Adv Pharm final exam

Factors (4) determining how a receptor will respond to a drug:

1.Receptor's affinity (strength of binding) for the drug 2.The quantity of receptors available and the amount of drug presented to the receptors 3.The efficacy of the drug 4.The potency of the drug Cell receptors think of musicle chairs because there are different receptors respond to different drugs Their receptors affinity, so the strength of the binding, the efficacy and potiency and the quality of receptors avalaible Are they all saturated or not Because drugs and receptors have sizes shapes and chemical properties You can have chirality meaning stereoisomers The idea of the different shapes and molecules effect differently and have different effects on the body Agnonist has an increased cellular activity Antagonist have a decreased cellular activity Drug receptor interactions have a generally defined as once a receptor site is saturated and has the specificity for receptor the site can decrease the response Usually specificity and receptibility when there is the specifics of a molecule But once that is saturated you can have a down regulation of the actual specificity of the drug

FDA Pregnancy Risk Categories

A : adequate and well controlled studies indicate no risk to fetus B : animal studies indicate no risk to fetus, yet no well controlled studies in pregnant women C : animal studies have reported adverse effects, no well controlled studies in humans, but benefits may outweigh risk D : positive human fetal risk has been demonstrated X : fetal abnormalities reported and positive evidence fetal risk in human or animal studies This is the historic older version of the FDA pregnancy risk category properally familary with A and B are drugs that have been around for a long time X is something that has some true tetotrogensy associated with it

agonist drug

A drug that binds to a receptor and triggers a response in the cell, which mimics or enhances a neurotransmitter's effect.

Adverse Drug Reactions in the Elderly

Adverse drug reactions increase with the number of drugs taken -Average elder in LTC takes 6-8 prescriptions -10% of patients taking one drug have adverse reactions -100% of patients taking 10 drugs have adverse reactions -Practitioner errors (not recognizing the pharmacokinetic changes of aging; not recognizing incompatible drug combinations) -Patient errors (non-compliance; use of over the counter drugs; physical disability) Looking at what is normal, most people that take 10 drugs or more are going to have some type of adverse reaction so it is important for us to be aware of things like changes with aging, drug drug interaction, as well as the patient errors So their belief system about it, their physicial state, Can they not open the bottles that are given to them from the pharmacy? Are they also using something else, like an over the counter asprin that is interacting with the other medications they are taking

Perinatal Pharmacodynamics

An important side note: -"A, B, C" categories have been dispensed of in favor of specified narratives for each drug Take away thoughts on this: -D and X will STILL be contraindicated in pregnant persons -It is good to know both updated pregnancy guidelines and older "terms" including A-B-C classifications, as it is a "language" of medicine -ALWAYS LOOK UP THE DRUG WHEN PRESCRIBING TO A PREGNANT PERSON (i.e. Zofran) The book talks about this We will still contraindicate with D and X but you want to look at the drug and you want to look at what is going on with the patient Sometimes there is a risk v benefit So if the mom has a pretty severe depression may want to look at the risk vs benefit of the SSRI med, the baby may get withdrawl but if she is not treated then the baby may not make it

Beta blockers

BB are used in treatment of cardiac disorders including HF and asymptomatic left ventricular dysfunction and after an acute MI they act by occupying beta receptor sites and competitively preventing occupancy of these sites by catecholamines and other beta agonist a major difference among these drugs is their selectivity for beta 1 and beta 2 receptor sites and this difference has important implications these drugs blockade beta-andrengic receptors and they are usually reffered to as beta blockers the highest concentration of B1 adrenergic receptors is located in the heart and when bound with NE and epinephrine they influence heart rate and myocardial contraction blockage of beta adrenergic receptors produces clinically significant action on the cardiovascular, renal, and respiratory system of the eye beta blockers are contraindicate in patient with respiratory conditions that include a bronchospastic component although there are beta 1 selective drugs, that have less effect on the beta 2 receptors in the lungs, to date no beta blockers is suffiencently selective to beta 1 to completely reduce the risk of beta 1 blockage these drugs are also contraindicated for patients with AV block because their actions to decrease heart rate and myocardial contracility result in increased reduction in cardiac output and worsening failure older adults often have limited cardiac and renal reserves. beta blockers are used to treat conditions that are common in older adults, but care must be taken with dosing beta blockers may precipitate or exacerbate type 2 diabetes, because of the effects on the carbohydrate metabolism and their ability to mask the common symptoms of hypoglycemia should use caution in patients with type 2 diabetes

Beers Criteria

Beers criteria for potentially inappropriate medications for the elderly Assignment: table & short summary in your own words •Basic principles behind the Beers Criteria •Discussion of the original 1991 paper & most recent 2019 updates •A list/table of medications / classes that are on the current Beers list: -***DO NOT COPY AND PASTE*** Please properly cite the Beers articles listed and create your OWN table. •àcreate your own list (can access when in clinicals) •May use bullet-points for some concepts Going to look at beers criteria, look at basic principles LOOK AT STUDY GUIDE

Perinatal Pharmacodynamics

Counseling women about teratogenic risk -Since thalidomide, medicine has been practiced as if every drug is a potential human teratogen -<30 drugs have been identified as teratogenic -Baseline teratogenic risk (without exposure) is about 3% -Must also address the maternal-fetal risks of the untreated condition if medication is avoided •Ex. Serious morbidity has been seen in women who have discontinued SSRIs during pregnancy This is talking about looking at tetrogensis vs the molecular effect This is why she talks about the molecular size Whats going on because that will also move into when we are looking at women who are breast feeding Is it going to come through the blood What is the half life of the medication

