----start--- pharm 2/4/98 Davies "breathing is dangerous" - it's been observed in animals 3 minutes before death in 100% of all fatalities. :) Michael Jackson bought a hyperbaric chamber - it didn't seem to help. Oxygen is toxic. No doubt about it. it's a relentless destroyer of DNA and membrane lipids. If you don't combat oxygen toxicity, oxygen radicals which your cells are constantly forming, then your brain will look like linseed oil in the air on a hot summer day. And you'll die. animals survive in the presence of oxygen because 1) they evolved cytochrome oxidase and 2) a whole system of protective enzymes to destroy radicals exist. origin of life: started in absence of oxygen. all animals at that time (no mammals) were anaerobes. then, there was this blue green algae that evolved - 2.5 billion years ago (if you believe that) they started making oxygen, which polluted the air. those animals which could use oxygen for energy, and defend themselves against it, were therefore selected for. then animals came out of water on to land, etc etc. he showed that slide of dr fluharty with long hair, again. dr fluharty and kotlikoff like to give structural formulas and explain structure:function relationships. Oxygen is O2 - you don't have to memorize it. Dr Klide likes to show how drugs are packaged. O2 is packaged in our atmosphere, or in a canister. Route of administration is inhalation. it's absorbed from the lungs by diffusion, and is metabolized in cells to form water. some is excreted unchanged in lungs, some in the urine. oxygen is used clinically to treat hypoxia. Oxygen therapy concepts: oxygen is a drug, so it should be administered in a prescribed manner - but usually isn't, usually we use O2 cage. should measure the response of the animal to oxygen by blood gas analysis - also usually not done. Here at VHUP we do blood gases, or pulseoximetry (transcutaneous ear oximetry) but most vets don't. If PaO2 is less than 60 mmHg, animal needs O2 therapy. because of shape of HbO2 curve, small doses of O2 are very effective if PaO2 is less than 60. At 60, Hb is 90% saturated, but below 60, PaO2 falls precipitously. you should interpret the response in terms of adequacy of tissue oxygenation, which is measured by the mixed venous pO2 - which is the effluent from the cells. this tells you how much cells are extracting. this is a hard sample to get - you have to get blood from a large vein or the right atrium. but this is the only measure of how well tissue is being oxygenated. High PaO2 with poor blood flow doesn't oxygenate tissues well. mixed venous PO2 is a function of oxygen consumption, blood flow, and arterial O2 content (set by PaO2, [Hb], HbO2 affinity). if HbO2 affinity is too high, oxygen won't be released to tissues appropriately. a fall in PvO2 to 25 mmHg is usally accompanied by inadequate oxygenation of some tissues, and metabolic acidosis. the aim is to keep PvO2 at about 35. Then you have adequate tissue oxygenation and no tissue hypoxia. In emergencies, there are no contraindications for the use of 100% oxygen for short periods of time (less than 12 hrs) - but you do have to watch the animal. O2 administration is a temporary therapy. the underlying cause must be treated. what causes tissue hypoxia? to know this, you have to go back to physiology and remember the transport systems. problems with ventilation, diffusion across lung, circulation, and diffusion from capillaries into cells. causes of hypoxia are usually listed as three: prepulmonary pulmonary postpulmonary prepulmonary: what's going on with ventilation before the blood:gas barrier. low inspired pO2 eg from altitude, or hypoventilation. hypoventilation can be due to obstruction (airway narrowing), muscle weakness (drugs, diseases), or CNS dysfunction (drugs, diseases, trauma). lead to hypoxemia, decreased PO2 and decreased content - easily reversed by O2 enrichment. how much enrichment? barometric pressure equals the sum of all the pressures of all the gases in alveoli. nitrogen and water vapor are inert. So, PaCO2 + PaO2 = Pb - PaH2O - PaN2 = constant. therefore, if PaCO2 goes up, PaO2 goes down, and vice versa. oxygen enrichment: lungs exchange CO2 for O2. this isn't like exchanging a sweater at bloomingdales for a different color. it's different. you can add oxygen to blood without eliminating CO2, because they fit different parts of Hb molecule. If CO2 isn't washed out fast enough, O2 can't be washed in fast enough. CO2 accumulates, O2 falls. PAO2 (alveolar O2) equals PIO2 (inspired O2) - O2 blood absorbs PAO2 = PIO2 - PACO2 x correction factor for RQ PAO2 = PIO2 - 1.2 x PACO2 THEREFORE, alveolar O2 PAO2 rises in parallel with PIO2. if you change inspired gas, you change alveolar gas. if you change inspired gas from 21% (air) to 30% O2, you raise PI02 from 150 to 213, you raise PAO2 from 100 to 163. this