----start---- pharmacology 1/21/98 fluharty last time we reviewed the basic properties of catecholamine synth, release, and alpha and beta receptors of them. now we're ready to talk about sympathomimetics, which may have high subtype specificity for the NT receptor or which may act by promoting release of endogenous NT, in which case they don't have subtype specificity. brief educational exercise: structure:activity relationships. there is a whole area of pharm that concerns itself with developing drugs. when it comes to agonists, drugs that interact w/receptors in similar ways as endogenous compounds, it's a general rule that the best way to start making these drugs is to look at the structure of the endogenous compound, understand the real receptor/compound interaction, and go from there. understanding how structure of a drug relates to activity profile is the structure:activity relationship. this is the case for all kinds of drugs that are designed as agonists. so, this is particularly true for sympathomimetics but is also true as a general pharmacological principal - you start with endogenous compound, and go from there. we don't need to know the structures for the exams. however, it is useful to know, so you can look at package inserts and stuff and know how things are likely to work. going on from there: how have sympathomimetics been developed? what structural features alter activity of the drug? 6 carbon benzene ring, terminal amine, and the alpha and beta carbons between those structures - this is phenylethylamine, the backbone of the sympathomimetic compounds. then, you just add things to the alpha or beta carbon or onto the terminal amine. this is how you change selectivity or whatever. note: antagonists do not look like the endogenous compounds. anyway, a few general features. for a sympathomimetic compound to be potent, you need the backbone, and the two carbon separation between the benzene ring and the terminal amine. this allows it to be active at both alpha and beta receptors. as a general rule, the larger the substitution on the terminal amine, the greater potency at beta receptors. the exception to that rule is a methyl group. remember the structure of epinephrine - it's methylated norepi. when you put a methyl group on there, you make something very similar to epi, so it is potent at alpha and beta receptors. but generally, large substitutions on the terminal amine give beta selectivity. if you add hydroxyls to the 3 and 4 position of the benzene ring, you make something like a catecholamine, conferring maximal adrenergic potency but no selectivity. shifting a hydroxyl from the 4th to 5th position generates a more selective compound - beta receptor selective, and in fact more active at the beta 2 receptor - effective for relaxation of airway smooth muscle. if there are no hydroxyl groups on benzene ring, compound solubility and degradation changes - compound will be able to enter CNS - cause insomnia, etc. no OH on C3 results in compound not easily degraded by COMT (extracellular enzyme that transfers methyl group to the OH at C3), so compound tends to be orally effective. compounds degraded by COMT are not orally effective. also, if you have an OH on the beta carbon with no other OH, you get an indirectly acting compound that promotes endogenous substance release. other non OH substitutions on benzene rings produce substances like fenfluramine, which interact with other receptors like serotonin receptors, or may serve as template for an antagonist. if there's no benzene ring at all, like the ergot alkaloids, you get some alpha specificity. in general, with alpha carbon substitutions, you can no longer use MAO to deaminate the substance, so it will have prolonged activity. this is because you physically interfere with ability of MAO to dock and act on the molecule. there is not necessarily a change in specificity, but there's an increase in length of action. beta carbon substitutions - OH on beta carbon gives something that looks like epi and norepi. so you have increased potency at alpha and beta receptors. on p 10 of handout - isoproterenol - nonselective, beta adrenergic agonist (baa). this molecule has the two carbon separation, OH groups on C3 and C4, and OH on beta carbon - it looks like a catecholamine. but then, on the amino group is a large substitution which results in beta selectivity. it