Blood-Brain Barrier

Dopamine, barbiturates can pass Lipid-soluble: atropine Anesthetics, psychotropics can cross barrier Neuro drugs we have to use a lot of these Make sure that these pass to make sure someone is asleep This will come into play when we look at the CNS medciation that effect he blood brain barrier, pain, seizure meds

Pharmacokinetics : PRODRUGS

Drugs must be able to reach their intended site of action after administration - Some are given as a precursor chemical called a prodrug that travels to its site of action and is then converted to the active drug. Examples of prodrugs •Levodopa (DOPA decarboxylase) to dopamine •Enalapril (esterase) to enalaprilat •Prednisone (CYP450's) to prednisolone •Heroin (esterase) or codeine (CYP2D6) to morphine • The prodrug principle can also be used to direct drugs to certain types of cells while leaving neighboring cells alone Predisone is turned into prednisolone With children do prednisolone With older adults predisone Never give Tylenol #3 to a pregnant person codeine turns into morphine Prednisolone is the active form and give to pediatrics Examples of prodrugs are these above This can be helpful when we are moving drug to active form Helpful when treating pregnant patients They are subject to meds given There was a pregnant patient that was taken care of she had an injury and had sutures, they gave her a medication for pain She was not sure if this was safe or not The prescriber wrote Tylenol with coden- coden is a prodrug and turned into morphine When pregnant the drugs (pro-drug) metabolise on top of eachother and increase the dose Cannot give a pro-drug without thinking about metabolism on fetus It will increase metabolism Perset may be safer because it will not be activated inside the body Pro-drug will reach toxic levels inside the body in pregnant women prodrugs can also have disadvtanges, terfernadine was a popular nonsedating antihistamine first pass metabolism by CYP3A4 biotransforms terfenadine, which is cardiotoxic, to fexofenadine to an antihistamine this inhibition could cause toxicity and death in some patients so it was replaced with active fexofenadine

As we age...our bodies change... slide 117

Ex: 75kg male/female Adults 20-30 years Adults 60-80 years % weight as water 60% 53% Lean muscle mass (Baseline) > 20% reduction % body weight as fat 26 - 33% (women) 18 - 20% (men) 38- 45% (women) 36 - 38% (men) Serum albumin (avg) 4.7 g/dL 3.8 g/dL Relative kidney weight 100% 80% Relative hepatic blood flow 100% 55-60% As we change our bodies change This is an average 75kg man or women These are a peak time 20-30 Things will start to go down at 30 Less hepatic blood flow, things shrink Look at what are we treating and is it safe to give

T ½ in Practice

Go from: Cp= concentration at time 1 •Cp - > Cp/2 in 1 half-life i.e. 50.0 % lost 50.0 %Cp - > Cp/4 in 2 half-lives i.e. 25.0 % lost 75.0 %Cp - > Cp/8 in 3 half-lives i.e. 12.5 % lost 87.5 %Cp - > Cp/16 in 4 half-lives i.e. 6.25 % lost 93.75 %Cp - > Cp/32 in 5 half-lives i.e. 3.125 % lost 96.875 %Cp - > Cp/64 in 6 half-lives i.e. 1.563 % lost 98.438 %Cp - > Cp/128 in 7 half-lives i.e. 0.781 % lost 99.219 % Thus over 95 % is lost or eliminated after 5 half-lives. When you get to 5 half lifes you get about 95% The goats are constantly coming in and out, have half lifes to get rid of the drug and then half lifes to leave, a specific dose that needs to happen If the drug is bad and see how long it will take to get out of the system Zpac and get a loading dose and then start them Look at drugs and look at their half life Nitroglycerin and zofran have different half lives The half life to check to see if you have enough to work and to also enough to excrete How long it takes to turn on and turn off After 5 half lives then the drug concentration is down to 96% it is almost all done At 7 half lifes 99% Worry about 5 half lives for the drug to eliminate This is why it takes a lot of time for things to reach a steady state Like paxil has a short half life, when deprescribing, it can have a faster side effect because half life fast

Pharmacodynamics

Pharmacodynamics: Drug-receptor activity Agonist-receptor: perfect fit for pharmacologic response

Pharmacokinetics

Pharmokinetics- is a branch of pharmacology dealing with the absorption, distribution, metabolism and excretion of the drug Remember that K- pharmacokinetics K-change in the body Need to have the drug in a usable form and move out through kidneys for renal elimination Pharmokinetics- is a branch of pharmacology dealing with the absorption, distribution, metabolism and excretion of the drug

Perinatal Pharmacokin

Placental drug transfer and drug effects on the developing infant depends on: 1.Physiochemical properties of the drug 2.Rate of transfer across the placenta 3.Amount of drug that reaches the child 4.Duration of exposure 5.Drug distribution characteristics in the child 6.Stage of child development at exposure 7.Drug effects when used in combination How much of the drug can cross the placenta and reach the child and what is the duration of exposure There may be specific language about what is safe for a infant and what is the FDA pregnancy risk categories

Perinatal Pharmacodynamics

Predictable Toxic Drug Actions -Chronic opioid use -ACE inhibitor Diethylstilbestrol Sometimes we have predictable toxic drug actions If you have a mom who is a chronic opioid user don't want her to sudden stop because not only her but the fetus will be going through withdrawl The fetus may not make it If the mom is addicted to heroin and on high dose then work with her to come up with a plan to monitor pain and keep her in a steady state She can deal with withdrawl once the baby is born

