Pharm Test 1 Review
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Tyrosine (amino acid) (by TH)> L-Dopa (by DD) > Dopamine (by DBH) active transport >
Norepi (by PNMT in CYTOPLSMA) > Epi
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80% of NE released from neurons is retrieved by re-uptake pumps back into the cytoplasmic pool (most important mechanism in stopping the neurotransmitter action at the receptor site)
 The 2 principle enzymes responsible for degradation of catacholamines are MAO and
COMT; liver has a lot of MAO and COMT for rapid metabolism or circulation catacholamines
 MAO found intracellular on mitochondria and COMT found at synaptic cleft
 Alpha agonist potency: EPI> NE > DA > ISO (END I)
 Beta agonist potency: ISO> EPI> NE > DA (I END)
 ISO pure Beta agonist: nonselective
 Alpha 1 : NE, EPI, DA (higher dose), Neosynephrine; stimulates increased intracellular Ca release by G protein; o ARTERIOLAR VASOCONSTRICTION o Increased arterial tone o Increased TPR o Increased diastolic pressure o Decreased HR (reflex) o Increased venous tone
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Alpha 2: Clonidine; inhibits adenyl cylase by G protein hyperpolarization; leads to decreased NE release from neurons; stimulation in the CNS leads to decreased sympathetic outflow and INCREASED PARASYMPTETHIC outflow o Increased tone in large arteries o Increased TPR o Increased coronary vasodilation
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Beta 1: NE, EPI, ISO< DA, Dobutamine; NE > EPI; leads to increased chrontropic and inotropic activity o Increased HR o Increased O2 consumption o Increased automaticity o Increased force of contraction o Increased SV and CO o Decreased filling volume o Increased coronary vasodilation
 Beta 2: Albuterol; EPI > NE (ie racemic Epi with croup); arteriolar vasodilation, bronchial smooth muscle relaxation and increased gylcogenolysis, decreases mast cell histamine release o Decreased arterial tone o Decreased TPR o Decreased diastolic pressure o Increased HR (reflexive)
 Beta 3 in colon in adipose; NE > EPI
 Beta in heart leads to increased inotropy and chronotropy controlled by Ca release; in smooth muscles, increased camp leads to relaxation as membrane hyperpolarizes
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Mixed acting compounds: Ampehetamines and Ephedrine
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NE : increase camp with B stimulation: decreases camp with A stimulation
 Alpha Antagonist: o Alpha 2 antagonists block at post synaptic, pre-synaptic, and heteroreceptors as well o Used for pheochromocytoma , HTN, and BPH o If competitive antagonist (ie Phentolamine (Regitine)) then shorter duration of action vs irreversible covalent binding (ie Phenosybenzamine/ Dibenzyline) o Side effects: dizziness, decrease ejaculation, fatigue, miosis, orthostatic hypotension, increased HR
 Beta Antagonists: o Side effects: decreased HR, CHF, decreased BP, heart block, insomnia, hallucinations, bronchospasms o Labetalol and Carvedilol are alpha 1 and beta 1 and 2 antagonist o Contraindications: asthma, severe decreased HR, cardiac failure o Esmolol is Beta 1 antagonist; must be given by IV gtt b/c half life is only a few mintues
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Metyrosine (Demser); inhibitor of tyrosine hydroxylase; used for pheochromocytoma;
DEC DA; DEC NE; DEC EPI therefore can lead to parkinsonism side effects
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Reserpine (Serpasil) inhibits storage of catecholamines, leading to depletion, used for
HTN and schizophrenia: contraindicated in mental depression
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SV is determined by : preload, afterload, and contractility
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In cardiac failure, the Starling curve is displaced downwards, meaning that increase in end-diastolic ventricular filling volumes (preload) are required to maintain performance o Therefore , if you INCREASE preload, you INCREASE CO o Increased ventricular stretch usually leads to increased contractility o Increased preload and increased contractility lead to increased stroke volume and ultimately increases arterial pressure
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Nitrates reduce preload, pulmonary venous pressure and edema
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ACE inhibitors: o Arterial and venous vasodilators o DECREASE preload, DECREASE afterload o Increase CO o DECREASE HR, DECREASE BP o Increase renal flow o DECREASE release of aldosterone o Increase excretion of Na/H20; DECREASE circulating volume o Most appropriate vasodilators for the long term treatment of heart failure
 By contrast in a failing heart, the exercise-induced increases in ventricular performance are minimal
 With disease progression, increases in left ventricular preload causes pulmonary capillary pressure to increase which produces pulmonary congestion and dyspnea o Systemic compensatory responses to heart failure include fluid retention and increased left ventricular afterload
