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antianginal drugs. drugs that increase regional blood flow (Drugs that…

- - - - Heart rate, with a higher heart rate the duration of the diastole is shorter
        
        there is no blood flow during systole
      - Perfusion pressure
        
        Diff. bet. diastolic aortic pressure and ventricular pressure
      - Size of the coronary lumen, this can be reduced due to atherosclerotic plaque, thrombus or arterial tone (vasoconstriction)
      - Ventricular contractility
      - Ventricular wall stress (radius, thickness and wall tension)
  - - - Also known as effort angina, it is caused by an atheroma, the pain is evoked due to spasm
    - - Occurs due to acute coronary syndrome e.g. plaque rupture and thrombosis formation
      - The pain occurs first during exercise and eventually during rest
    - - Evoked by vasospasm
      - The pain occurs at rest
- - - - polyol esters of nitrous acid or nitric acid
      - Amyl nitrite
        
        Highly volatile liquid
      - Nitroglycerine
        
        Moderate volatile & oily liquid
      - Isosorbide dinitrate & mononitrate
        
        Highly molecular compound, solid
      - Prodrug
        
        nitric oxide (NO) is released partly by enzymatic reduction and partly by endogenous extracellular and intracellular reductants
    - - Nitrates and nitric oxide activate guanylyl cyclase through NO. producing cGMP with the help of the enzyme phosphodiesterase (sildenafil blocks enzyme) -> cGMP dependent protein kinase activates myosin light chain phosphatase, which deactivates Myosin light chain phosphate, leads to relaxation
    - - at low doses
        
        venodilation
        
        ventricular end-diastolic volume and pressure↓ -> reduced O2 demand
      - at high dose
        
        further venous pooling + arterial vasodilation
        
        TPR↓ -> reduced O2 demand (may be orthostatic hypotension)
      - General
        
        coronary blood flow increases by dilation of the large epicardial arteries
        
        dilation of collateral vessels -> redistribution of flow to damaged region
    - - reduction of cardiac O2 consumption by reduced preload and afterload
      - redistribution of flow towards ischemic regions by dilation of collateral vessels
      - improved subendothelial perfusion
      - relief of coronary vasospasm
      - inhibition of platelet aggregation by NO
    - - NO has a positive lusitropic effect on the heart : increased relaxation
      - NO inhibits platelet aggregation
      - NO results in bronchodilation
      - NO relaxes the smooth muscle of GIT
    - - Angina pectoris
      - Infarction
      - Hypertensive crisis
    - - frequently repeated or continuous exposure -> diminished effects
        
        8-12h drug free period is needed each day
      - various mechanism are thought to be involved
        
        impaired NO release via depletion of vascular SH stores (glutathione reductase↓)
        
        compensatory responses : tachycardia & salt/water retention
        
        oxidative stress via superoxide production : enhance NO degradation
    - - SH-compounds and other antioxidant
      - vasodilators
      - β-blockers
      - ACE inhibitors
      - diuretics
      - Monday morning disease : tolerance ceases during weekend
    - - headache (due to meningeal vasodilation)
      - flushing (due to cutaneous vasodilation)
      - orthostatic hypotension
      - reflex tachycardia
      - methemoglobin formation
    - - administration
        
        sublingual spray with 0.5mg or transdermal patch
        
        fast action and no first pass metabolism
        
        Ointment
        
        buccal tablet
      - indication
        
        All types of angina
        
        pulmonary hypertension
      - Pharmacokinetics
        
        absorbed well from GIT and skin -> metabolized in liver to less active glyceryl dinitrates and mononitrates
        
        low bioavailability
        
        very expressed first-pass effect upon oral administration
        
        T1/2 : 3 min
        
        elimination
        
        hydrolyzed by hepatic glutathione-S-transferase
      - side effect
        
        Head ache
        
        too strong venodilation -> loss of consciousness
        
        too strong arterial dilation -> tissue hypoxia
      - tolerance
        
        Unknown mechanism but exist
    - - it is the active first metabolism of isosorbide dinitrate
      - less activity but longer duration than isosorbide dinitrate -> T1/2 : 3-6 hour
      - no first-pass effect -> excellent oral bioavailability
      - sublingually or orally
      - excreted renally
    - - Prodrug
    - - extremely volatile -> used inhalation
      - acts within 1-2min -> duration of action is short (now obsolete for angina)
    - - cytoprotective anti-ischemic agent
      - improves myocardial glucose utilization through inhibition of fatty acid metabolism
      - T1/2 7-12 hrs
      - Orally
      - Bioavailabilty takes 5 hours
      - Excreted mainly unchanged in urine
  - - - effect of β-blockers : reduce metabolic demand of the myocardium
        
        induce negative chronotropic & inotropic effects -> better coronary filling and decrease work load of the heart
        
        β1-blockers are used as cardio-selective drugs
        
        useless in prinzmetal angin
      - Indication
        
        verapamil + β-blockers -> may potentiate negative inotropic effect (dangerous)
    - - not vasodialtors
      - MOA
        
        decrease the Ca2 influx in cardiac muscle
        
        leading to a negative heart effect and lower O2 demand
      - Used for
        
        stable angina
        
        Hypertension
      - It has some harming effects such as increasing ejection time and EDV
      - Contraindication
        
        Asthma
        
        Bradycardia
        
        AV-block
        
        LV failure
      - Side effect
        
        Insomnia
        
        Fatigue
        
        Impaired exercise tolerance
        
        Erectile dysfuntion
        
        Worsening claudication
- - - - synthetic PGE1 which does not occur naturally in mammals
      - short T1/2 -> i.v. infusion
      - used for peripheral perfusion problem
    - - synthetic PGI2 derivative
  - - - PDE and TNF inhibitor
      - increases the plasticity of RBCs allowing them get into otherwise inaccessible tissues (additional activity)
      - i.v. infustion with high dose
      - used in treatment of intermittent claudication(limb circulation) and vascular disorders involving the inner ear
      - used in anti-rheumatic action due to TNF inhibition
    - - PDE and voltage-gated Na+ channel inhibitor
      - T1/2 : 2 hours
      - hepatic metabolism and renal excretion
      - tablet or i.v. infusion with high dose
      - used in the treatment of cerebrovascular disorders and age related memory impairment