Polypharmacy

Significant factor in the morbidity and mortality of elderly patients -Explore alternatives -Combination therapy -Start low, go slow, get to goal -Simplify the regimen -Med boxes -Educate patients and caregivers -Review medications (med reconciliation) all prescribers working with these populations should take care to minimize polypharmacy, unless clinically necessary, to reduce the risk of drug-drug interactions confusion between medications and drug accumulation with insufficient renal and hepatic function

Perinatal Pharmacodynamics

Teratogenic Drug Actions -A single exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure -Teratogenic mechanisms - poorly understood, probably multifactorial. Possible factors: • primary effects on maternal tissues with secondary effects of fetal tissues • interfere with passage of oxygen or nutrients • direct actions on the process of differentiation of developing tissues • due to a deficiency of a critical substance This is why to look up the drugs The various safety classes change Zofran has changed that it used to be given in first trimester and then some said it can cause heart issues Changes of safety can occur over time

Perinatal Pharmacodynamics

Teratogenic Drug Actions -A substance or process is considered a teratogen if it: •Results in a characteristic set of malformations with selectivity for certain target organs •Exerts its effects at a particular stage of fetal development •Shows a dose dependent incidence There is a concept of tetaterogenic drug interaction and not specifically refers to a characterstic set of malformation that reach certain target organs

common ACEI

The other drugs, lisnopril- these are a longer acting, used most in the outpatient setting Can see the initial dose and the maximum dose Typically what we do, start low and then go slow, and then we get to goal We have to be careful that just cause a negative side effect and not have the actual therapeutic effect Manage the patient and have them come in two weeks after they start the medication to see how they are responding Anapril is a prodrug for anaprolat Almost every test question- first line is HCTZ- 12.5mg daily, check in 2-3 weeks Always start with life style measures- always try to start with the lowest dose possible Want to balance tolerance with what is the therapeutic goal Do not want to use more than we have to to get to therapeutic range ANGIOTENSION 2- ARBS- act on the angiotension aldosterone system, good in kindey disease until late stage, less likely to have cough No everyone that is on an ACE is on because it is high, they may be on it because have microalbumina

Perinatal Pharmacodynamics

Therapeutic Drug Actions in the Fetus : fetal therapeutics is an emerging area -Drugs are administered to the mother with the child as the target •Corticosteroids - stimulate fetal lung circulation •Phenobarbital - induces fetal hepatic enzymes for glucuronidation of bilirubin and decreased jaundice •Antidysrhythmics - given to mothers for treatment of fetal cardiac dysrhythmias •Zidovudine - decreases HIV transmission from mother to child by 2/3 (combinations can eliminate fetal infection almost entirely) Sometimes we have a therapeutic region If you have a mom who is going to go in preterm labor, you may need to give her more corticosteroids because I need try to facilitate fetal lung circulation If we have cardiac dysrthmia, can give an antidsyrthmia Can give zidovudine if you have an HIV positive mom and want to try to prevent transmission to fetus

slide 42 keep in back pocket

These can all interact with eachother So caffine with a med can cause them do have a build up because it eats less The table, can see that st johns wart is an inducer and grape through juice is a inhibitor Want to worry about over the counter meds can effect metabolism as well Example of man that smokes and drinks coffee, if he stops smoking, but still drinks coffee, he is going to have to cut back because coffee is an inducer of the CYP182 so if he keeps drinking large amounts of coffee he will feel toxic effects Make sure look at whole picture of patients This is a good slide to keep in back pocket Things that are picked out from the text as well as other resources Beta blocker need to know which beta blocker and which statin Fast metabolizers and slow metabolizers along the pathway Paxil and totral together then this can cause a 2d6 system issues Minor pathway is cyp2d6 Major is cyp2c9 Cyp system is strictly talking about metabolism Such as an inducer or an inhibitor Know both for induction and inhibition Easy one- tabocco and caffine- smoker is an inducer, if you stop smoking and drink the amount of caffine, it will intensify because its not moving along as fast because the tobacco was the inducer and ate it up Lipitor and grape fruit juice- is increasing the pathway where Lipitor is metabolized and an increase amount, more of the drug than is prescribed, can have more rhabdomylosis Lipitor is a high intensity statin Start them on pravator (moderate) Try to get categories of low, moderate and high

antagonist drugs

drugs that block or change the effects of an addictive drug

Perinatal Pharmacology

in pregnant women and rapidly maturing infants special pharmacokinetic factors exist -In many cases, the pharmacodynamic information (receptor characteristics, receptor responses, etc.) is incomplete, if not completely unknown •Most drugs can cross the placenta •Developing infant is exposed to -Pharmacologic effects -Teratogenic effects When we look at perinatal effects Pharamcology this is very specific to what is happenng in the female body as the fetus is gestating Developing infant can be exposed pharmacologic and teratogenic effects

bioavaliability

not all of the administered doses may be dissolved, absorbed, or survive liver metabolism, only a fraction of an administered dose makes it to the bloodstream this percentage of the administered dose that dose enter the blood stream is called bioavaliability of the dosage form when the bioavaliability of an oral preparation is low, a higher dose will be given, so that amounts reaching the blood stream are similar ex. 500mg po cipro, will be 400mg IV cipro