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The amount of NE released by cardiac adrenergic nerve endings is the most important acute factor in changing the position of the force-velocity in ventricular function curves
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Vasodilators may improve myocardial performance by reducing ventricular afterload
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RAS: renin-angiotensin system activation occurs with the declining CO:
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o Increasing concentrations of circulating angiotensin II and aldosterone results in excess vasoconstriction and salt and water retention o Patients with heart failure often have elevated circulating NE levels, which provide for critical inotropic support for the failing heart o Administration of beta blockers to patients with severe failure may worsen CHF
 Increasing heart rate and contractility by ISO, EPI, or NE may adversely affect cardiac performance in damaged myocardium; they may increase myocardial oxygen requirements and induce arrhythmias
 Dopamine is a positive inotrope, produces less of an increase in HR, DILATES RENAL
ARTERIES promoting better kidney perfusion
 Dobutamine does not increase renal flow; is favored over dopamine in the most advanced heart failure ; doesn’t increase HR but does increase heart contractility
 Milrinone (Primacor) is the agent of choice among the phosphodiesterase inhibitors for short-term parenteral support in severe heart failure
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Cardiac Glycosides: DIGOXIN o Inhibitors of Na and K transmembrane transport by binding to alpha subunits of
Na/K ATPase o Positive inotrope by increasing Ca , secondary to increase in Na = prolongs refractory period = SLOWS HR o Prolongs the refractory period by enhancement of vagal tone o Digitalis toxicity include:
 CNS effects: psychiatric, visual, GI, and cardiac
 Electrophysiologc effects
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Reduction in angiotensin II levels results in venous and arterial vasodilation which decreases preload and afterload; CO improvement reduces sympathetic tone which may further decrease peripheral resistance o Angiotensin II receptor blockers are new class = -SARTAN drugs
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High Loop diuretics most common type used for fluid load reduction in CHF (ie Lasix); cause a large, rapid diuresis o Hypokalemia is especially problematic, since many patients are taking digoxin and can increase risk for toxicity o Increase renal flow by decreasing renal vascular resistance o Watch for ototoxicity
 Thiazide diuretics are used for milder cases of CHF, since they are less powerful o Act in the proximal end of the distal tubule to inhibit the Na/K transport system
(has less loss of K) o Major side effects: hypokalemia, metabolic ALKALOSIS, e imbalance, hyperglycemia (hypokalemia reduction of insulin secretion), hyperuricemia (can lead to gout attack)
 K sparing diuretics work in the last area where Na ions are absorbed = fairly weak drug
 Inhalational agents depress myocardial contractility, with exception of halothane, they all decrease systemic vascular resistance, decrease BP with reflexive increase HR o Halothane decrease HR by vagal stimulation and sensitizes heart to catecholamines with ventricular ectopics seen
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The normal myocardium accounts for 11% of the total body oxygen consumption, but the coronary circulation only receives 4% of the CO = myocardium is one of the more poorly perfused tissues in the body
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o Myocardial oxygen supply: HR, coronary perfusion pressure, arterial oxygen content, CORONARY ARTERY DIAMETER o Myocardial oxygen demand: HR, ventricular preload and afterload, contractility
 Most common cause of angina is ATHEROMA, with retrosternal chest pain
 Prinzmetal’s angina is caused by coronary vasospasm, reduction of coronary blood flow, usually at REST
 Antianginal drugs: o REDUCE PRELOAD = Nitrates ( systemic venodilation = dilates coronaries, peripheral vasodilation = pooling of blood in veins = reduces venous return and decreases ventricular volume = decreases oxygen demand)
 1 st choice of treatment
 Nitrates vasodilate through NO and increased levels of cGMP
 If given IV, 40-80% absorbed in IV tubing
 Longer acting Nitrates are more stable o DECREASE HR, HEART WORK, and DECREASE O2 CONSUMPTION = Beta Blockers
 Prevent angina as well as treat HTN
 Contraindicated in ASTHMATICS
 Cold extremities, worsening of peripheral vascular disease, hypoglycemia, and impotence are also caused by beta 2 blockade
 In patients with reduced left ventricular function and limited myocardial reserve, beta blockers may precipitate heart failure by blocking essential sympathetic drive o CORONARY VASODILATION = Ca Channel Blockers
