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Vasodilators & the Treatment of Angina Pectoris (Vasodilators &…

- - - - Toxicity & Tolerance
        
        Adverse Drug Reactions: Tiredness /fatigue/lethargy,
        Bradycardia, Bronchospasm, Impotence
        
        Rebound Phenomena: Sudden cessation may precipitate MI (Rebound beta R up-regulation); Those at risk: patients w/ angina and men >50 yrs receiving beta blockers for other reasons
      - Mechanisms of Clinical Effect: :arrow_down: myocardial O2 requirements at rest and during exercise (:arrow_up: exercise threshold at which angina occurs)
        
        :arrow_down: BP
        
        :arrow_down: contractility
        
        :arrow_down: HR (--> :arrow_up: in diastolic perfusion time--> :arrow_up: coronary perfusion)
      - Clinical Use: extremely useful in management of effort angina + considered first-line drugs in chronic effort angina.
        
        Only for prophylaxis of exertional angina
        
        Ineffective (or contraindicated) for variant angina (may make attacks worse)
        
        post acute MI
        
        prevention of tachycardia
        
        secondary prevention in the survivors
        
        I.V. ATENOLOL or METOPROLOL reduce mortality following an acute MI by 10-15%
        
        Oral beta blockade started weeks or months post MI reduce cardiac death by 22% and second MI by 26%
      - Pharmacodynamics: reversible antagonists of beta Rs
      - Contraindications: Asthma, Peripheral Vascular Disease, Heart failure, severe Bradycardia / Heart block,bradycardia-tachycardia syndrome, and severe unstable left ventricular failure
      - Drug -Drug Interactions (Primarily Pharmacodynamic)
        
        Bradycardia when used with drugs such as verapamil or diltiazem
        
        Cardiac failure when used with negatively inotropic agents such as verapamil, diltiazem
        
        Hypotension when used with other hypotensive agents
        
        Exaggerate the hypoglycaemic actions of insulin or oral hypoglycaemics
      - Contraindications
        
        use of rapidly acting vasodilatatory-CCBs (nifedipine) may
        precipitate acute MI or stroke
        
        Post MI: May :arrow_up: morbidity and mortality in impaired LV function
        
        Unstable angina: dihydropyridines may :arrow_up: infarction rate and death in unstable patient
    - - Potassium channel openers: Preconditioning: NICORANDIL:
        • Activate “silent” K channels--> K influx into cardiac myocytes inhibits Ca influx--> negative inotropic action
      - Sinus node inhibition: (bradycardic drugs), relatively selective <If> Na channel blockers (eg, ivabradine), reduce cardiac rate by inhibiting hyperpolarization-activated Na channel in SA node. No other significant hemodynamic effects have been reported. Ivabradine appears to reduce anginal attacks with an efficacy similar to that of calcium channel blockers and β blockers. The lack of effect on gastrointestinal and bronchial smooth muscle is an advantage of ivabradine, and it is approved for use in angina and heart failure outside the USA. موضوع اینست که بتابکر ها و متضاد های کانال کلسیم هم تعداد بانات را کم میکنند و هم زور انقباضی را. فکر کرده اند داروئی بسازند که تعداد را کم کند و به زور کاری نداشته باشد. محل اثر دارو فقط و فقط گره سینوسی است.
      - Rho kinase inhibition (fasudil): Rho kinases (ROCK) (Es that inhibit vascular relaxation + etc) Excessive activity implicated in coronary spasm, pulmonary hypertension, etc. Fasudil is an inhibitor of smooth muscle Rho kinase and reduces coronary vasospasm in experimental animals.
      - Metabolic modulation (trimetazidine): partially inhibit FA oxidation pathway in myocardium. (metabolism shifts to oxidation of FAs in ischemic myocardium--> oxygen requirement per unit of ATP produced :arrow_up:)
      - Late Na+ current inhibition (ranolazine): act by reducing a late sodium current that facilitates Ca entry via Na-Ca exchanger--> :arrow_down: in IC [Ca]--> :arrow_down: diastolic tension, cardiac contractility, and work
    - - Clinical Uses of Calcium Channel-Blocking Drugs
      - Toxicity
        
        Adverse Drug Reactions (ADR)
        • Ankle oedema: Affects 15-20% of patients and does not respond to diuretics
        • Headache
        • Flushing
        • Palpitation
      - Mechanisms of Clinical Effects
        
        :arrow_up: coronary blood flow (useful in vasospastic angina)
        
        :arrow_down: O2 Demand - probably “most” important
        
        :arrow_down: contractility
        
        :arrow_down: afterload (TPR, BP) (arterioles appear to be more sensitive than veins; orthostatic hypotension is not a common adverse effect)
        