Angiotensin II Receptor Blockers (continued_1)

sartan suffix Want to know whether the drug is being used on label or off label use If something goes wrong with this drug, then it is us that will be sued Need to know why we are using the drug Clinical note for soap notes- need to write why we would use this drug

pharmacodynamic factors

the pharmacodynamics of a drug must be specific and selective to target the tissues affected by the disease to have the greatest theraputic effect with the least severe adverse side effects the relationship between a drugs desired theraputic effects and its adverse effects is called its therapeutic index drugs with low or narrow therputic index may require close monitoring for toxicity or adverse effect whereas drugs with wide theraputic index are fairly safe and require less monitoring

first pass metabolism

the substance degradation of an orally administered drug caused by enzyme metabolism in the liver before the drug reaches the systemic circulation This is a pocture showing the difference btween nasal, intravaginal, IV, PO The nasal can go directly into the veins where as PO has to go through first pass and go through the stomach and then move to the liver And then metabolized Does the medication need to be activated immediately, does it need to skip the first pass. This helps us decide why to use a med specifically

pharmacokinetic factors

when deciding which drug in a class to prescribe, the pharmacokinetic properties of a drug may influence drug selection example is drugs within a drug class may differ in their ability to cross the blood-brain barrier, either being more effective (anti-seizure) or causing CNS effects (1st gen antihistamines) another consideration is metabolism, different drugs in a class may use different CYP450 enzymes, which may influence metabolism or drug interaction

SSRIs (continued_1)

§ADRs •CNS, GI, sexual dysfunction •Serotonin syndrome §Patient education •Adherence, avoidance of alcohol, avoidance of OTC medications that stimulate, insomnia or drowsiness, suicide ideation •Pregnancy: Category B, C, or D •Withdrawal symptoms if abruptly discontinued Common side effects includes sexual dysfunction, or nausea, diarrhea, abdominal discomfort Can have some sleep disturbances Seratonin syndrome is a very rare complication of use of seratonin medication If they have serotonin syndrome They are going to have a fast heart rate, look febrile, look very ill, often present to the emergency room with a history of using these medication Keep in mind what else the patient is using If you have all these drugs going along the pathway, if the SSRI is a 2d6 then will get a serotonin syndrome because the pathway of the 2d6 is being inhibited by the other medication A lot of these drugs we want to avoid alcohol and avoiding other things that can stimulate or cause insomnia or drowsiness Pregnancy categories vary widely Something like Zoloft is a category B but something like paxal is a category D Often withdraw symptoms if abduptly discontinued Make sure they don't feel uncomfortable when we plan to D/c most common adverse side effects include nausea, and sometimes vomitting, light-headedness, dizziness, dry mouth, increased sweatiing, weight gain or loss, exacerbation of anxiety and aggitation sexual side effects may occur in up to 35% of patients and may manifest as delayed, diminished or absent organsim, premature ejactulation and decreased libido a significant adverse side effect is serotonin symdrome which can occur in the presence of excessive serotonergic activity maximum recommendation dose must be adhered to and adjuntive combinations of serotoneric agents must be avoided, and adequet time for titration when changing from one serotonergic to another must be provided symptoms of seratonin syndrome include nausea, dizziness, and paresthesia, electric shock and visual tracers with eye movement fluoxetine is the only SSRI that does not require gradual and slow tapering because of its long half life

Angiotensin II Receptor Blockers (continued_2)

§ADRs: similar to ACEIs •Typically no problem with cough §Monitoring •Like ACEI orthostasis with dose changes §Patient education •Do not double dose if one is missed Hypotension most common ADR Typically no problem with the cough but keep in mind that their can be Orthostasis as a potiental side effect

New Approach to Targets

§After serial BP measurements indicate a persistent 150 to 160 mm Hg systolic blood pressure (SBP) in individuals without other major deep vein risks: •Medications are initiated after diet and exercise. •Target values below 140 mm Hg SBP are not rigidly enforced if adherence to medications and exercise have proven beneficial, especially in older adults with hypotensive episodes. Goal blood pressure, care about systolic and diastolic when think about end organ damage If we are able to reduce the blood pressure then we can reduce things like stroke, myocardial infarction and heart failure As you may know, when you have increase pressure on the lining of the blood pressure can cause cracks in the endothelium and lead to development of clot

Drugs Affecting the Sympathetic (Adrenergic) Nervous System

§Alpha-adrenergic physiological activities •Vasoconstriction of arterioles, resulting in higher blood pressure •Pupil dilation Relaxation of the gut §Beta-adrenergic physiological activities •Cardiac acceleration and increased contractility •Vasodilation of arterioles supplying skeletal muscles •Bronchial relaxation •Uterine relaxation the parasympethetic nervous system is made up of the neurotransmitters Ach (acetylcholine), and the sympethetic nervous system and its neurotransmitters are epinephrine, noroepinephrine and dopamine The sympathetic system is associated with the "fight-or-flight" response, and parasympathetic activity is often referred to as "rest and digest."

