculate different epinephrine solutions?
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
Epi CV Effects
- 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
aR stimulation by epi
-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
What determines epinephrine’s effect on BF to a particular organ?
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
beta 2 R effets of epi
b2: SkM dilation
* More sensitive to epi at lower doses
Beta 1 effects of epi
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
Epinephrine in cats
(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
Does epinephrine induce tachyphylaxis?
No
Effects of super therapeutic doses of epi
acute heart failure, pulmonary edema, arrhythmias, hypertension, myocardial infarction
Unwanted Cardiac Effects of Epi
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
Proarrhythmogenic Effect of Epinephrine
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
Arrhythmogenic effects of halothane, epinephrine
- 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
Resp Effects of Epi
- 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
MAC sparing or increasing effect of epi?
None
GIT effects of epi
Relaxation of gastric SmM
Hepatosplanchnic VC – greater impairment of splanchnic circulation than NE or DOP
Metabolic Effects of epi
- 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
What is the increase in metabolic rate per 1*C?
13% increase in metabolic rate
Potassium effect of epi
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
Renal effects of epi
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
UG effects of epi
beta R relax detrusor m of bladder, alpha R contracts trigone, sphincter m
Ophthalmic effects of epi
mydriasis, exophthalmos (ctx of orbital m, likely a1)
Epinephrine’s effect on coag
Accelerates coagulation, potent inducer of platelet aggregation, increases factor V activity
Epinephrine’s PK
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
Effects of chronic epinephrine secretion
Decreased plasma volume DT loss of protein-free fluid in ECF
Arterial wall damage
Local myocardial necrosis
Epinephrine Reversal
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
NE selectivity
Agonist at α1=α2, > β1 > (β2)
Clinical use of NE
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
NE
o Endogenous NT synthetized/stored in postganglionic sympathetic nerve endings
Released with SNS stimulation
o Immediate precursor to epi
Structure of NE
Absence of methyl group on nitrogen atom vs epi
Formulation: 1mg/ml solution bitartrate salt
CV Effects of NE
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»_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»_space;> NE
Venous VC: decreased venous capacitance, increased venous return –> increased SV, CO
NE Unwanted CV Effects
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
Other Unwanted AEs of NE
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
Effects of Chronic NE Release
Similar to epi
Precapillary VC
Loss of protein-free fluid into ECF
NE Metabolic Effects
o Minimal metabolic effects
PK NE
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
Dopamine R Selectivity
Effects, receptors dose dependent; DA-1=DA-2 > β1 > β2 > α1, a2
DA1
postsynaptic, activation (mediated via AC) elicits VD in renal, mesenteric, coronary, cerebral vascular beds, inhibition of Na-K ATPase pumps
GPCR: Gs
DA2
: 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
Dose-dependent effects of dopamine
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
Formulations of dopamine
40mg/mL dopamine HCl sln, preservative sodium metabisulfite
Dopamine HCl 100mL dextrose 5%, 0.8-6.4mg/mL
Clinical CV Uses of Dopamine
- 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
CV Effects of Dopamine
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
How discontinue a dopamine CRI
Decrease dose in stepwise manner DT decrease in CO/MAP after cessation
Dogs and dopamine
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
Cats and dopamine
> 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
Horses and Dopamine
– 5mcg/kg/min increases myocardial contractility, CO with little effect on BP (decreased smooth muscle tone by stim of DA-1 and DA-2)
Adverse CV Effects of Dopamine
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)
Other Unwanted Effects Assoc with DOP
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
Resp Effects of DOP
No inhibition of HPV
May decrease PVR in patients with COPD
Improves resp m contraction
Increases lung edema clearance
Inhibition of bronchoconstriction
Other Effects of DOP
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
Onset, Absorption of DOP
Short half life, ~3min – requires CRI
Slower onset, up to 5 min
No PO absorption
Metabolism of DOP
Metabolized by monoamine oxidase, catechol-O-methyltransferase in liver, kidney, and plasma
Excretion of DOP
Excreted in urine as sulfate and glucuronide conjugates
25% converted to NE in sympathetic nerve terminals
Dobutamine R Selectivity
β1> β2»_space;»α1
Dobutamine
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
Main use of dobutamine
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
MOA Dobutamine
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
Formulations of dobutamine
12.5-50mg/mL, sodium metabisulfite preservative
Horses and Dobutamine (under halothane ax)
- 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
Dogs and Dobutamine (under isoflurane ax)
- <10: limited effects on BP; increased CO, HR, SVR
- Usefulness in improving hemodynamic function?