        :arrow_down: HR
      - Pharmacodynamics
        
        A. Mechanism of Action: Prevent Ca influx into myocytes + smooth muscle lining arteries and atrerioles by blocking the L-Type Ca channel
        
        B. Organ System Effects
        
        Skeletal muscle: not depressed by CCBs bc it uses IC pools of Ca to support excitation-contraction coupling and does not require as much transmembrane Ca influx
        
        Cerebral vasospasm and infarct following subarachnoid hemorrhage—Nimodipine
        
        Cardiac muscle
        
        CCBs like nifedipine or amlodipine may produce a reflex tachycardia (dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil. The relatively smaller effect of verapamil on vasodilation may be the result of simultaneous blockade of vascular smooth muscle potassium channels described earlier)
        
        Rate limiting CCBs like diltiazem and verapamil also reduce heart rate
        
        Other effects
        
        Smooth muscle
      - Examples
        
        Dihydropyridines: Amlodipine, Nifedipine
        
        Miscellaneous: Diltiazem, Verapamil
    - - Clinical Use
        
        • GTN
        
        – Used for rapid treatment of angina pain.
        
        – To avoid first pass metabolism is given by sublingual route.
        
        – May be used frequently and prophylactically
        
        • Oral Nitrates
        
        – Commonly given as a once a day sustained release formulation
        
        – Used for prophylaxis
      - Mechanisms of Clinical Effect
        
        B. Nitrate Effects in Variant Angina: by relieving coronary artery spasm
        
        C. Nitrate Effects in Unstable Angina:
        
        A. Nitrate Effects in Angina of Effort: The reduction in oxygen demand is the major mechanism for the relief of effort angina: Arteriolar dilatation :arrow_down: cardiac afterload + Peripheral venodilatation :arrow_down: venous return, cardiac preload
      - Toxicity & Tolerance
        
        B. Tolerance
        
        overcome by: doses of nitrate 8 am and 2 pm (2 and miss the third dose) or using a sustained release preparation which incorporates a “nitrate free period"
        
        Continuous exposure to high levels can occur in the chemical industry--> workers find that upon starting their work week (Monday), they suffer headache and transient dizziness (“Monday disease”)
        
        can develop rapidly to effects of nitrate therapy
        
        C. Carcinogenicity of Nitrate and Nitrite Derivatives
        
        A. Acute Adverse Effects: major acute toxicities of organic nitrates direct extensions of therapeutic vasodilation: orthostatic hypotension, dizziness, tachycardia (baroreceptor mediated), and throbbing headache.
      - Pharmacodynamics
        
        A. Mechanism of Action in Smooth Muscle: relax almost all smooth muscle by releasing NO--> release of cGMP
        
        B. Organ System Effects
        
        Vascular smooth muscle
        
        2) Redistribution of coronary blood flow: can selectively :arrow_up: blood flow to ischemic areas
        
        3) A reversal of coronary vasospasm
        
        1) Venodilation - primary mechanism
        
        • more E converting TNG to NO in venous smooth muscle vs. arterial.
        
        • --> :arrow_down: “preload” (:arrow_down: ventricular chamber size, end diastolic pressure, fiber tension) = :arrow_down: work ( PARK)--> :arrow_down: O2 demand
        
        • afterload (arterial resistance) :arrow_down: can be produced at higher doses -can produce reflex tachycardia
        
        Other smooth muscle organs
        
        Action on platelets
        
        Other effects
      - Pharmacokinetics
        
        The liver contains a high-capacity organic nitrate reductase--> oral bioavailability of traditional organic nitrates (eg, nitroglycerin + isosorbide dinitrate) is low
        
        Nitroglycerin + isosorbide dinitrate both absorbed by sublingual route and reach therapeutic blood levels within a few minutes. However, total dose administered by this route must be limited to avoid excessive effect--> total duration of effect is brief (15–30 minutes)
        
        partially denitrated metablolites have much longer half lives and oral bioavailability (isosorbide mononitrate)
      - Examples
        
        • GLYCERYL TRINITRATE (GTN) (NITROGLYCERIN)
        – Sublingual, buccal, transdermal
        
        • ISOSORBIDE MONONITRATE AND
        DINITRATE
        – Sustained release formulation, tablets
    - - Aspirin : potent inhibitor of platelet thromboxane production (thromboxane stimulates platelet aggregation + vasoconstriction)
      - Cholesterol lowering agents: SIMVASTATIN, PRAVASTATIN, ATORVASTATIN (HMG CoA Reductase Inhibitors and the most effective cholesterol lowering agents) Reduces cardiovascular mortality by 42% and total mortality by 30%