isn't selective for beta 1 or beta 2, though, b/c OH on benzene ring are still in 3 and 4 position, not the 3 and 5 position. but it's obviously potent as it resembles the catecholamines so closely. beta selectivity is also obvious due to substitution on terminal amine. that's the deal with structure activity relationships. ok. sympathomimetics: why we use them, what are some side effects? note: alpha adrenergic agonist = aaa; beta adrenergic agonist = baa major therapeutic uses: alpha receptor stimulation: often used when there is compromised circulation. sympathomimetics that are potent at alpha receptors - will produce increased BP in vascular beds, vasoconstriction - useful for local hemorrhage, hypotension, shock. the vasoconstrictive properties of alpha adrenergic agonists are very useful in these situations. alpha adrenergic agonists are also used as decongestants - nose drops, etc. phenylephrine, etc. produce constriction of vessels in nasal mucosa. most OTC decongestants like sudafed, etc are alpha adrenergic agonists (aaa). aaa also treat tachycardia by a reflexive action - baroreceptors detect the increased BP caused by the aaa, conduct info via afferents to cardiovascular centers in brainstem, and then produce vagal slowing of the heart - this is an autonomic reflex that can also be produced by carotid massage on one side. aaa are also used to treat glaucoma (they constrict engorged vessels in the eye to reduce intraocular vessels, and they decrease aqueous humor production) and to produce mydriasis (pupillary dilation) for eye exam. beta receptor stimulation: uses are a bit more limited, though some of them dovetail nicely with alpha receptor effects. include producing improved cardiac performance in dz states (beta 1) eg giving epi into the heart, or CHF can be treated this way. beta 2 receptors in airways are stimulated to produce relaxation of airways in asthmatics, etc. beta receptor (beta 3) in human fat is involved in metabolism - not sure about in animals. major side effects of sympathomimetics: can be nothing more than a nuisance, or can be really big problems. for beta receptors - excessive cardiac stimulation can result in arrhythmias and myocardial damage. you have to be careful. vascular difficulties associated with increased in blood pressure with aaa aaa and baa cause decreased GI motility and can result in nausea and vomiting. aaa and baaa can cause CNS effects such as headache and nausea when the drugs are lipid soluble. specific drugs: this discussion is not intended to be all inclusive. we'll focus on a few drugs, discuss why we'd use them based on known profiles of the drugs. some of the compounds are not that popular anymore. see table 2 p 12 and compare with table 1 from before. this is the key to autonomic pharmacology starting with most nonselective of compounds and get more selective. we'll also consider if it is direct, indirect, or mixed (stimulates receptor and produces endogenous release) alpha, beta1 and beta2 agonists: most nonselective: epinephrine: stimulates alpha, beta 1 and beta 2 (note that norepi doesn't stimulate beta 2). is used rapidly IV primarily as a cardiac stimulant - beta 1 activity main thing, also alpha activity stimulates coronary blood flow. also as bronchodilator in allergic reactions - beta 2 stimulation. alpha mediated constriction also helps to reduce congestion and edema. beta receptors are coupled to adenyl cyclase - increasing cAMP. so, sometimes you use beta 2 receptor agonists with phosphodiesterase inhibitors to prevent rapid breakdown of cAMP. because this is a potent, full agonist, desensitization can develop rapidly, so this is used as a temporary measure only. ephedrine: broad spectrum of activity at alpha, beta 1 and beta 2 receptors. has mixed action. the methyl on the alpha carbon prevents MAO from acting, so this has longer duration of action and also can be used orally. there's no OH on C3 so COMT can't act on it either. this is a longterm bronchodilator and decongestant in OTC medication. also is a mixed sympathomimetic, so it not only stimulates the receptor, but causes release of norepi from postganglionic neurons. for some compounds, being mixed isn't good, because it changes a potentially selective compound into a nonselective compound. here, it doesn't matter, this is already a nonselective drug. alpha and beta 1 agonists: