Anti-hypertensives Part II Flashcards
Nitroglycerin
MOA
E1/2t
- Generates NO through a glutathione-dependent pathway which involves glutathione S-transferase
- NO then stimulates cGMP to cause peripheral vasodilation
- E1/2- 1.5 minutes
How does nitroglycerin cause methemoglobinemia?
How is metHgb treated?
- Nitrite metabolite oxidizes ferrous ion in Hgb to ferric form which leads to the formation of metHgb
- Caution with high doses
- Treated with methylene blue 1-2 mg/kg IV over 5 min to reconvert metHgb to Hgb
What are the CV effects of Nitroglycerin?
- venodilation
- decreased venous return (preload)
- decrease L and R ventricular end-diastolic pressure
- decrease CO
- no change, or slight change to HR
- b/c drop in BP is not as significant so the baroreceptors dont respond
- No change to SVR
- Increase in coronary blood flow to ischemic subendocardial areas (opposite of SNP)
Nitroglycerin systemic effects:
CNS
Pulm
Heme
GI
- CNS- vasodilation, increased ICP, HA
- Pulm
- decreased PVR
- bronchial dilation
- inhibits hypoxic pulmonary vasoconstriction
- Heme- inhibits platelet aggregation causing dose related prolonged bleeding time
- GI- relaxes smooth muscles of GI tract
- this is why it is one of the treatment options for SOO spasm
What are the clinical uses of nitroglycerin?
- Angina
- venodilation and increased venous capacitance decreases venous return to the heart which reduces RVEDP and LVEDP
- reduces myocardial O2 requirements by reducing cardiac work
- Cardiac failure
- decreases preload
- relieves pulmonary edema
- limits damage of MI
- Controlled hypotension
- less potent than SNP, better choice
- Sphinctor of Oddi spasm
- during laparoscopic cholecystectomy or opioid use
- bolus 200 mcg (1 ml) at a time
What is the dose if you are using Nitroglycerin for controlled hypotension?
when is it NOT recommended?
- start at 10-20 mcg/min
- titrate by increasing 5-10 mcg/min every 5-10 min
- usual dosage 50-200 mcg/min; max 500 mcg/min
- NOT recommended in cranial surgery prior to opening the dura
Isosorbid Dinitrate
Use
administration
How does it work?
SE
Active metabolite
- used to treat angina
- Administered PO (DOA 6 hours) or SL (DOA 2 hours)
- Works predominantly on venous circulation, improves regional distribution of myocardial blood flow in patients with CAD
- Side effects: Orthostatic hypotension
- Active metab: isosorbid-5-mononitrate
- more active than parent drug
Trimethaphan
what does it do?
dose
onset
SE
- Ganglionic blocker and peripheral vasodilator
- blocks the ANS and relaxes capacitance vessels
- lowers SVR,BP, CO
- Can have increased HR d/t PNS blockade, not becasue of baroreceptors
- Dose: 10-200 mcg/kg/min IV
- Onset: rapid onset, must be given continuously
- Side effects:
- mydriasis, decreased GI activity, urinary retention
What are the three major classes of Ca channel blockers?
What drugs belong to each class?
- Dihydropyridines- more effect on Ca channels in vasculature (-pine)
- Nifedipine
- Amlodipine
- Nicardipine
- Felodipine
- Phenylalkylamines- more effect on Ca channels on the heart
- Verapamil
- Modified Benzothiazepines- works on both heart and vasculature
- Diltiazem
Why do the different classes of CCBs work in different places?
- Because the different classes bind to different places on the Ca channels
- Dihydropyridines- cause extracellular allosteric modulation of the channel at the binding site
- Phenylalkylamine- pore blocker of channel at the binding site
- Benzothiazepine- mechanism unclear
Where are L-type Ca channels found?
- vascular smooth muscle- predominatlye arterial
- SA node
- AV node
- Cardiac myocytes
Which CCBs block entry of Ca, and what does that cause?
- All classes block entry of Ca
- Causes:
- decreased contractility in cardiac muscle
- Coronary vascular dilation (good choice in variant angina)
- Systemic arterial diltation (artery > vein) causing decreased afterload, wall tension and BP
Which CCBs slow Ca channel recovery?
What does this cause?
Who should you avoid these drugs in?
- Phenylalkylamines
- Causes:
- SA node: chronotropic effect, decreasing HR
- AV node: dromotropic effect, decreasing conductivity and HR
- **Avoid in pt with uncompensated HF, bradycardia, or heart block
During what part of the ventricular action potention do CCBs have effect?
- Ventricular cardiomyocyte (pic below)
- During plateau phase, which is why it decreases contractility
- SA/AV node (front pic)
- During the initial depolarization in phase 0, slowing the depolarizing rate and lengthening the recovery phase to decrease HR
What are some anesthetic specific drug interactions with CCBs?
- Myocardial depression and vasodilation with IA
- Can potentiate NMB
- Verapamil contraindicated with Beta blockers
- Verapamil increases risk of LA toxicity
- cardiac toxic?
