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CARDIOVASCULAR-RENAL DRUGS (Agents Used in Cardiac Arrhythmias (■ SPECIFIC…

- - - - has a much lower positive inotropic action than many other inotropes, but the other agents are not effective over the long term
      - Pharmacologic Actions
        
        in humans
        
        :arrow_up:contractility
        
        vagal stimulation
        
        in pts w/ CHF
        
        :arrow_up: CO
        
        vagal stimulation
        
        :arrow_down: SNS activity- indirect arteriolar dilation, venous dilation
      - Mechanism of Action
      - neurohormonal actions
        
        :arrow_down: Plasma norepinephrine
        
        :arrow_down: RAAS activity
        
        :arrow_down: SNS activity
        
        :arrow_up: vagal tone
      - cardiac toxicity (Digoxin has a narrow therapeutic margin, and digoxin intoxication remains relatively frequent)
        
        Arrhythmias: - Ventricular - Supraventricular
        
        Digitalis blocks: - S-A and A-V nodes (prolongs refractory period + depresses conduction velocity across the A-V node (lengthens the PR interval on the ECG))
        
        CHF exacerbation (Exacerbation of heart failure should raise the question of digoxin toxicity)
      - long term effects: Fewer hospital admissons BUT Survival similar to placebo; More serious arrhythmias; more MIs
    - - BETA-ADRENOCEPTOR AGONISTS
        
        dobutamine, dopamine
      - BIPYRIDINES
        
        amrinone, milrinone: :arrow_up:contractility; in CHF :arrow_up:CO; mech: inhibits cGMP, cAMP PDE; milrinone better tolerated
      - INVESTIGATIONAL POSITIVE INOTROPIC DRUGS
    - - DIURETICS (almost always necessary)
        
        effects
        
        slightly improve arterial distensibility, but not clinically significant
        
        Neurohormonal activation:
        Levels of NA, Ang II
        
        No direct effect on CO, but may :arrow_down: CO w/ excessive preload reduction
        
        :arrow_down: Volume and preload--> effective in improving signs of pulmonary and systemic venous congestion
        
        adverse effects
        
        Unsuccessful as monotherapy
        
        Potential for electrolyte imbalance
        
        Less improvement in exercise capacity
        
        More frequent reoccurrence
        
        main drawback: their effect on the neurohormonal milieu, :arrow_up: plasma levels of noradrenaline, Ang II and aldosterone, and the plasma renin activity
      - ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, ANGIOTENSIN RECEPTOR BLOCKERS, & RELATED AGENTS
        
        ACE-I should be used as 1st line drugs in all pts w/ LV dysfunction who do/don't have symptoms. this is also the recommendation for the use of BBs; the cornerstone of drug therapy for heart failure, in that administration over time leads to amelioration of symptoms, beneficial hemodynamic changes, increased functional capacity, regression of structural changes, and, unequivocally, prolongation of survival. Prolonged administration of ACE-inhibitors reduces mortality in symptomatic heart failure.
        
        Mechanism of action: inhibits ACE and also kinase II (that degrades bradykinin)
        
        Indications
        
        clinical cardiac insufficiency: all patients: improve quality of life :arrow_up: survival
        
        asymptomatic ventricular dysfunction: LVEF>5%: prevent disease progression
        
        Advantages:
        
        Best drugs for inhibiting LV remodeling post-MI--> :arrow_down: # + duration of hospitalizations + improving symptoms + survival.
        
        Modify progression of chronic CHF (In class II-IV heart failure treated w/ diuretics and digitalis, ACE-I :arrow_down: symptoms, improve hemodynamics and functional class, :arrow_up: exercise tolerance; :arrow_down: LV dimensions, improve cardiothoracic index, improve renal function, and improve hyponatremia. )+ retard progression to heart failure in asymptomatic V dysfunction
        
        In contrast to other vasodilators: don't produce neurohormonal activation / reflex tachycardia + tolerance to these agents does not seem to develop over time.
        
        :arrow_up: plasma renin, bradykinin, and Ang I activities + :arrow_down: plasma and tissue levels of Ang II, and plasma levels of aldosterone + cortisol; :arrow_down: plasma norepi, esp after long-term therapy, which has been attributed to suppression of stimulating effect of ang II on synth and release of nore; also :arrow_down: arginine-vasopressin levels.
        