Cats and dobutamine
- <10: limited effects on BP; increased HR
- decreased SVR DT beta2 – peripheral VD in SkM
Other CV Effects of dobutamine
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
Potential Unwanted effects of dobutamine
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
Resp Effects of Dobutamine
Inhibits HPV, lower PAP/PVR
Potential to worsen VQ mismatch
PK Effects of Dobutamine
Short half life
Primarily metabolized via catechol-O-methyltransferase in liver to inactive metabolites that are conjugated and excreted in urine
Dopexamine Selectivity
β2»_space;> β1, DA-1, DA-2
Dopexamine Uses
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
CV Effects of Dopexamine
–Cardiac β2 – positive inotropic effect, drop of systemic BP (vasodilation particularly in SkM) –> promotes increased CO
Dopexamine in Horses
(Halothane) - NOT RECOMMENDED
At high doses, tachycardia, arrhythmias, m twitching, poor recoveries from GA
Dopexamine in Dogs
Increase CO, HR in dose-dependent manner
Lower arrhythmogenic potential vs DOP
Other Effects of Dopexamine
–BD
–Increased GI, RBF DT increased CO, reduced regional vascular resistance
–Increased UO
PK Dopexamine
Short half life
Hepatic Metabolism via O-methylation, sulfation
Isoproterenol Selectivity
B1=B2
VERY potent synthetic catecholamine
NO ALPHA EFFECTS
ISOP use in People
Increase HR, myocardial contractility – promote arrhythmias during EP studies (humans)
Low doses: test dose to detect IV needle placement during epidural in children
ISOP formulation
0.2mg/mL solution, light sensitive preservative sodium metabisulfite
CV Effects of ISOP
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
ISOP and Dogs
Dogs, very low dose infusion (0.1, isoflurane): increase CO, HR while increasing myocardial BF – maintained adequate myocardial oxygenation
Unwanted CP Effects of ISOP
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
Other effects of ISOP?
Increases splanchnic, renal BF
β receptor – increase in BG, free fatty acid concentrations, decrease in serum K DT shift of K into cells
PK Effects of ISOP
Short half life
Metabolized by catechol-O-methyltransferase in liver
Unchanged or conjugated sulfates excreted in urine
EXPENSIVE
Other Positive Inotropes
- Calcium (esp LA)
- Digoxin
- Pimobendan
Calcium
Fxn: + inotrope
Tx hypotension in LA, raises threshold potential for AP during tx for hyperkalemia
iCa affects pH, albumin, can be proarrhythmogenic (hypercalcemia, parathyroidectomy)
Digoxin
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
Digoxin - PSNS Effects
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
Digoxin - positive inotropic effects
–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
Digoxin - Arrhythmogenic Effects
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)
SE of digoxin
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
Pimobendan
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
Function of PDE-3 Inhibitor
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
Pimobendan as Ca Sensitizer
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]
Other Cardiac Effects of Pimobendan
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
When to give pimobendan?
Always give morning of anesthesia
Contradicted in outflow tract obstructions (?)