 Papaverine derivaties –Verapamil
 Benzothiazepines – Dilitizem
 Dihydropyridines – Nifedipine (works prominently on vascular smooth muscles/peripheral)
 They are coronary vasodilators, reduce arterial pressure and myocardial contractility, reduce afterload, and reduce myocardial oxygen requirements. (have little or no effect on preload or venous system)
 Negative inotrope and shouldn’t be used in patients with cardiac failure
 Variant angina (Prinzmetal’s angina) is effectively treated with Ca Channel blockers
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>90% of HTN is essential HTN with unknown ideology
 a principle mechanism for arterial BP control is the baroreceptor reflex found in the chest and neck
 HTN therapy should be continued into the perioperative period
 For HTN crises, sodium nitroprusside (Nipride) is the agent of first choice o Direct acting, nonselective peripheral vasodilator o Reduced systemic vascular resistance o Positive inotropic and chronotropic responses o Net increase in CO to increased contractility and decreased left ventricular ejection pressure o Immediate onset of action o Short DOA, rqs IV gtt o Works through NO (nitric oxide) activates cGMP which inhibits Ca entry into vascular smooth muscle, which produces vasodilation o can produce cyanide free ions and can build up into toxicity
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o Nitroprusside may worsen MI damage due to “coronary steal” where blook is directed away from ischemic areas by arteriolar vasodilation o Increases cerebral blood flow and volume o Rapid, predicatble vasodilation and decrease in BP allos a nearly bloodless surgical field, required in some operations (spine surgery, neuro)
 Aortic surgery
 Cardiac surgery necessitating bypass
 pheochromocytoma
 Spironolactone is an antagonist at mineralcorticoid receptors (aldosterone antagonist)
 Methyldopa (Aldomet) is a PRODRUG which is metabolized to the active agent, alphamethylnorepinephrine; inhibits sympathetic outflow which decreases BP and decreases preload
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Beta 1 blockers are preferred over nonselective beta-blockers for patients with insulindependent DM, symptomatic peripheral vascular disease or pulmonary disease
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Vasodilators such as Hyralazine are not typically administered as monotherapy due to significant, reflex-mediated cardiac stimulation and water retention, and are combined with sympatholytic drugs (ie propanolol) and diuretics
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Hydralazine: great arterial dilation (decreases afterload, decrease BP, with reflexive tachycardia) o Most pronounced dilation: coronary, renal, splanchnic, and cerebral circulation o Extensive hepatic first pass o Patients with “rapid aceylators” (Asians) reduce bioavailablity to 30%
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For low-renin HTN patients (elderly and African American) Ca channel blockers appear good choices for monotherapy o In anesthetized patients with preexisting left ventricular dysfunction—don’t give
VERAPKILL (verapamil) o Also verapamil possesses local anesthetic properties due to Na channel blockade which in effect contributes to potentiation of neuromuscular blocking drug effect with increased risk of LA toxicity in regional anesthesia o A case study found that HTN patients taking short-acting Ca channel blockers were 1.6 times more likely to have a MI compared to patients taking other HTN drugs o Ca channel blockers my inhibit SA node and lead to bradycardia or SA nodal arrest
 ACE inhibitors are considered first line treatment in patients with systemic HTN, CHF, and mitral regurgitation o Decrease systemic vascular resistance (secondary to a decrease in Na and water retention o Decrease in renal vascular resistance o Reduced BP with no change in HR or CO o Are advantageous in management of diabetic patients, reducing the development of diabetic neuropathy and glomerulosclerisis, patients with hypertrophic left ventricles, and who have had ischemic heart disease with impaired LV function o Reduce the normal adlosterone response to Na loss o Surgical procedures that are likely to cause major body fluid shifts are more likely associated with hypotensive reactions in patients receiving ACE inhibitors –in these patients, dc ACE treatment and use shorter acting IV antiHTN o Angioedema, although rare, may be potentially fatal: resp distress can be managed with EPI SQ
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o Should not be used in pregnancy o Captopril, end in –pril
 Angiotensin receptor blockers: Losartin (-sartin) block the interaction between angiotensin II and its receptor in vascular smooth muscle; metabolized to active metabolite that is 10-40 times more active; BP decreases with fewer side effects
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