sl more selective (no beta 2 activity): main thing you lose here is effect on airways - no bronchodilation with these drugs, but they're still good decongestants. norepinephrine: given IV like epi but doesn't have the beta 2 activity. used for pressor activity in cardiogenic shock (powerful alpha effects). concurrent beta 1 stimulation of heart can be a problem. desensitization develops quickly. mephentermine: used as pressor in hypotensive states - may be used to prevent hypotension with spinal anesthetics. alpha action stimulates increased BP, beta action stimulates increased CO. has longer duration of action - big substitution on alpha carbon prevents MAO action. mixed sympathomimetic metaraminol: used as pressor in hypotensive states like above. also mixed sympathomimetic. so these two drugs can give some beta 2 stimulation, due to endogenous NT release from adrenal medulla - but this would be transient. mainly acts on alpha and beta 1 receptors. metaraminol also acts as a false NT, but the consequences here are really initial displacement of norepi. dopamine - has a lot of usefulness in clinic esp to improve CO in shock due to beta 1 stimulation- inotropic action. especially effective in cases where renal function is compromised because it seems to dilate renal blood vessels via stimulation of dopamine receptors there, so helps maintain renal function during times of reduced perfusion. selective alpha1 stimulation: a. phenylephrine: potent alpha1 agonist with little beta activity. used as a decongestant (OTC) and was once used to treat atrial tachycardia (reflexive, due to increased BP invoking autonomic reflex and vagal slowing of the heart). very potent. notice it resembles epi but lacks an OH in the C4 position. b. methoxamine: also relatively potent for alpha1 receptors - more potent than phenylephrine - has methyl substitution on alpha carbon, so can't be deaminated by MAO (unlike phenylephrine). treats hypotensive crises and atrial tachycardia. might also possess beta adrenergic antagonist activity. selective alpha2 receptors - remember, these receptors are located presynaptically, as inhibitory autoreceptors on the nerve terminals a. clonidine: reduces norepinephrine release. also acts on brain to decrease sympathetic outflow. so, can shut down sympathetic activity during hypertensive states. even though it's an agonist it has opposite effects. some people say it has its own receptor in the brain. there is an associated withdrawal system - if you stop the drug, high BP returns, worse. nonselective beta stimulation: isoproterenol - this is the one we used as an example of a nonselective baa. directly acting compound. used in cardiac failure (beta 1) and bronchodilator (beta 2). used to be found in inhalers. if there is a heart problem, you wouldn't wnat to use this for asthma. then, you would use a beta2 selective agonist like terbutaline or metaproterenol. the beta 2 selective agonists - good bronchodilators used in asthma, often with phosphdiesterase inhibitors. terbutaline also used to treat preterm labor by relaxing the uterus. beta 1 selective agonist - dobutamine - new compound - affects the heart, improves cardiac function in heart failure without relaxing smooth muscle. positive inotropic agent. less effect on chronotropic activity (unlike epi), so less oxygen demand - increases force of contraction without increasing rate. may have some alpha adrenergic properties too - may contribute to overall inotropic mechanism of action. so. those are the drugs. three big major uses for these compounds - aaa useful to treat compromised circulatory situations - hemorrhage, shock, hypotension, tachycardia, and decongestion. b1aa - gets heart going. b2aa - bronchodilates. just don't want to go too far - aaa can increase BP too much, b1aa can cause MI if not enough O2 to heart, and both can decrease GI motility causing anorexia, nausea, and vomiting. ---break--- adrenergic blocking agents (aba) - the opposite of sympathomimetic/adrenergic agonists. the aba prevent the physiological effects of catecholamines. strictly speaking, can divide into two classes - presynaptic blocking agents - this means, interferes in some way w/release of norepi from postganglionic neurons. eg, inhibits synthesis, release, storage,etc. these compounds are inherently limited in usefulness since they are so nonselective. it is a