        Adverse Actions
        
        Hyperkalemia (relatively rare): rare in Pts w/ normal renal function At risk: K-sparing diuretics, renal insufficnency, K supplements, b-blockers, NSAIDS
        
        Acute renal failure
        
        Cough -- #1: more frequent in women, reversible, accumulation of BK, substance P or PGs in lung
        
        Fetopathic potential (including 1st trimester): but not in the first trimester so not contraindicated in females. It may be due to hypotension
        
        Hypotension -- first dose effect: a steep fall in BP may occur on first dose in pts w/ high PRA. those at risk: w/ CHF (also salt depletion and pts on multiple antihypertensive drugs)
        
        Precautions/Contraindications
        
        High plasma renin = dose reduction
        
        Renal insufficiency
        
        Arterial hypotension
        
        Hyperkalemia
        
        Concomitant administration with digoxin (Reduce digoxin dose)
        
        AT1 R antagonists: losartan, valsartan. irbersartan and candersartan (all selective + competitive block of AT1 Rs) (if ACE-I had adverse effects, treat w/ losartan)
      - VASODILATORS
        
        Ateriolar: Hydralazine
        
        Ateriovenous: ACE Inhibitors (Ang II potent vasoconstrictor in arteriovenous system), NItrates
      - BETA-ADRENOCEPTOR BLOCKERS
        
        suggested mechanisms: attenuation of adverse effects of high [catecholamines] (including apoptosis), up-regulation of β Rs, :arrow_down: HR, and :arrow_down: remodeling through inhibition of mitogenic activity of catecholamines.
        
        Metoprololol, Carvedilol, Bisprolol
      - OTHER DRUGS
  - - - ACE INHIBITORS & ANGIOTENSIN RECEPTOR BLOCKERS
      - VASODILATORS
      - SODIUM REMOVAL
      - BETA BLOCKERS & ION CHANNEL BLOCKERS
      - DIGITALIS
      - CARDIAC RESYNCHRONIZATION & CARDIAC CONTRACTILITY MODULATION THERAPY
- - - - Chlorothiazide
      - Hydrochlorothiazide
    - - Amiloride
      - Triamterine
    - - Furosemide
    - - UREARETICS
      - ANTIDIURETIC HORMONE ANTAGONISTS
      - ANTIDIURETIC HORMONE (ADH, VASOPRESSIN) AGONISTS
      - OSMOTIC DIURETICS
    - - POTASSIUM-SPARING DIURETICS & PROXIMAL TUBULE DIURETICS, LOOP AGENTS, OR THIAZIDES
      - LOOP AGENTS & THIAZIDES
  - - - KIDNEY DISEASE AND RENAL FAILURE
      - HEPATIC CIRRHOSIS
      - HEART FAILURE
      - IDIOPATHIC EDEMA
    - - HYPERTENSION
      - NEPHROLITHIASIS
      - HYPERCALCEMIA
      - DIABETES INSIPIDUS
      - RENAL & CARDIAC PROTECTION
- - - - Actions: – :arrow down: sinus rate; :arrow down: AV nodal conduction velocity; Cause negative inotropy; Produce coronary and peripheral vasodilation
      - VERAPAMIL + DILTIAZEM
      - Treatment of supraventricular arrhythmias
      - Adverse effects: constipation, headache, ankle edema
    - - VERNAKALANT
      - RANOLAZINE
      - IVABRADINE
      - ADENOSINE
      - MAGNESIUM
      - POTASSIUM
      - DRUGS THAT ACT ON CHLORIDE CHANNELS
    - - SOTALOL
      - DRONEDARONE
      - DOFETILIDE
      - AMIODARONE
        
        some class I and II actions noted
        
        Adverse events
        
        cardiac: May cause arrhythmias, bradycardia, hypotension, congestive heart failure, and cardiac arrest
        
        Extracardiac effects: • pulmonary toxicity (e.g. pulmonary infiltrates, pulmonary fibrosis) • Hepatotoxicity • hypo- or hyperthyroidism • nausea, vomiting, constipation, anorexia
        
        Prolongs AP, Na channel blocker, K and Ca channel blocker, Supaventricular tachycardia
      - IBUTILIDE
    - - :arrow_down: mortality in patients w/ MI
      - Adverse effects: – Bradycardia – Depression – Fatigue – Nightmares
      - Prototypical agent: propranolol
      - Contraindications – asthma, diabetes. AV block, peripheral vascular disease
    - - (SUBGROUP 1B)
        
        LIDOCAINE: little toxicity, NO ORAL, DC: MI
        
        MEXILETINE
      - (SUBGROUP 1A)
        
        QUINIDINE
        
        Extracardiac Effects: alpha blockade + anti-muscarinic effect
        
        Pharmacokinetics: Usually administered ORALLY
        
        Cardiac Effects
        
        Depresses pacemaker rate & conduction
        
        Slows repolarisation
        
        Lengthens action potential duration (QT)
        
        Therapeutic Use: Used in every form of arrhythmia: Atrial fibrilation and flutter Occasionally ventricular tachycardia
        
        DISOPYRAMIDE
        
        PROCAINAMIDE: Similar to quinidine
        Less antimuscarinic effect
      - (SUBGROUP 1C)
        
        FLECAINIDE
        
        PROPAFENONE
        
        MORICIZINE
- - - - 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%