Other Effects of Pimobendan
Antithrombotic effects in dogs at supraclinical doses
Alterations of proinflammatory cytokines
PK of Pimobendan
- 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
Metabolism of Pimobendan
demethylation in liver to more potent metabolite, UDCG-212
* Metabolite = more potent inhibitor of PDEIII, longer half life
Phenylephrine selectivity
a1 ONLY
Phenylephrine
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
Uses of Phenylephrine
Increase SVR –> increase ABP
Topical administration to mucosal surfaces: localized VC, reduce edema/hemorrhage
Horses: medical management of nephrosplenic entrapment, splenic ctx
Phenylephrine Formulations
Formulations: 10mg/mL with hydrochloride salt
Nasal decongestants, topical ophthalmic preparations
CV Effects
Dose-dependent increase in SVR and MAP, reflex reduction in heart rate
* CO minimally altered or falls DT increased afterload with bradycardia
Not Proarrhythmogenic
Phenylephrine in Dogs
- > 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
Horses and Phenylephrine
- 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
Patients that Benefit from Phenylephrine?
If arrhythmogenic
Coronary artery dz, AS - increase coronary perfusion pressure without chronotropic YEs
Phenylephrine in Cats
- 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
Other Effects of Phenylephrine
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!)
Methoxamine
a1 agonist - longer DOA vs phenylephrine
Direct VC of arterioles, little effect on capacitance vessels
B2 R Agonists:
clenbuterol , albuterol (salbutamol), terbutaline
Uses: management of bronchospasm, hypoxemia in horses
Clenbuterol Uses
illegally to increase muscle mass, reduce fat composition of production animals
Clenbuterol: COPD in horses
Delay parturition in cattle via uterine relaxation (clenbuterol inj)
Limitations of Administration of Inhalation Beta 2 Agonists
12% of drug delivered to lungs – ETT decreases that 12% by an additional 50-70%
CV Effects of Beta 2 Agonists
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
Other Effects of Beta 2 Agonists
Relaxation of bronchial SmM
Stimulate Na/K ATPase pump – increase K+ uptake by cells, hypokalemia
Increased BG
Clenbuterol IV for Tx Hypoxemia in Horses
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
Albuterol IN for Tx Hypoxemia in Horses
improvement of PaO2
* Predominant MOA: sympathomimetic effect on hemodynamic function
use is supported
Bronchospasm in Cats
Face mask or terbutaline for BAL or bronchoscopy
Ephedrine
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
Limitations of Ephedrine
o Tachyphylaxis with repeat doses DT depletion of NE stores therefore reduction in magnitude of indirect sympathomimetic effects
Other Effects of Ephedrine
Antiemetic effects IM
Mydriasis
CNS stimulation
No hyperglycemia
Resp Effects of Ephedrine
bronchodilation (b2)
Chronic oral medication to tx bronchial asthma PO, 1hr onset time
CV Effects Ephedrine
Increase CO, HR, BP, coronary BF, MVO2
Metabolism of Ephedrine
rapid N-demethylation to norephedrine in dogs, ponies
Norephedrine = active metabolite
Metaraminol
o Synthetic amine: direct, indirect sympathomimetic effects that predominate a with some beta activity
o Increase BP through increase in SVR, CO often falls
Vasopressin
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
Uses of Vasopressin
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
Desmopressin
VP Analogue
Used to treat central diabetes insipidus, management of coagulopathy - reduced vascular effects
Uses of Desmopressin
Perioperative management of von Willebrand disease, management of central diabetes insipidus
Prazosin
Highly selective a1 antagonist
Sympatholytic, quinazoline derivative
Primarily for management of functional UO in cats, dogs
CV Effects Prazosin
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
SE Prazosn
Vertigo
Fluid retention
Orthostatic hypotension
Lethargy
Increased urination
NSAIDS: may interfere with antihypertensive effects
PK in Dogs
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
Other Uses of Prazosin
+/- use for tx of pheochromocytoma
Prazosin + B blocker = refractory hypotension during regional ax DT blunted a, b responses
Phentolamine
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
MOA Phentolamine
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
Phenoxybenzamine
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
Main use of Phenoxybenzamine
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
SE Phenoxybenzamine
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
Consequence of chronic beta blocker use?
increases # of betaadrenergic R
Myocardium: 75% B1, 20% B2
Beta Blockers - Dose Response Curve
RIGHT displacement of dose response curve DT competitive inhibition
At high enough doses, agonists can still exert full effect
MOA Beta Blockers
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
Potential AEs of Beta Blockers
Prolonged systolic ejection time
Dilation of ventricles
Increase in coronary vascular resistance (due to antagonism of coronary vasodilatory B 2 receptors)
How Do Beta Blockers Control HR/CO?
