5 4_part2. Aya Alomoush. Alia Shatanawi

Transcription

1 5 4_part2 Aya Alomoush Alia Shatanawi 1 P a g e

2 This sheet will talk about vasodilators and an introduction of Ischemic Heart Disease(IHD) which is the topic of lecture 7 and half of lecture 6(starting from 24:00)-you can find the links of the records in the last page- The doctor said you don t have to memorize numbers onlyyou should get interpretations from them. Mechanism of Action : Vasodilators Relax Vascular smooth muscle cells Vasodilate Arterioles Decrease PVR Decrease Blood Pressure so they are used in hypertension. Work on 2 types of channels (k+ and Ca++) as we will see. A)Hydralazine -One of the oldest antihypertensive agents -Its mechanism is Not well understood but it is thought to work by HYPERPOLARIZATION of vascular smooth muscle cells by opening of K+ channels and inhibition of Ca++ channels so inhibiting Ca++ influx so inducing relaxation (VASODILATION). -Direct vasodilatory action on arterioles altering smooth muscle cell Ca2+ by hyperpolarizing cell Decreases total peripheral resistance Remember any drug work on TPR it will induce reflex response. -Hydralazine induces Sympathetic activity (Reflex responses) which includes : Increased heart rate Increased heart contractility Increased plasma rennin activity -Plasma half life is 1 hr, but antihypertensive action of 12 hrs possibly due to storage in arterial wall, it has high volume of distribution. Side-effects - Reflex tachycardia: Can precipitate MI in elderly patients or patients with coronary artery disease Reflex response can be blocked by addition of propranolol ( a beta blocker) - Sodium and water retention(due to activation of the rennin-angiotensin system),can be prevented by addition of a diuretic -Headache, Nausea, Dizziness - Lupus syndrome: development of some symptoms of SLE(Systemic Lupus Erythematosus) due to immunologic reaction of the active ingredient of the drug -> Stop the drug if this happen. 2 P a g e

3 B)Minoxidil -Mechanism of Action Activates ATP-sensitive K+ channels to cause hyperpolarization and smooth muscle cell relaxation-> Arteriolar vasodilation -> Decrease in total peripheral resistance In addition to its usage as an antihypertensive drug also it is used to treat male pattern baldness as an injection in the scalp since it causes Hypertrichosis accentuated hair growth- -Plasma half lifeis 4 hrs, but hypotensive effect for hrs (because even after metabolism it still has an activity which prolongs its antihypertensive effect ) - Must be metabolized by the liver to form the active metabolite, minoxidil N-O sulphate. -Side effects : Similar to hydralazine. It could be used as an IV infusion in hypertensive crisis with beta blockers and diuretic. Minoxidil is reserved for treatment of severe,resistant hypertension and must be given with a diuretic and a sympatholytic (usually a beta blocker). Vasodilators in hypertensive crisis A)Sodium nitroprusside (SNP) the same as nitrates that we will talk about them later Mechanism of Action Liberates nitric oxide(no: an endogenous vasodilator) which dilates vascular smooth muscle Thereby, decreases total peripheral resistance Is light sensitive and unstable in aqueous solution so they are contained in dark bottles. How does NO cause vasodilaton?(important) NO activates guanylyl cyclase which increase cgmp inside the cell which activates phoshatases tha dephosphoryllate MLC PO4 so inhibition of contraction so dilation. From the slides,not mentioned by the doctor about SNP: Given by I.V. infusion Antihypertensive effect ceases upon stopping infusion Metabolized to sodium thiocyanate slowly cleared by kidneys,toxic accumulation of cyanide can lead to lactic acidosis Side-effects : Rebound hypertension, Tolerance 3 P a g e