real advantage to have antagonists specific for receptor subtypes. when we build antagonists, there isn't as much of a structure:activity relationship, so we don't have to get into that. see handout p 12. alpha receptor abas (alpha receptor antagonists) 1. major therapeutic uses of alpha receptor blockers are hypertension, preipheral vascular dz, shock (only as temporary measure, to produce vasodilation, and only with IV fluids at the same time, so you can fill vascular beds with fluids), heart failure with pulmonary congestion (decrease preload and afterload). opposite of alpha agonists. we use the alpha blockers in situations of excessive vascular constriction. these drugs are vasodilators 2. major side effects of alpha receptor antagonists: in a biped, postural hypotension is a big problem. it decreases total peripheral resistance, blood pools in venous side, you get up quickly and have a hypotensive crisis. increased GI motility - diarrhea nasal stuffiness - due to dilation of vessels in nasal mucosa increased blood volume and Na+ retention - problem when you use these drugs to tx high blood pressure, because you don't want volume expansion then. so you ofte use a diuretic to counter this effect. you're decreasing GFR. impaired ejaculation - blocking something- constriction? in the vas deferens. reflexive tachycardia - a side effect. you lower BP with drug, baroreceptor sends signal to brainstem, resulting in reflex increase in HR. increased norepi release can also occur - if you block alpha 2 receptors, which are inhibitory autoreceptors, you remove the inhibition, and increase the norepi release. this may not be a big deal, but it can occur. representative drugs: for agonists, we had to consider if drug was direct acting, indirect, or mixed. for antagonists, we think about if it is reversible or irreversible (competitive or noncompetitive). competitive/reversible - binds with high affinity to receptor, stays on receptor, preventing agonist from acting. reversible by displacing antagonist with tons of agonist. irreversible ones alter the receptor when they bind, so that that an agonist can't bind there after the antagonist dissociates. irreversible/noncompetitive means that recovery requires synthesis of new receptors. turnover rate for receptors may be several days. 1. irreversible and insurmountable alpha receptor antagonists: dibenamine and phenoxybenzamine. have high affinity for alpha receptors (maybe a tad more for alpha 1 than alpha 2). mechanism involves covalent binding to active site of receptor and a chemical modification of receptor - renders those receptors incapable of ever binding agonist. slow onset - takes about an hour - long duration of action - 3-4 days, typically, after withdrawal of compound, due to long halflife of g protein coupled receptors. recovery requires synthesis of new receptors. these drugs used to be used to treat hypertension, but aren't used as much any more. are orally active, as are many antagonists (because they don't look like the catecholamines and aren't degraded by COMT/MAO). pretty nonselective, but maybe more for alpha 1. before we talked about the adrenal pheochromocytoma which caused increased release of catecholamines. before surgery, you could block receptors with these drugs, instead of using a synthesis inhibitor. 2. surmountable/competitive/reversible antagonists of alpha receptors - faster onset, faster recovery. - phentolamine - fairly nonselective - alpha receptor antagonist. at clinical doses, 3x more selective for alpha 1 than alpha 2, but at high doses nonselective. blockade is transient. may have initial sympathomimetic activity. was originally made as antihypertensive drug, still used that way. potent at lowering BP, but does have cardiac complications - reflexive tachycardia due to autonomic adjustment, and at high doses blocks alpha 2 receptors which may increase norepi release. - ergot alkaloids - first alpha blockers discovered - product of a fungus that grows on rye. also relatively nonselective. their importance is decreasing over time. very complex hemodynamic profile -affect ANS and CNS and are partial agonists also. about the only thing they are used for is to stimulate uterine contractions, and that doesn't have much to do with alpha receptor properties. but, controls postpartum bleeding. also can be used to treat migraine. 