Pathophysiology of Hyperlipidemia

§Atherosclerosis major cause of coronary artery disease §Lipoproteins: all contain triglycerides (TGs), phospholipids, and cholesterol •Low density (LDL) •High density (HDL) •Very low density (VLDL) •TGs As we know, we all have cholesteral and fat in our bodies, it is a handy tool for developing our brains and hormone levels Helps with structure of the cells We want to be careful of high triglycerides, even though it is a fuel source Higher triglyceridemia is associated with heart disease If you draw blood on the patient, the triglyceride around 1100 It will look foamy like a gineuss Be careful on how to present that to a patient LDL is our primary treatment target If you have someone who has a very high LDL, this is what we want to lower with cholesterol medication The lousy cholesterol When these are damaged with free radicals or oxidated stress they trigger the immune mechanism and the macrophages will start to eat the the damaged LDL Once the macrophages get going it is more difficult to stop them and once they eat more LDLs there can be an over abundance of macrophage While a macrophage eating an LDL is not a bad thing, the problem is if there is too many LDL The macrophages they are kind of like big dumb cows, they keep eating and eating and eating These gigantic macrophages can get to the intermal lining of the blood vessels and get stuck and then this can how you accumulate fatty streaks This is why we need to treat it aggressively, especially for those who are at increased risk for metabolic syndrome Lasix will effect the sodium and the solutes In our general lipid profile, ADL, HDL, VLDL, cholesterol LDL is more tricky to lower, statin do all the things we want them to do Triglycerides can be high for a number of reasons, the only thing that will be off in a not fasting is the triglycerides Triglycerides can be high if sugar in the systems (i.e diabetes) or if chronic alcohol user Higher cholesterol will create fatty deposit on children serum fat and cholesterol are carried in the circulation in complexes of lipids and proteins called lipoproteins fat is transported as TG and phospholipids, and cholesterol is transported in free and esterified forms most of the cholesterol is carried in LD

BBs for Angina

§BBs decrease the force of myocardial contractility and decrease heart rate and conduction velocity. §BBs decrease systemic vascular resistance and BP (afterload). §Decreased myocardial oxygen demand = decreased anginal pain. With beta blockers up and down regulation of cells To go over this, this relates to our beta blockers With beta blockers it is blocking the receptor site of the beta receptors on the cell, blocks action in the heart, blocks the aginergic receptor in heart This is helpful to slow the heart rate down and help move the force and help relieve some of that systemic vascular resistance The beta blockers will help with the pain of angina and help with oxygen demand Upregulation is what we will see with our beta blockers Blocking the receptors of the beta in our cells So if you have this block, taking this blocker for a long period of time will have an increase in number in the sensitivity and number of receptor cells It is not being stimulated so its got an increase in the sensitivity When you stop the medication can have quit a rebound of the tachycardia and blood pressure This is why beta blockers need to be weened over a course of a month 2-4 weeks is what it typically says in various text books Do not quickly stop the beta blocker due to the upregulation at the cellular site

Statins: HMG CoA Reductase Inhibitors

§Block synthesis of cholesterol in the liver by competitively inhibiting HMG CoA reductase activity §Decrease levels of LDL by 25% to 65% §Modest decreases in TGs (10% to 40%) and very modest increases in HDL (5% to 17%) may occur. §Pregnancy: old category X; fully contraindicated These will block the synthesis in the liver This can decrease LDL by about 50% and decrease triglycerides and increase HDL This is our go to drugs Most patients are started on this We have had some improvement of medication This is not something you want to give to someone who is planning on achieving a pregnancy any time soon They block synthesis in the liver inhibiting HMC CoA reductase It blocks conversion of metaolic acid It is also doing its activity in the liver As we are managing a partient Myagia is the number one side effect!!!! Do not start them on a high dose Start on a low or moderate dose Want to watch- this is where we take time with patient and with the side effects If they have this problem, then call us Give cocu10 with the statin- this is what helps with muscle pain We do not want them on a bunch of stuff that will hurt the liver as well Cholesterol is produced at night, so take med at night

Pathophysiology of Hyperlipidemia (continued)

§Exogenous pathway: involves absorption of lipids via intestine §Endogenous pathway: lipids originate from liver The book goes into this and differentiating the exhauginist pathway and the endogingous pathway Lipids can orginate from the liver and be formed through that People may be very fobic of statin drugs, ask where they are willing to wiggle or move If they have high fat diet, guidelines of when to start statins Guidelines for boards- start low, go slow, something that does not have a lot of drug interactions Fluvastatin may be a friend Pediatric life style measures- family life style measures

CCB

§Functionally act as vasodilators, lowering calcium (Ca++) influx into smooth muscles §First choice for African Americans with HTN •Can be used as add-on medications for others They lower calcium into smooth muscles They are one of our first choice with our African American patients Start someone on stage 2 with a calcium channel blocker and pair it with a thaizde or an arb *****good definition to remember Calcium channel and what that does, it causes relaxation of the smooth muscle, potiental swelling, this is how it is acting to lower the blood pressure This should not effect solutes, like sugar or uric acids CCBs have multiple indications including angina, HTN, and selected tachyarrthymias The L-type or long last, channels are predominant in cardiac and smooth muscle and are the ones blocked by most calcium channel blockers

SNRIs

§Major depressive disorder, general anxiety disorder, neuropathy pain, fibromyalgia •NOT approved by U.S. Food and Drug Administration (FDA) for use in children §Considered "atypical antidepressants" §Pharmacodynamics •Inhibit reuptake of both norepinephrine and serotonin Consider these for fibromyalgia, neuropathic pain Want to be careful with what else is going on with the patient Some fibromyalgia want to have opioids for there pain An SNRI is actually more apporpiate for the patient because it can increase serotonin Fibromyalgia causes a decrease in serotonin Need to look at big picture venlafaxine (effexor or effexor XR), dsvenlafaxine (pristiq), duloxetine (Cymbalta), milnacipran (savalla) and levomilnacipan (Fetzima). Milancipran (Savella) was approved by FDA to treat fibromyalgia Nefazodone is an serotnin antagonist and reuptake inhibitor that inhibits reuptake of norepinephrine Venlafaxine, duloxetine, and desvenlafaxine block the serotonin and norepinephrine transporters and inhibit reuptake of the NT and increasing the avaliability to bind with the postsynaptic receptors the exact mechanism of action of milnacipran and levomilnacipran is unknown but it is thought that they inhibit reuptake of serotonin and norepinephrine

CCBs (continued_1)