- Verapamil and dantrolene can cause hyperkalemia due to slowing of inward movement of K ions can result in cardiac collapse
What are some general (non anesthetic) drug interactions with CCBs?
How can CCB toxicity be reversed?
- Digoxin- CCBs can increase the plasma concentration of digoxin by decreasing its plasma clearance
- H2 antagonists- ranitidine and cimetidine alter hepatic enzyme activity and thus could increase plasma levels of CCB
- CCB toxicity can be reversed with IV Calcium or dopamine
Verapamil
Classification
primary site of acction
effects
- Phenylalkylamine; synthetic derivative of papaverine
- levoisomer is specific to the slow Ca channel
- Primary site of action is the AV node
- depresses the AV node
- negative chronotropic effect on SA node
- negative inotropic effect on myocardial muscle
- moderate vasodilation on coronary as well as systemic arteries
What are the clinical uses of verapamil?
- SVT
- vasospastic angina
- HTN
- hypertrophic cardiomyopathy
- maternal and fetal tachydysrhythmias
- premature onset of labor
Verapamil Pharmacokinetics:
PB
absorption
metabolite
peak
E1/2t
- 90% PB; presence of other agents such as lidocaine, diazepam, propranolol will increase activity
- Orally almost completely absorbed with extensive hepatic first pass metabolism
- PO dose 10x higher than IV dose
- Active metabolite: norverapamil
- Oral peak: 30-45 minutes; IV peak 15 minutes
- E1/2t = 6-12 hours
Nifedipine
CCB class
clinical uses
Primary site of action/effect
- Dihydropyridine derivative
- Clinical uses
- angina
- HTN
- Primary site of action: peripheral arterioles
- coronary and peripheral vasodilator properties > verapamil
- little to no effect on SA or AV node
- decrease SVR and BP
- reflex tachycardia
- can produce myocardial depression in pts with LV dysfunction or on BBs
Nifedipine pharmacokinetics
route
PB
metabolism
E1/2
- IV, oral or SL
- Oral effects seen in 20 minutes, peak in 60-90 min
- 90% PB
- Nearly completely hepatically metabolised and metabolites excreted in urine
- E1/2t is 3-7 hours
Nifedipine Side effects
- vertico
- HA
- flushing
- hypotension
- paresthesias
- muscle weakness
- can induce renal dysfunction
- coronary vasospasm with abrupt d/c
Diltiazam
CCB class
principle site of action
uses
- Benzothiazepines derivative
- Principle site of action is the AV node
- Uses
- 1st line tx for SVT
- HTN
- Intermediate potency between verapamil and nifedipine
- minimal CV depressant effects
- do not combine with BB
What are some other clinical uses of Diltiazam?
Route
Dose
- Vasospastic angina
- hypertrophic cardiomyopathy
- maternal and fetal tachydysrhythmias
- Route: PO or IV
- Dose: 0.25-0.35 mg/kg over 2 min; can repeat in 15 min
Diltiazem pharmacokinetics
oral onset
PB
E1/2t
- Oral onset is 15 min and peaks in 30 min
- 70-80% PB
- Excreted in the bile and urine
- E1/2t is 4-6 hours
- Liver disease may require a decrease in dose
Chart comparing the prototypes of the three classes of CCBs
Selectivity
Adverse effects
contraindications
drug interactions
What are the two centrally acting anti-hypertensive agents?
MOA?
Clinical uses?
- Clonidine and dexmedetomidine
- MOA: selective alpha-2 agonist that reduces sympathetic outflow from vasomotor centers in the brain stem
- Clonidine site of action: Alpha-2 receptors in CNS
- Clinical uses:
- hypertension
- sedation
- decrease anesthetic requirements
- improve peri-op hemodynamics
- analgesia
Clonidine results in ______
Rebound hypertension can be caused by ______.
- clonidine results in BP reduction from decreased CO d/t decreased HR and peripheral resistance
- Rebound HTN can be caused by abrupt cessation (withdrawal)
What are the side effects of the centrally acting agents?
- bradycardia
- sedation
- xerostomia (dry mouth)
- impaired concentration
- nightmares
- depression
- vertigo
- EPS
- lactation in men
Pharmacokinetics of centrally acting agents
route
metab
- Available as PO or transdermal patch
- 50/50 hepatic metabolism and renal excretion
When does withdrawal syndrome occur with patients on centrally acting agents?
- Occurs in pts on doses of >1.2 mg/day
- Occurs 18 hours after acute d/c of drug
- lasts 24-72 hours
- Can be treated by rectal or transdermal clonidine
Which anti hypertensives do you have the pt continue before surgery?
Which ones do you hold?
why?
- Give BB- b/c it reduces peri-op MI
- Give CCBs- benefits outweigh risks unless severe LV dysfunction
- Hold ACE inhibitors- for one or two dose intervals, depending on DOA of drug
- will cause labile BPs during procedure
What is considered a hypertensive crisis?
How can you treat it?
- DBP > 120 mmHg with evidence of end organ failure
- Goal to decrease DBP to 100-105 mmHg ASAP
- Treatment:
- NTP- most effective, first choice
- NTG
- Labetalol