doubles the normal diffusion gradient, to get good diffusion into pulmonary capillary blood. normal diffusion gradient is 60 mmHg; now we've made it 120 mmHg. causes of tissue hypoxia cont. pulmonary: the exchange membrane. -diffusion block - thickened membranes. rarely seen by itself. edematous lungs. readily overcome by O2 administration - 30% O2 doubles driving force; 100% O2 raises driving force tenfold. so you could get gas across a membrane that's 10 times thicker than normal. - ventilation/perfusion mismatch - most common cause with lung disease. ventilation occurs in one part of lung, perfusion occurs in another part of lung. this is the most common cause of hypoxia w/lung dz. you have to increase the PO2 in the poorly ventilated parts of the lung. O2 tx usually effective but depends on severity, pattern of inequality, and PIO2 you employ. - shunts - absolute anatomic shunts. this is where blood isn't ventilated at all. you can't get O2 into blood that isn't entering lungs. O2 therapy won't help. you will see a small increase in the O2 content of the ventilated blood due to dissolved oxygen, which is beneficial. post-pulmonary: -low cardiac output -impaired carrying capacity (anemia, CO, methemoglobinemia) -impaired O2 release (low DPG, low CO2) -celular and enzyme abnormalities (cyanide poisoning) arterial PO2 is normal, arterial O2 content may be normal (cyanide poisoning) or not (anemia), O2 therapy more limited in effect, because blood is ventilated normally already. benefits come from increasing dissolved O2, therefore need a high inspired PO2 - 100% or hyperbaric chamber with >100% O2. whole blood may be of benefit if anemia or low cardiac output. transfusion increases O2 delivery to tissues. O2 also used in anesthesia - it's usually the carrying gas for the inhaled anesthetic, to prevent tissue hypoxia. O2 delivery isn't easy in veterinary medicine. it requires either restraint, or cooperation. animals are not usually cooperative. restraint comes from drugs, which you may not want to use if animal is compromised, or from animal being very ill and unable to resist. can put small animals in oxygen cages which deliver 30-50% O2. not stressful, not invasive, animal usually ok - but you cna't neglect them. this is a temporary fix. you can't put a horse in a cage, but horses tolerate masks and nasal O2 very well. horses tolerate intubation well (??!!) so you can use catheters or intubtion or masks to deliver O2 but you need cooperation, which horses will give, but dogs usually won't (and he didn't mention cats...) hazards of O2 therapy: carbon dioxide retention: high PO2 depresses peripheral chemoreceptor activity. low oxygen is a stimulus to breathe. high oxygen removes stimulus to breathe, depressing ventilation, increasing CO2. so you now have patient hypoventilating and having increased CO2. patients with CO2 retention often have blunted ventilatory responses to CO2. this is patients with longstanding pulmonary disease, longstanding CO2 retention. they don't respond to CO2 - they do what dr klide said - don't increase ventilation in response to CO2 stimulus. normally, if you give increasing doses of halothane, you increasingly knock out the response to CO2. animals with the longstanding CO2 retention don't hve good response to CO2 because the brain bicarbonate is high. if animal doesn't respond to CO2 then they are driven by peripheral chemoreceptors. then, O2 administration will lead to profound hypoventilation and respiratory acidosis. effect of inhalation of 100% O2 in patient with pulmonary insufficiency. on air, oxygen is low, CO2 is 125. on 100% O2, oxygen is high, but CO2 is 150, and pH is 7.06, down from 7.12 now: NEVER withhold oxygen therapy. the dangers of hypoxia are worse than danger of too much CO2. if patient is hypoxic and has CO2 retention, start with low concentrations of O2 (24%). be prepared to intubate and ventilate if needed. if you raise pO2 from 30-50, saturation goes from 58 to 85, adding 5.6 mL O2/ 100 mL blood. tremendous benefit to animal! note also that discontinuation of O2 (removal from cage) may lead to profound hypoxemia on room air. due to the hyperoxic depression, the CO2 must be high, therefore PO2 must be low. if animal isn't breathing normally, is on O2, ventilation is depressed. CO2 is very high. disease + oxygen --> increased CO2. but then if you remove animal from cage - animals have low stores of oxygen. animal starts breathing air, uses up all the O2 it has stored, and now is breathing air. has high CO2 stores, takes time to get rid of it, and remember O2 + CO2 = constant, so if CO2 is high in lung, O2 will be very low. patients without chronic hypercapnia are NOT in danger from ventilatory depression. so don't worry about them. absorption atelectasis: any gas pockets in the body will be gradually resorbed. - including