§Metabolized by the liver, CYP450 3A4. §ADRs: very constipating and can cause dizziness, headache, edema, rash, and gingival hyperplasia. §Monitoring •Verapamil has strongest negative inotropic effect and should be avoided in patients with HF. •CCB/ACE combination decreases peripheral edema by 50% vs high-dose CCB alone. Calcium channel blockers are metabolized by the liver They can be constipating and cause things like dizziness (orthostatic hypotension), edmea is a side effect It causes vasodilation of the smooth muscles and cause things like swelling Boards question Can see off lable use of calcium channel blockers in use of a kidney stone and can use calcium channel blockers on our patients in raynauds because we are having problem with vasopasms Gingival hyperplagia- important to familiarize ourselves with some of these side effects If they have gum issues, then maybe it's the drug that we are prescribing, mechanism of action within the drug category and then side effects Vasodilation!! Common with calcium channel blocker Verapamil- is the major one in the room, problem in heart failure patients all CCBs are well absorbed orally but there is a variance in the bioavaliability among them verpamil and diltaizem prototype type 1 CCB, are rapidly absorbed but rapidly metabolized to yeild bioavaliabilities distribution is to most body tissues with only nimodipine crossing the blood brain barrier all CCBs cross the placenta all CCBs are extensively metabolized by the liver via the CYP3A4 channel. Inducers and inhibitors of that isoenzyme system can affect CCB metabolism this is more of a problem for type 1 CCBs than for dihydropyridines. Many CCBs have elimination routines in both the urine and the feces

SSRIs (continued_2)

§Monitoring •Never give more than 4 weeks on first prescription. •Monitor target symptoms. Ssri are titrated up slowly, usually over 6-8 weeks It takes 6-8 weeks to feel better so this is something that may take patients and time One clinical pearl is especially the first time you are going in to treating someone Never never never give more than 4 weeks If you have an adolescent then then give no more than 7 days of a medication Had a friend that was working a pediatric clinic, have a symptoms of depression, she refered them to therapy, psychiatry, and took a long time to get into therapy, then it took too long to get in The NP prescribed 1 month of the prescription and checked on the patient The patient took the whole months prescription because attempted suicide What should be standard is no more than 7 tablets at a time Increase risk of suicide Act with in reason and what is appropriate If patient has bipolar disorder, do not give dopamine!! May put them in mania significant drug interactions may occur the most significant are with MAOIs and other seratonin drugs, With MAOI there needs to be at least a 14 day wash out period before initating an SSRI and at least a 21 day wash out period with fluoxetine before initating MAOI no specific monitoring is required, continue to assess ongoing mood

ACEIs (continued_2)

§Monitoring •Possible orthostasis within 1 hour of administration when starting and with each dosage change §Patient education •Do not double dose if one is missed •Hypotension most common ADR •Cough common with older-generation agents Think about any time that we are treating a problem, well sometimes the adverse event can be we did the job too well We have to be worried about orthostasis So often advise patients who are at a high fall risk to get up slowly Another common side effect is a dry cough We will typically get a base line lab that evaluates renal function as well as the electrolytes, that is something that is routinely managed and checked up A red flag rule!! Do not give an ACE or ARB or renin inhibitor in anyone who is pregnant who has renal artery stenosis or who as a history of angioedema On pg 273 of the text book talks about 3 contraindications Highlight, star this and that is something that is going to be asked on the board and possible test question When someone is pregnant they are developing the fetus in their body and as that fetus developes the first trimester is when all of the organogenesis happens If you are taking an ACE inhibitor, will develop a fetus who has severely damaged kidneys Likewise if you are giving someone with high bp an ACEI and their blood pressure is not coming down, want to get an US of those kidneys because can have renal artery stenosis patients should have their serum potassium levels checked before titrating therapy within 1 week to note trends 0.2% of patients have angioedema due to the increased bradykinin level associated with inhibition of an ACE it is not known if the DRIs interact with bradykinin but they have caused angioedema. it usually occurs within the first dose or within the first month of therapy and is more common with longer acting ACEI agents adverse reactions for ACEI and ARBs and DRI are usually transient, mild, and more common in long acting agents most common is hypotension, and others include dizziness, headache, fatigue, orthostatic hypotension also some patients have a dry hacking cough with ACEI and usually occurs within the first week of therapy bradykinin is responsible for the cough

Beta Adrenergic Blockers (continued)

§More effective in African American and older patients §BBs may NOT be abruptly withdrawn, because it will increase beta receptor sensitivity §No longer first-line HTN drug choice Any beta blockers should not be ubruptly withdrawn because we have an increase in the beta receptor sensitivity This is related to the beta blocker, down regulation Blocked the beta receptor at the cellular level, took the medication for a while so then we have the down regulation of the receptors Once you withdraw it you will have much increased response when those cells are exposed to the same neurotransmitters Want to be careful in our patients that have asthma or COPD because you can get the increased bronchoconstriction, you can also have the blocking of some of these side effects or hypoglycemia So this is really not a first line hypertension drug choice, but keep in mind for all of those things hydralazine- is the first line for HTN (is a diuretic) Class II drugs (BB) reduce andrenic activity in the heart blockade by these drugs increases threshold potiental and prolongs ERP, thereby decrease heart rate and conduction velocity they also exert a significant negative inotropic effect, reducing the force of contraction. This class includes Beta 1 selective drugs that act on the lungs, arteriole, pancretic, kidney, adipose, and liver tissues resulting in a range of adverse responses