4 B)Labetalol and Carvedilol Mechanism of Action Mixture of alpha 1 antagonist and non-selective beta receptor antagonist - Block adrenergic receptors in blood vessels and heart(additional vasodilatory effect) -Differ in selectivity, according to the doctor carvedilol has higher activity on alpha 1 than labetalol. Labetolol 1:3 selectivity (alpha1:beta) Carvedilol 1:10 selectivity(alpha1:beta) -They decrease cardiac output and TPR with No reflex responses because of their beta blocking activity -Administered orally or IV (for hypertensive crisis) -Useful in pheochromocytoma (labetolol)-> an adrenaline and noradrenalin releasing tumour. -Plasma haalflife2 hrs orally and 5 hrs for IV. C)Diazoxide (NOT mentioned by the doctor but here what is in the slides about it ) Mechanism of Action Dilates arterial smooth muscle through activation of K-ATP channels Little or no effect on venous smooth muscle, Decreases total peripheral resistance. Administered I.V. Onset of action within 2 min, Duration of action 6-24 hrs Side-effects : Tachycardia,Angina. So how we can determine the best treatment for hypertension(ht)? Remember the following MilD-moDerate HT ->Diuretics especially African Americans and elderly HT with diabetes or hyperlipidemia if they are : At low risk -> betablockers (don t forget that they impair glucose tolerance) At high risk-> ACE inhibitors or ARBs if they develop ACE induced cough. Additional blood pressure control -> CCB(Ca++ Channel Blockers) or ACE Resistant/Refractory/Unresponsive->gUanithidin or Reserpine ( sympatholytics) Under age 55(volume expanded HT), may consider giving ACE/ARB 4 P a g e

5 Future Considerations -Calcium Channel Blocker/ACE combination is better than beta blocker/thiazide combination in reducing CV events not blood pressure- (Dahlof et al., Lancet, 2005) - Multi-drug approach to managing hypertension: beta Blocker, diuretic, ACEI,(Polypills, statin(lipid lowering drug), aspirin, folic acid) -Implantable mechanical baroreceptors ->European trials ongoing-understudy - Conclusion Beta Blockers,Diuretics, ACEI and CCB s are most commonly used antihypertensives With relatively few side effects and at low-moderate cost these agents provide effective blood pressure control Combination strategies are useful in managing hyptertension while also giving long term cardiovascular benefits. Categories : IHD First setion is pathology if you don t have time go to treatment section -Fixed /Stable/ Effort Angina: upon exertion Pathology -Variant /Primary Angina : without a major risk factor mainly due to VASOSPASM. -Unstable Angina :even at rest -Myocardial Infarction : complete blockage of the coronaries leading to death and necrosis of the affected area. -Symptoms and signs of angina : severe sudden compressing chest pain radiating to the shoulder, jaw or the back. -Cause : ischemia of the heart =reduced blood flow to the heart ( imbalance between O2 supply and O2 demand ) -Overlapping diseases(stable can become unstable). -Endothelial dysfunction (which occurs in HT and diabetes) precedes atherosclerosis( a major risk factor for IHD) : normally endothelium produces NO by enos(endothelial Nitric Oxide Synthase) from L-arginine, this production is decreased in endothelial dysfunction so decreased ability of blood vessels to relax (dilate). Endothelial dysfunction with LDL deposition cause Atherosclerosis. **The 2 figures below was mentioned by the doctor : 5 P a g e

6 -in primary angina there may be some atherosclerotic plaque but they aren t the main cause. -spasm: decreased perfusion so any drug will relieve that spasm will help in reperfusion. -Ischemic reperfusion injury : damage to the heart muscle by ROS happens after reperfusion of a previously obstructed artery. 6 P a g e

7 Cascade of effort angina : Effort->ischemia->diastolic dysfunction->systolic dysfunction ->ECG changes ->dyspnea (shortness of breath )->pain relief->normal ECG->systolic recovery starts ->STUNING*-> full recovery. * Myocardial stunning is the reversible reduction of function of heart contraction after reperfusion not accounted for by tissue damage or reduced blood flow. Treatment of IHD Mechanism of vascular smooth muscle contraction ( steps demonsrated in the figure below) (1)influx of Ca++ (2)Ca++ binds calmodulin forming Ca++-calmodulin complex (3) the complex activates MLC-K(myosin light chain kinase) (4)phosphorylation of MLC by MLC-K (5)contraction 7 P a g e

