Treatment of Angina Flashcards
Angina
- definition
- treatment
Angina - chest pain caused by reduced blood flow to heart muscles
Treatment:
increase delivery of 02 or decrease 02 demand
Determinants of the volume of O2 required by the heart
- Diastolic factors: blood volume and venous tone
2. Systolic factors: peripheral resistance, heart rate, heart force, ejection time
Agents used in angina
- Organic nitrates (nitroglycerin)
- Calcium antagonists
- B adrenoreceptors antagonists
Organic nitrates (nitroglycerin) -mechanism of action (7)
- Nitroglycerin is converted to Nitric oxide
- NO activates guanylate cyclase
- cGMP synthesis is increased
- Activate protein kinase dependent phosphorylation in smooth muscle
- Dephosphorylation of myosin light chain in smooth muscle
- Decrease preload and wall tension, increase collateral vessel diameter
- Decrease work in the heart, decrease BP = relief angina
Mechanism of the interaction between nitrates and drugs used in erectile dysfunction
-SILDENAFIL - phosphodiesterase-5-inhibitor
- reduce cGMP metabolism
- synergistic effect on blood pressure resulting in dangerous hypotension
Indications: erectile dysfunction, pulmonary hypertension
Nitrates
-names
NITROGLYCERIN (GLYCERYL TRINITRATE)
ISOSORBIDE MONONITRATE
Nitroglycerin
-pharmacokinetics (6)
- liver –> removes nitrate groups from the parent molecule and ultimately inactivates the drug
- oral bioavailability is low
- sublingual route –> avoid first pass effect
- excretion via kidney in the form of glucuronide derivatives
- may loose potency when stored as a result of volatilization, should be kept in glass containers
- short onset and duration of action
Nitroglycerin
-pharmacodynamics
- must be bio-activated with the release of NO
- Activation requires –> denitrated by glutathione-S-transferase (in smooth muscle and other cells), mitochondrial enzyme, aldehydre dehydrogenase isoform 2 and 3 (release NO)
- NO activate guanylyl cyclase
- increase cGMP
- activates protein kinase G
- decrease activity of contractile proteins and intracellular Ca2+
Nitroglycerin
-actions on vascular smooth muscle (4)
- response on veins at lower concentrations than in arteries
- large arteries and large veins relax
- cardiac ouput decrease
- pulmonary vascular pressure and heart size are reduced
Nitroglycerin
- actions on platelets
- other effects
- contraindications
- decrease cGMP –> decrease platelet aggregation
- nitrite ion reacts with hemoglobin –> produce methemoglobin (low affinity for O2)
- intracranial pressure is elevated
Nitroglycerin
- unwanted effects
- tolerance
- orthostatic hypotension, tachycardia, headache
- very large doses –> pseudocyanosis, tissue hypoxia, death
- occurs with continuous exposure
- decrease in tissue cysteine, systemic compensation (sympathetic discharge and retention of salt)
- supplementation of cysteine may partially reverse tolerance
- nitrate free period of at least 8h between doses to reduce or prevent tolerance
Nitrates
-indications (4)
- stable angina –> isosorbide monitrate (oral), nitroglycerin (oral prolonged, sublingual before exertion)
- unstable angina –> nitroglycerin (intravenous)
- acute heart failure –> nitroglycerin (intravenous)
- chronic heart failure –> isosorbide monitrate (oral)
B adrenoreceptors antagonists
- names and function
- effects
Propranolol –> both beta 1 and 2 antagonism
Metoprolol –> b1 selective blocker
Labetolol –> mixed antagonism of both beta and alpha-1 adrenergic receptors, both beta 1 and 2 antagonism, intrinsic sympathomimetic action (ISA), could cause additional vasodilation
Nebivolol –> vasodilation action via NO and b3 stimulating effects, b1 selective blockers
-decrease heart rate and contractility
Intrinsic sympathomimetic action (ISA) (5)
- both agonism and antagonism at a given beta receptor
- depends on the concentration of the beta blocker and the concentration of the antagonized agent
- labetolol exhibit it
- useful in individuals exhibiting excessive bradycardia
- not used after MI, may be less effective than others in the treatment of angina and tachyarrhythmia
Beta blockers
- indications
- unwanted effects
- arrhythmias, angina, MI, hypertension, heart failure, glaucoma, anxiety, migraine
- bronchoconstriction, cardiac depression, bradycardia, hypoglycemia, fatigue, cold extremities
Calcium antagonists (Ca2+ channel blockers)
- names
- mechanism of action
-VERAPAMIL, DILTIAZEM, NIFEDIPINE
- decrease afterload by blocking L-type calcium channels
- verapamil has a smaller effect on vasodilation because it also block vascular smooth muscle potassium channels
- by blocking Ca2+ channels, the amount of calcium intracellularly decrease –> no calcium to activate MLCK –> myosin light chains are not phosphorylated –> contraction doesn’t happen
- cGMP dephosphorylate light chains –> relaxation
Main effects of
- Nifedipine
- Diltiazem
- Verapamil
- decrease BP and vascular resistance (mainly)
- bind to closed channels
- decrease vascular resistance and heart rate (mainly)
- bind to open channels
- decrease heart rate (mainly)
- bind to open channels
Calcium antagonists
- indications
- unwanted effects
- Verapamil: cardio-selective, arrhythmias, migraine
- Diltiazem: angina, MI
- Nifedipine: hypertension, heart failure, Raynaud’s phenomenon
- headache, cardiac failure or heart block, ankle edema, constipation
- nifedipine: tachycardia, vasodilation
- diltiazem: bradycardia, AV node inhibition, constipation, negative inotropic effect
- verapamil: all BUT tachycardia
Which drugs mainly decrease resistance of veins?
Nitrates - nitroglycerin
Cellular and systemic effects of nitrates
Cellular –> nitric oxide is released from nitrates, leading to a higher production of cGMP –> decrease Ca2+ –> relaxation
Systemic –> decrease veins pre-load, better blood supply, pressure to endocardium is lower.
higher doses - act on arteries
lower doses - act on veins
Why does Tolerance happens when using Nitroglycerin?
Because in order to release nitric oxide, enzymatic reactions are necessary and for them we need Sulfhydryl groups.
Those groups could be exhausted, so in order to maintain a normal level all the time, we need some break from nitrates.
Nitroglycerin vs. Isosorbide mononitrate
-pharmacokinetics
Isosorbide mononitrate has a slower onset but a longer duration of action
B blockers mechanism of action
- Beta-1-adrenoreceptor are found in the heart and by blocking them we are able to decrease heart rate and blood pressure.
- Blood pressure is decreased because those receptors are responsible for the release of renin
- they are effective during heart failure because they decrease non-desirable sympathetic effects
How does Labetalol, exhibiting ISA, works effectively?
if a patient with heart failure, have episodes of bradycardia it is dangerous to prescribe beta blockers because it could exacerbate bradycardia. So, in this case Labetalol is useful. It will act as an agonist and no competition with norepinephrine would happen –> heart rate would increase
if the same patient experiences situations that activate the sympathetic system where norepinephrine levels would be increase, Labetalol would act as an antagonist
Ca2+ channels blockers and grapefruit juice
-the juice increases the bio-availability of calcium channels
- it inhibits CYP3A4
- higher amount of the drug will reach the circulation
- stronger effect
- could lower blood pressure too much