gas in lung trapped behind a blocked airway. resorption is slow b/c N2 is resorbed slowly. BUT - if you breathe 100% O2, N2 gets washed out - all the N2 in the body is washed out, not just lung N2. oxygen compared to nitrogen is very soluble because Hb picks it up...so O2 is rapidly picked up by blood. so, if an alveolus is poorly ventilated, eg you're only adding little bit of O2 to it, all the O2 that enters it may get picked up by the blood that's passing by - then the alveolus will collapse, because there is no N2 there holding it open and while there is some CO2, there isn't enough pressure to hold it open. this leads to shunting. this leads to hypoxia. some animals have "collateral ventilation" like dogs, preventing some collapse. this is connections between the alveoli, pores between them. oxygen toxicity: in the absence of cytochrome oxidase, the spontaneous, monovalent reduction of oxygen, produces highly reactive intermediates. if you add electrons to O2 one electron at a time (which is prevented by cytochrome oxidase which binds oxygen), you get superoxide radical from adding 1 e-, hydrogen peroxide from adding 2 e-, or hydroxyl radical from adding 3 e-. all highly reactive oxidizing agents. these oxidations occur spontaneously in all cells due to oxidative enzymes like p450. they damage cells by oxidizing the hell out of enverything. they inactivate sulfhydril containing enzymes, they do DNA damage, and they peroxidize lipids in the membrane. superoxide radical can undergo spontaneous dismutation - this means there is a simultaneous oxidation/reduction (redox) reaction - producing H2O2. this permits the most damaging rxn - O2- + H2O2 --> OH* + OH- + O2 Fe++ + H2O2 --> OH* + OH- + FeO2 OH* is the most potent oxdant known. it oxidizes everything near it. it can attack any organic substance in cells, so you can't have a specific enzyme to scavenge it b/c enzyme would get oxidized. solution to free radical problem: keep concentrations of O2- and H2O2 vanishingly small. several enzymes do this: superoxide dismutase - keeps superoxide radical low. catalase and peroxidases keep H2O2 and other peroxides low. as long as you have those, you don't get damage to cells. additional protectants against oxidizing environments: glutathione - peroxides use glutathione befoe protein SH groups. this is the preferred substrate for oxidation. glutathione is repeatedly oxidized and reduced, sopping up peroxides. cellular antioxidants - H+ donors - alpha tocopherol, vitE; ascorbate, cysteine. these confine lipid peroxidation chain rxns, prevent SHenzyme inactivation. 100% O2 over long time (>30hrs) will produce damage to epi and endothelium of lung, pulmonary edema, due to free radical damage to lung tissue, since 100% O2 overwhelms the protections against free radical damage. ---break---- dr spear cardiovascular drugs/cardiovascular control regulation of arterial BP - two main components are CO and total peripheral resistance. the product of CO and resistance is BP. CO is made of HR and SV (stroke volume) - HR x SV = CO. total peripheral resistance, which determines your arterial blood pressure, is under local vasomotor control (local compounds) and extrinsic (circulating hormones) vasomotor control. HR is controlled by sympathetic and parasympathetic input. SV is controlled by myocardial contractility and diastolic filling. diastolic filling relates to blood volume and venous return. as one increases ventricular end diastolic volume, stroke volume increases. remember that starling curve thing? if inherent myocardial contractility were lower, stroke volume would be lower. all cardiovascular drugs act somewhere in this system. sites of action: inotropic drugs - increase myocardial contractility by increasing intracellular free calcium or modifying sensitivity to intracellular free calcium antiarrhythmics - modulate heart rate/rhythm - some act to modify automaticity and conduction to bring dysrhythmic heart back into normal rhythm. if you have bradycardia, HR too slow, CO will drop, so you need antiarrhythmic. these drugs also can act on SANS or PANS (symp and parasymp) vasodilators - modify venous return to decrease preload, or act at periphery to modify total peripheral resistance, which determines afterload that ventricle has to pump against antihypertensive - modify blood volume - excretion of water and electrolytes; or modify total peripheral resistance. consider vasodilators: for tx of pathological conditions such as atherosclerosis, hardening of arteries, restricted blood flow, excessive vasoconstrictor tone, vascular spasms (esp w/in coronary arteries), ischemia, myocardial infarction, hypertension. these are all times when you might use a vasodilator. also they are important for modifying afterload and preload. classes of vasodilators: calcium blockers/modifiers nitrates ACE (angiotensin converting enzyme) inhibitors alpha adrenergic blockers indications, mechanism of action, clinical effect, example of drug - see table in handout! calcium blockers/modifiers: verapamil, diltiazem, nifedipine. these are used mainly for angina pectoris (pain in chest due to mismatch b/w O2 delivery to myocardium and myocardial O2 demand) and hypertension, and also sometimes for arrhythmias. verapamil, diltiazem and nifedipine are all three different classes of drugs and act at different sites. verapamil acts at the heart to modify myocardial conduction through AV node, change rate of automaticity of pacemaker cells. nifedipine acts peripherally - used to tx angina or hypertension. diltiazem is in between - used for both cases. nifedipine is best to act on vasculature. verapamil and diltiazem better for arrhythmias, act on heart. diltiazem also acts on periphery. all act to change calcium current, all act on calcium channels. clinical effect is vasodilation, increases blood flow, decreases resistance in periphery, decreasing afterload. also modify how Ca++ is handled - change sensitivity to calcium to produce vasodilation. nitrates: tx angina pectoris, heart failure. nitroglycerine, amyl nitrate. mechanism is to elevate cGMP via production of NO. cause venodilation (primarily) and some arteriolar dilation. mainly these drugs decrease preload on heart very quickly - rapidly absorbed, rapidly effective. angina pectoris resolved via reducing workload on heart. ACE inhibitors: hypertension, heart failure. interfere w/conversion of ATI to AT II. produce vasodilation to decrease peripheral resistance, decrease sodium retention and therefore blood volume. captopril, enalapril. alpha adrenergic blockers: treat hypertension. reduce a adrenergic stimulated vascular tone. vasodilation occurs. phenoxybenzamine is an example antihypertensive agents: generally fall into 3 categories: diuretics, vasodilators, and drugs acting on sympathetic nervous system (alpha blockers like propanolol). we won't discuss these. inotropic agents: to understand these, you have to understand the calcium cycle in the contraction/relaxation cycle. there are pumps in the surface membrane, pumps in the SR, and release sites in the SR, as well as voltage gated membrane channels. pumps can be passive, driven by concentration gradients, or active, requiring energy. squiggles are energy requring pumps in handout. normally all the Ca++ is in the SR, near the T tubules, in the lateral sacs. in resting muscle, intracellular Ca++ is 0.0001 mmol, and extracellular is 1.0 mmol. then, you have the Na/K ATPase pump, which sets up the concentration gradient of Na and K required for membrane excitability. this is important re: action of digitalis as inotropic agent. they set up a concentration gradient so that if the voltage sensitive channels are activated, there is Na+ influx, Ca++ influx (fast and slow components of the AP as you recall). what triggers contraction? first, membrane is excited, then there is contraction. there is inward Na+ current responseible for fast upstroke. calcium enters during plateau. impulse conducts down T tubular system, and calcium moves across membrane during AP in t tubule causing Ca++ induced calcium release from lateral sacs of SR, increasing intracellular Ca++ up to 0.01 mmol from 0.0001. this activates contractile elements. relaxation occurs when SR calcium pump, located along longitudinal surface of SR, pumps Ca++ back into SR, lowering free Ca++. also sarcolemmal Ca++ ATP pump pumps calcium out of cell, and sodium calcium exchanger pumps Ca++ out driven by Na++ concentration gradient. this returns cell to low intracellular Ca++ state. sensitivity of contractile elements have a certain sensitivity to Ca++ that can be modified. at resting state, there is no generation of force b/c concentration of calcium is low. as concentration increases, you get more and more force, until you maximize the contractile force at a certain concentration of calcium. now, you could do something to shift curve to the right, if you make contractile elements less sensitive, or to the left, if you makeit more sensitive. they are developing drugs to shift this curve to the left, to give more force at a lower Ca++ concentration. but the drugs used now generally modify the free calcium ion concentration in the cell, not the sensitivity to it. they do this in several ways. increasing intracellular sodium concentration is one (maybe he meant calcium?). increasing current through voltage gated Ca++ channels is another. increasing release of Ca++ from SR release sites is another. drugs that modify cAMP in turn alter free calcium. can do this by increasing production by activating b receptors; can decrease phosphodiesterase activity to prevent cAMP breakdown with phosphodiesterase inhibitors. catecholamine