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
High Doses of Beta Blockers
(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
B1 Selective
> P: atenolol, esmolol, metoprolol
Non B Selective
pindolol, propranolol, sotalol
Atenolol
Prescribed to delay onset of adverse sequelae in cats with HCM or management of ventricular arrhythmias (cats and dogs)
Beta 1 R antag - PO
Esmolol
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
Metabolism of Esmolol
Rapidly metabolized by red blood cell esterases to essentially inactive metabolite (long half life) and methanol
Metoprolol
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
Pindolol
Non-selective Beta antagonist
Intrinsic sympathomimetic, membrane-stabilizing properties
Also a serotonin receptor antagonist, may potentiate analgesia provided by tramadol in dogs
Propanolol
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
Sotalol
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
Nitroglycerin
Venodilator: organic nitrate that acts principally on venous capacitance vessels, large coronary arteries to produce peripheral blood pooling, decrease cardiac ventricular wall tension
MOA Nitroglycerin
Nitroglycerin generates NO = stimulation of cGMP, vasodilation
Requires presence of thio-containing compounds, nitrate group biotransformed to NO via glutathione-dependent pathways
Sodium Nitroprusside
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
Effects of SNP
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
Coronary Steal Assoc with SNP
- 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
SNP - Words of Wisdom
Can cause inadvertent hypotension or reflex tachycardia
Very potent: requires careful titration, ideally monitor via direct ABP
Other Effects of SNP
Cyanide Toxicity
Cyanine Toxicity
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
Cyanine Toxicity CS
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
Tx Cyanine Toxicity
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
Hydralazine
o Direct systemic arterial VD: hyperpolarizes SmM, activates guanylate cyclase to produce vasorelaxation
o Arterial vasodilation causes reflex SNS stimulation = increase in HR, contractility
NO
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”
iNO MOA
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
iNO Pulmonary Vasodilation
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
Toxicity Assoc with iNO
iNO can increase metHgb: life-threatening rebound arterial hypoxemia, pulmonary hypertension may accompany discontinuation of NO
* Must wean patients off slowly
Silo-Fillers Disease
NO –> oxidation > NO2 > pulmonary toxin
* “Silo-filler’s Disease:” chemical pneumonitis, alveolar damage, acute hemorrhagic pulmonary edema
* May be NO + O2 product
Fenoldopam
Dopamine type 1 R agonist: systemic arterial VD through increased cAMP
Increases RBF, urine output – increases splanchnic BF DT lots of DA1 R
SE Effects Fenoldopam
Can get BRR-mediated increase in HR, plasma catecholamine concentrations
Also increases ICP
PDE 3
positive inotropy on intracellular Ca movement
PDE 5
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
Sildenafil
Orally active PDE 5 inhibitor - prevent degradation of cGMP-specific PDE 5, resulting in relaxation of pulmonary vascular SmM
Amrinone
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
SE Amrinone
- 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
Milrinone
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
Labetalol
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
Carvedilol
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
Role of Na Channel Blockers for Arrhythmia Management
Fast Na channels determine speed of AP = how fast membrane depolarizes
Related to conduction velocity: if slow Na channels, slow conduction velocity
Prolongation of the refractory Period
-Prolong AP = prolongation of ERP
-K channel blockers, delay depolarization
Delay of Depolarizing PM potentials
Ca channel blockers
reduce PM firing rate
Reduce conduction velocity through AV node