3. selective alpha1 antagonist: prazosin - specifically blocks alpha1 postsynaptic receptors, doesn't increase norepi release, so less reflexive tachycardia. orally active and very good at treating hypertension. called "minipress". acts as vasodilator so limited usefulness in CHF as well. 4. selective alpha2 antagonist yohimbine - specifically blocks alpha2 receptor- opposite of clonidine - has sympathomimetic activity. increased norepi release. treats impotence in men, increased erectile state occurs. also reverses drugs like clonidine or other tranquilizer. so largely, the alpha adrenergic antagonists are used to treat high blood pressure around the world. side effect that limits the usefulness is the reflexive tachycardia which opposes the effectiveness of the drug. ok, beta receptor antagonists - when are they used? opposite of times when we use beta agonists. use to treat cardiac arrhythmia (but must avoid heart block). use to treat hypertension - how? they have a broad spectrum of activity - decrease CO by blocking cardiac B1 receptors, decrease renin release from kidney, so prevent vasoconstriction that way, and also decrease norepi release, b/c beta 2 stimulation is a facilatory autoreceptor which stimulates norepi release. also used prophylactically to prevent repeat myocardial infarction. coronary circulation is compromised, myocardium is damaged - you want to prevent HR from going up too high and becoming hypoxic. so these drugs prevent an increase in HR. some people complain about exercise intolerance with beta receptor antagonists. CNS effects - beta blockers were used to treat migraine for a while due to effects on cerebral blood flow, but not popular use anymore side effects - largely confined to heart too much heart block, decreased CO bronchoconstriction - nonselective beta receptor antagonists are totally contraindicated in asthmatics. don't want to block beta 2 in these patients. also contraindicated in diabetics - block compensatory responses to hypoglycemia, and in people they remove a perceptible cue that is used by diabetics to tell them they are hypoglycemic - sympathoadrenal response is activated during hypoglycemic state -> release of epinephrine which stimulates beta 1 receptors in the heart and increases HR. beta blockers will block this, and the diabetic may not recognize the hypoglycemic state. drugs: all reversible nonselective beta receptor blockers- propranolol aka inderal - the first real beta antagonist used to tx hypertension and prevent second MI. orally active. tx arrhythmia, hypertension (here you lower BP, but do not get any reflexive tachycardia, because you've blocked the beta 1 receptors). this is why these drugs are prescribed more than alpha antagonists for hypertension. problems with this drug - two - first, membrane stabilizing effect - propranolol is powerful beta adrenergic antagonist but also has some local anesthetic properties - so is much more powerful and therefore more risky wrt producing heart block. also, associated with withdrawal syndrome. not a problem until you stop the drug - then you get a return in exacerbated form of the original problem. pindolol, nadolol, timolol, - second generation beta blockers developed to avoid problems with inderol. pindolol - also a partial agonist - much less of a withdrawal syndrome. less decrease in cardiac function, because not a full antagonist. note that it establishes a level of antagonism because doesn't stimulate receptor as much as the endogenous substances. also, no membrane stabilizing properties so less likely to get heartblock nadolol - also no membrane stabilizing effects, less heart trouble. longer acting, can take once a day. (also atenolol is once a day) timolol - no membrane stabilizing properties, useful to manage chronic glaucoma - very short acting in eyedrops, decreases production of aqueous humor. new class of compounds - nonselective alpha1 and beta antagonist labetalol - used to treat hypertension. not only a beta antagonist, but also an alpha antagonist. so, lowers CO, renin release, and norepi release, AND produces vasodilation. no reflex tachycardia. selective beta receptor blockers beta1 selective - cardioselective - metoprolol (lopressor). as potent as propranolol at beta 1, 100x less potent at beta 2. much less pulmonary complication - won't affect airways. antihypertensive and cardiac drug. atenolol is also