inotropy: when you give a catecholamine (IV dosing, or sympathetic stimulation, or whatever), you stimulate the beta adrenergic receptors on the membrane - which are coupled to G protein, which elevate cAMP levels (using up ATP). increased cAMP intracellularly results in increases in peak contractile force, with earlier relaxation. this has an advantage - what causes increased HR, CO during exercise? catecholamines, SANS. now, if your duration of contractile phase (systole) remained the same while you accelerated the HR, your diastolic phase would be way too short, you couldn't fill the heart up with blood. but with catecholamines, you do shorten the contractile phase, shortening systole, so you have enough time for the heart to fill between beats. also they increase the force of contraction. how do they do this? they elevate cAMP levels. your cAMP then decreases Ca++ sensitivity of the contractile elements (contributing to early relaxation) increases Ca++ pump of SR (early relaxation) increases Ca++ stores in SR (increases contractile force) increases inward Ca++ current (increases contractile force) increases Na/K pump; greater Na+ gradient increases Na/Ca exchange (early relaxation) increases Ca++ pump at sarcolemma (early relaxation)(?) why do we need inotropic agents? because for some reason, myocardium loses contractility. coronary artery dz, cardiomyopathy ---> decreased strength of contraction --> decreased cardiac output --> decreased BP --> decreased renal blood flow --> increased renin-angiotensin --> increased aldosterone --> increased sodium and water retention --> edema--> pulmonary edema --> decreased arterial PO2. decreased cardiac output also causes increased filling pressure and end diastolic volume (preload) which is compensatory in terms of the decreased strength of contraction, but also leads to increased work for the heart, and also to pulmonary edema because you back up blood, increasing pulmonary venous pressure. for a dilated heart, to generate a given pressure, each cell must see more tension, use more oxygen, do more work. this is based on LaPlace work, remember? this is why nitroglycerin decreases angina - heart shrinks, there is less tension in the wall. when you decrease BP, you activate baroreceptors, increasing sympathetic activity. this has compensatory action - increases the HR, increases CO. also increases myocardial contractility, which is compensatory in terms of strength of contraction, but which is more work for the heart. the increased HR is compensatory in terms of the decreased CO, but again increases work and oxygen demand. The increased sympathetic activity also leads to decreased renal blood flow due to vasoconstriction - of course this activates renin/AT system causing increased peripheral resistance (afterload), which is compensatory in terms of the decreased blood pressure, but which also increases load that heart has to work against. then the aldosterone system kicks in due to renin/at system, causing water and sodium retention and edema, again increasing workload on heart. this is congestive heart failure.... there are various ways to attack this sequence of events. a recent way is the ACE inhibitors. if you decrease the increased peripheral resistance, reduce edema, and decrease preload, you help a lot. this is probably the mechanism of choice. you could also attack the primary mechanism, the decreased force of contraction, using a - what? calcium channel blocker? NO. catecholamine? well, you already have high sympathetic activity. maintaining that increases workload, increasing contractility but at an expense. you only do this when you have really decompensated heart failure, the patient is in the hospital and is in complete heart failure, desperate states, then you might give a sympathomimetic. but in general, you want to get rid of water load (diuretics) nad then increase Fc without sympathetic stimulation. so you'd use digitalis. digitalis: what does it do? digitalis increases myocardial contractility. it gives you a larger ventricular stroke volume for the same ventricular end diastolic volume. in CHF (uncompensated), your stroke volume can be below half of normal at a normal ventricular end diastolic volume. now, if less blood is pumped out, less is coming back, but more is staying in the heart, the end diastolic volume increases, until you reach a normal stroke volume - but at a much much higher end diastolic volume. this is the point of frank starling compensation -but now you've got this big dilated heart that's working much harder. so with digitalis, you can increase force of myocardial contractility so that the stroke volume vs end diastolic volume curve is more normal. not entirely normal, but much better. now, you can reduce the end diastolic volume to much closer to normal, to get a normal stroke volume. ---end----