opioids

§Morphine - prototype •All opioids rated against morphine §Single agent products: oxycodone, morphine §Combination products: Vicodin, Percocet, Percodan, Tylenol with Codeine §Pharmacodynamics: bind to opioid receptors in CNS §Pharmacokinetics: vary §ADRs: CNS sedation, constipation, euphoria Opioids are really important Required to have a solid formation in opioids Keep close eye on opoids and opioid training Pain was the fifth vital signs and we went to over prescribing narcotics but now the ball has swung the other way that can look up patients and see what they were prescribed Can be common to see that a patient goes dr. shopping between states to get opioids Keep in mind we have pain meds for a reason, there are real reason by patients need pain medications To be the best providers is if we look at the whole picture and how can we help them If they are looking for certain narcotics you will see them saying allergic to Tylenol, mom took pills They need help, they may know they have a problem It is important to add empathy because we need to look at the whole pocture help them as much as we can agonist include codeine (tylenol #3 or #4) fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodon, oxymorphone, and propoxyphene narcotic anaglesics are active at various opioid receptor sites and act as agonist, partial agonist or mixed agonist-antagoinist of endogenously occuring opioid peptides opioid interact with mu, kappa, delta, and sigma receptors, producing both the desired and adverse effects of opioids mixed agonist-antagonist can cause withdrawl symptoms when given to narcotic-dependent individuals because of their preference at specific opioid receptor sites narcotic antagonist block or reverse opioids by competing at their receptor sites and reverse respiratory depression, hypotension, and sedation opioid analgesic may be administered via oral, parenteral, rectal, sublingual, and transdermal routes the rate of absoprtion depends on the route used overall, the onset of action of opioids anaglesics is rapid and variois over 2-3 minutes to up to 60 minutes depending on the route of adminstration

Changes to General Hypertension (HTN) Care

§Newest clinical guidelines focus on patient outcomes, based on the understanding that if patients take their medications it is more likely to have good clinical outcomes than if artificially selected numeric targets create falls, hypotensive episodes, and generalized fatigue. §Targets for blood pressure (BP) readings must be individualized. Look at current clinical guidelines They will focus on patietns outcomes If patient take medications they will have better patient outcomes Hypertension is our most common cardiovascular disease It is something that is cummaltive (28% of adults effected by it) it increases in prevelance as we age Most persons once we live to 70-80 years old, 60-80% have hypertension by the time we reach age 80 It can lead to blood vessel damage It can lead to end organ damage Only about half of people that have blood pressure issues have it under control This is one of the hardest diseases to treat because it is not something you feel symptoms of It is difficult to explain to a patient Clarify that most of the time you clarify this is opposed to primary hypertension Secondary hypertension can be from renal disease, cushings, aortic issues, aldosterone issues For essential hypertension, increase resistance to blood flow related to cardiac output It is psychological stress, and dietary factors, mostly genetic and dietary factors Psychology and enviorment can play a role in it A lot of the guidelines for management If we know what the guidelines are then we Stage 2 hypertension may need 2 medications If we have a series of blood pressure readings- have to look at what the patient is going through Use clonidine if someone is going through alcohol withdraw Can use something temporary until their body is back to normal after withdrawl Clonidine not on long term Can lose a lot of blood pressure by making diet, exercise changes

Drug Therapies for Dyslipidemia (continued)

§Niacin (has lost its popularity) §Ezetimibe (Zetia): most effective in combination with statin §Vitamins/antioxidants/herbs/natural products •Vitamin E, vitamin C, folic acid, garlic, fish oils, fiber, coenzyme Q10, flaxseed •*Active liver disease is a contraindication for all except bile acid sequestrants Niacin- we do not use niacin anymore!!! Studies show that the benefit does not out way the risk and it is not therapeutic enough Niacin should not be used anymore at this time Zetia- this is adjunct therapies, something that can be used in combination with a statin Someone has elevated cholesterol look at the break down, is it High HDL and high LDL, is it a medium HDL and low LDL but cholesterol high because lot of HDL HDL- happy, these are cardioprotective If someone has a a terrible cholesterol panel Someone has a high cholesterol and the HDL is low, if someone has really high LDL, someone has a terrible cholesterol panel, usually address this with a higher dose or more potient cholesterol panel and consider adjuct therapy like zedia Will also see various herbs, this is not the most therapeutic, recommend a heart healthy diet Fatty fishes can be okay or avacodos Want to be congnizent about some of these herbs may lower cholesterol but not as therpautic as a statin coQ10 will not lower the cholesterol but what it will do is can help with the side effects and other effects of using things like a statin Can help manage with muscle discomfort with the result of taking a statin

Angiotensin II Receptor Blockers (continued)

§No bradykinin-mediated cough like ACEI §Considered alternatives for patients who cannot tolerate ACE or become resistant §Many combined with hydrochlorothiazide (HCTZ) ARBS are the drug of choice for patients who are younger and white and for patients with diabetes, HF, or MI and for whom they are most effective and have the lowest incidence of adverse reactions they are generally not effective for black patients

ACEIs Use (continued_1)

§Not as effective in African American patients •When combined with a diuretic, race no longer an issue §However, three to four times greater risk of angioedema in African Americans and Asians §Adverse drug reactions (ADRs): dry cough (bradykinin- mediated), hypotension, loss of taste, angioedema, blood dyscrasias, teratogenicity, hyperkalemia, acute renal failure, cholestatic jaundice, pancreatitis, rash When we want to be careful about that it is not as effective in our African American patients Remember that we often start with a thiazide or a calcium channel blocker in those particular patients (AA) all ACEI except for catopril and lisinopril are produgs converted into active metabolites in the liver the kidneys are the primary organ of excretion for all ACEI except fosinopril and moexipril and impaired renal function can significant prolong their half life Catopril with a half life of less than 2 hours is the only short acting ACEI it requires two to three doses daily all other classes have a 6-12 hour half life and require more time to achieve effect