potent at beta1, much much less potent at beta2. beta2 selective blocker - butoxamine no clear therapeutic advantage. may decrease norepi release, but not that useful. blocks smooth muscle relaxation, no pronounced cardiac effects. so, in summary, when we use alpha antagonists, they help reduce BP during hypertensive crisis but you can see reflexive tachycardia and increased GI motility, diarrhea. beta antagonists decrease cardiac function, reduce BP, reduce renin release, prevent reinfarction, and can produce complications in asthmatics so you look for selective blockers. also contraindicated in diabetics. watch for full heart block with membrane stabilizing drugs eg inderal. also can see increased GI motility and diarrhea. ---break--- dr robinson - review - pharmacokinetics - email robinson@pharm.med.upenn.edu 1. you hav developed a new drug that has an amino group with pKa of 8.4 and no other charged groups. you want to give it orally. where will it be absorbed, and why? + ok, this weak base is R-NH3, we should assume. we know it has pKa 8.4, so it will be absorbed in the intestine because it is basic, and it will tend to \be uncharged in the basic environment of the intestine, so it will be uncharged, and uncharged particles will be better able to cross the membrane. + you have to realize - when he says "weak base" he means R-NH3 you want it to become uncharged, and it does that in a basic environment. the other thing that will happen with this kind of drug is that as you get more and more alkaline - plasma is pH 7.4, intestine is 8.4 - you find the unprotonated spp equilibrates across the membrane, so concentrations on both sides you can set equal to one, and now at pH 7.4, the charged species is favored by a factor of 10, and at pH 8.4 it's 50-50, so you have 11 units of drug in plasma, and 2 units in intestine. 2. your new drug has a half life of 6 hrs. you give one dose. how much of initial dose will remain at 24 hrs? 1/2 at 6 hrs 1/4 at 12 hrs 1/8 at 18 hrs 1/16 at 24 hrs 3. as you give higher doses, can the kinetics of elimination change? how and why? yes. enzymes and transport systems ("elimination systems") can become saturated. think of alcohol poisoning. also multidrug administration, when drugs use same elimination system. before saturation of the system, kinetics do not change. this prolongs the apparent half life. the kinetics do not slow down, per se, but the half life is prolonged. 4. you are considering giving the drug every 6 hrs. you'd like to minimize peak/trough variations because at high concentrations it causes toxicity. how do you want to adjust the rate of absorption to acheive this goal? what routes of administration would you use to do this? why? slow the rate of absorption. this has another advantage - you can reduce the frequency of dosing. good with antiparasitic agents in cattle :). you could use oral administration of time release formulations, you could use transdermal patches, you could give it IM, or you could put in a subcutaneous implant like Norplant. there are also some new drugs coming out that are biodegradable polymers - you put a pellet with the drug into the body, and it diffuses locally - good for chemotherapy. 5. the volume of distribution is 150 L in a 20 kg dog, yet a 20 kg dog has only 14 L of total body fluid. name two factors that could explain the volume of distribution being larger than the total volume of the individual. could this alter the pharmacokinetics of the drug? consider the graph in the handout of drug concentration vs time for a drug with a large Vd - you have that two compartment model. 150 L in 20 kg dog = 7.5 L/kg 20 kg dog --> 14 L body fluid trapping the drug in fat, or in a particular organ, like the rumen (weak bases get trapped there), will increase the volume of distribution. pharmacokinetics may display a two compartment model - rapid phase and prolonged phase. this would "sort of" slow the rate of elimination from plasma because it isn't getting into plasma. 