8 Important : -B2 agonists activate adenylate cyclase leading to increased camp intracellularly which activates protein kinase A which phoshphorylate MLCK leading to its inhibition so inhibition of contraction so vasodilation. -Nitrates release NO which activates guanylyl cyclase which increase cgmp inside the cell which activates a phoshatase tha dephosphoryllate MLC PO4 so inhibition of contraction so dilation. -alpha 1 agonists activate phospholipase C (PLC), which increases formation of inositol triphosphate (IP 3) from phosphatidylinositol bisphosphate (PIP 2), leading to increased release of calcium from the sarcoplasmic reticulum. Remember : the main target in IHD treatment is to decrease the O2 demand (heart's work) and increase the O2 supply(coronary blood flow). -So we classify the drugs to : 1)Agents increasing O2 supply : vasodilators, CCB, statins, antithrombotic,anticoagulants,aspirin by increasing coronary and regional blood flow. 2)Agents decreasing O2 demand : beta blockers,ccb,nitrates by decreasing heart rate,contractility(work) and affecting the preload and afterload You can use beta blockers or CCB as prophylaxis of IHD since they decrease cardiac work. Opoids (analgesic) are also used to relieve pain. **The figure below was mentioned by the doctor(important because it summarise the action of IHD drugs) : 8 P a g e

9 Organic Nitrates Nitroglycerine (GTN) -Prototype, used for more than 140 years. -Nonspecific smooth muscle relaxant. -Action not antagonized by any known antagonist. -It was used in the past as an explosive, don t forget its light sensitive so it must be contained within dark bottles. -Usually administered sublingually,why? to avoid high degree of first pass metabolism (99%)before reaching systemic circulation and for quick absorption -Can be administered by various routes-as we will see- -Fast onset of action(1-3minutes, Peaks at 10 minutes). -Short duration (15-30minutes) -Reductase enzyme in liver will breakdown the drug. -Causes general vasodilation: a)arteriolar dilation: short lived (5-10 min)-mainly systolic- Decreases systemic blood pressure (afterload), causes reflex tachycardia and increased contractility, might increase MVO2( myocardial requirement of O2) b)venous dilation: more intense, even with low doses, lasts for 30 minutes. Decreases venous return (preload) and decreases MVO2. 9 P a g e

10 So the effects of GTN are : Decreasing afterload,preload,wall tension and epicardial blood flow increasing endocardial blood flow, stenosis diameter (decreasing occlusion) increasing heart rate as well as contractility by reflex responses. Here is the full list of beneficial and deleterious effects : - Headache. - Hypotension and tachycardia. Side Effects: - Increased intraocular and intracranial pressures. - Methemoglobinemia. -Tolerance: only for the arteriolar effects -Withdrawal: in workers in ammunition industry-not mentioned by the doctor but what does that mean? you can find the answer in the box below it is an EXXTRA you can ignore it.. EXXTRA: Continuous exposure to high levels of nitrates can occur in the chemical industry, especially where explosives are manufactured. When contamination of the workplace with volatile organic nitrate compounds is severe, workers find that upon starting their work week (Monday), they suffer headache and transient dizziness ( Monday disease ). After a day or so, these symptoms disappear owing to the development of tolerance. Over the weekend, when exposure to the chemicals is reduced, tolerance disappears, so symptoms recur each Monday. Other hazards of industrial exposure, including dependence, have been reported. 10 There P a is g no e evidence that physical dependence

11 Remember we have short acting as well as long acting nitrates also we have various routes of administration like : Inhalant (Amylnitrate),sustained(slow)release transdermal patches,ointment and orally. -isosorbide nitrate is a member of the nitrate family. Record 5 ( 7361A13DD4590B94%21308&parId=7361A13DD4590B94%21248&o=OneUp) Record 6 ( 7361A13DD4590B94%21309&parId=7361A13DD4590B94%21248&o=OneUp) We make a living by what we get, But we make a life by what we give. -Good Luck- 11 P a g e