6. a) will a weak acid with a pKa of 4.4 be better absorbed in the stomach or intestine? stomach. the acid will become uncharged in the acid environment of the stomach. b) a series of weak base derivatives of a new drug have similar pharmacodynamic properties but have 3 different pKas - A = 5.6, B= 6.6, C = 7.6. which is best absorbed in the intestine, and why? pH of intestine is drug A - pKa 5.6 - drug B drug C drug A pka 5.6 you end up with 1.01 in plasma to 1.001 in intestine for drug B: pKa = 6.6 both plasma and intestine, environment is alkaline compared to pKa. let concentration of B = 1 on both sides, and BH+ is .01 on intestine side, and .1 on plasma side, so you have 1.1 in plasma and 1.01 on intestine side C, pKa 7.6, will be best absorbed in the intestine, because it is a weak base. we're assuming pH of intestine as 8.6 and pH of plasma of 7.6. weak base will equilibrate across membrane so at pH 7.6 B and BH+ are equal at concentrations of 1 each (on the plasma side) and at pH 8.6, there is 1 B and 0.1 B+, so you have a 2:1.1 ratio of drug in plasma to drug in intestine. HOWEVER - if you assume you're in an acid part of the intestine, before it gets alkaline, then drug A is best absorbed. ** note to self ** go over #6! 7. a 10 mg/kg dose of a drug is given by IV injection to a 20 kg dog. what is the volume of distribution of the drug if plasma concentration is 0.1 mg/L (assume instantaneous distribution).? what would the volume of distribution be if the same drug had been given orally and only 50% of the drug was absorbed (the concentration of drug at time zero is 0.1 mg/L)? give units! Vd = bioavailable dose/plasma concentration plasma concentration after distribution and prior to any elimination is 0.1 mg/L note that when you give drug IV, it is all bioavailable. bioavailable dose: 10 mg/kg x 20 kg = 200 mg Vd = 200 mg/0.1 mg/L = 2000 L => normalize for body weight by dividing by body wt 2000 L / 20 Kg = 100 L/kg (you don't have to normalize for body wt, though) if only 50% was absorbed, it would be 50 L/kg 8. how much drug is eliminated after 4 half lives? what happens to elimination if system becomes saturated? 15/16ths, or 94% if system becomes saturated, elimination will stop/slow. 9. rate constant for elimination of a drug is 0.1 per hour. what is the half life for elimination? volume of distribution is 200 L in a 10 kg dog. what is the clearance? give units. half life = 0.693/rate constant = 0.693/.1 = 6.93 hours Vd = 200 L in a 10 kg dog --> normalized = 20 L/kg Cl = Ke * Vd = 0.1 h-1 * 20 L/kg = 2 L/hr/kg 10. what are the possible routes of administration of a drug that is absorbed essentially instantaneously? name at least three. nasal sublingual IV inhalation 11. you plan to give a new drug that has to be given repeatedly to have the desired therapeutic effect. you plan to give it at an interval that approximates the half life for elimination. how many doses have to be given before plasma concentration plateaus? drugs is available in two formulations - normal oral form and time release form. you are worried about possible toxic side effects. which formulation would you choose and why? 4 doses have to be given before plasma concentration plateaus. if you give drug at every halflife interval, this is how it works out. dose 1: 1 dose 2: 0.5 + 1 = 1.5 dose 3: 0.75 + 1 = 1.75 dose 4: 0.875 + 1 = 1.875 dose 5: 0.9 + 1 = 1.9 so you end up giving a loading dose to get to therapeutic level right away, then put on standard dose. when you're concerned about the toxic side effects, you would use the time release form. if you make rate of absorption = rate of elimination, you get a nice even plateau instead of a yo-yo effect. 12. a new anxiolytic is available. a test dose - 10 mg given to 20 kg dog - yielded the data below. construct a concentration vs time curve. time (hours) plasma conc (ng/mL) 0.2 150 0.4 50 0.6 38 1 32 2 22 4 16.5 8 10.5 12 6.5 16 4 20 2.6 you get a curve, starts at high conc and goes down. first point is 12 min. this tells us the drug is absorbed essentially instantaneously - so was given IV, nasal, or inhalation route. graph is biphasic on this log scale - two connected lines - so this means pharmacokinetically that it is a 2 compartment or more system. first distributes in central compartment - blood, highly perfused organs half life for redistribution phase and elimination phase? half life for metabolism - 6 hrs? 8 hrs 10.5, 20 hrs 2.6 -> two half lives occurred in 12 hrs. so half life is 6 hrs. based on that, what's the halflife for redistribution? 0.2 hrs or about 12 minutes. redistribution occurs very quickly. we see this because at t=0.2 conc = 150, then it goes to 38 in two increments of 0.2 hrs. the rest of this I do not want to think about. ---end---