SNRIs (continued_2)

§Patient education •Adherence, suicide ideation, avoidance of OTCs §Monitoring •May increase serum transamine levels: Watch in patients with liver disease. •Monitor suicide risk, activation of hypomanic or manic symptoms Watch for suicide risk For someone who is suicidal, there is also a risk that putting them on an anti depressant, it may give them enough energy to proceed with killing themselves Likely to closely manage sucidial with pyschology When looking at hypomania and mania, they have a lot of energy, may be over spending, or having a lot of sex or using drugs so do own assessment of patient on where the are but also be aware of co morbid psychiatric conditons that could be making things more difficult for you no specific monitoring levels are needed for SNR with duloxetine, liver function should be monitored once weekly, once monthly, and biannually, and finally annually careful to monitor suicide risk and monitor activation of hypomania or mania patients should be given description of side effects pregnant women need to be tapered off medictions, especially in 3rd trimester

Opioids (continued)

§Patient education: ADRs, drug interactions Monitoring: ADRs, withdrawal, refills There is going to be drug monitoring with opiods It is going to be important to look at what else they need and what is rational An equa-anagesic chart A certain amount of morphine is kind of the same as this much viadin to compare opioids to opioids That is helpful chart as baseline As you switch between opioids, may have to go lower Some people may process things differently adverse side effects include respiratory depression, hypotension, confusion, sedation, nausea, vomitting, dizziness, visual disturbances, hallucinations, euphroia, lethargy, uncoordinated movements, constipation, agitiation, depression of cough reflexes, and paresthesia most patients experience constipation monitor for adverse reactions, such as opioid withdrawl symptoms of opioid withdrawl include flu like symptoms such as muscle cramps, dilated pupils, lacrimation, rhinorrhea, yawning, sneezing, anxiety, anorexia, nausea, vomitting, diarrhea, and gooseflesh tell patients about possibily for physical dependence and advise these agents should primarly be used for relief of acute, severe pain

CCBs (continued_2)

§Patient education: pregnancy category C •Avoid nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, being in a jacuzzi alone. •Gastroesophageal reflux disease symptoms get worse because of decrease in esophageal tone. Try to avoid in pregnant patients, it is not contraindicated in the way that ACEs and ARBS are May also see that people who have GERD there symptoms become worse because they have a decrease in their esophogeal tone and additionally have the dilatation of the blood vessels This can also worsen some of the symptoms ***being in a jacuzzi alone- with alcohol and NSAID will cause you to pass out the more common adverse reactions of CCBs are extensions of their actions. Reduction in BP secondary to vasodilation may result in dizziness, headache, hypotension, and syncope. These lead to HF congestion, shortness of breath, cough, and palpitations; though a potiential class effect, HF is worse with verapamil, diltiazem, and nifedipine GI symptoms can include dry mouth, nausea, vomitting, reflux, and constipation the guidelines for hypertension indicate that black patients as a group are more responsive to diuretics and CCBs than they are to RAAS medications CCBs are also indicated for hypertension in pregnancy the medication should be taken at the exact same time everyday as prescribed. substained release drugs taken once daily are taken best in the morning for theraputic effects missed doses should be taken as soon as remember unless it is almost the time for the next dose

SSRIs

§Pharmacodynamics •All SSRIs have selective inhibitory effects on presynaptic serotonin reuptake and weak effects on NE and dopamine neuronal uptake. §Pharmacokinetics •Slow absorption, half-life: 26 hours, has extensive first-pass metabolism ‒Fluoxetine half-life: 1 to 3 days and first metabolite 4 to 16 days! •Liver metabolism may involve CYP2C19 and CYP2D6. SSRI these are often used in the primary care setting They have the inhibitory presynaptic serotonin reuptake This is going to help improve the levels of serotonin in a depressed or anxious patient Different medications have different reasons for use Fleuoxitine has a long half life of 2-3 days and it is one of the oldest drugs that we have used examples of SSRI include fluoxetine (prozac) first one established then paroxetine (Paxil), sertaline (zoloft), fluvoxamine (Luvox), citalopram (celexa) and escitalopram (lexapro) all the SSRI affect the seratonin NR in the synaptic cleft by blocking the serotonin transporter from returning remaining serotonin to the presynptic cell each one works differently and has different effects on the neurotransmitters all SSRI are given orally and absorbed through the GI tract the SSRI have significatn first pass effect in the liver and are considered metabolized predominantly by the CYP450 system consideration of the half life requires consideration of active metabolites as well as possibility of inhibiting the SSRI's own metabolism Contraindications to SSRI's are limited to hypersensitivity to any of the drugs and concurrent or within 14 days of administration of an MAOI. They should be used cautiously in patients with severe hepatic or renal impairment and should be avoided in the first and last trimester of pregnancy fluoxetine is labeled effective for major depression in children ages 8-17 and effective in treating OCD in children 7-17 years there is greater risk of suicide within the first 3 weeks of taking an SSRI and other antidepressents

ACEIs

§Pharmacodynamics •Inhibition of angiotensin-converting enzyme (ACE) activity results in decreased production of both angiotensin II (AT II) and aldosterone •Can lower vascular resistance without decreasing cardiac output (CO) or glomerular filtration rate (GFR) •Does not produce reflex tachycardia Lets go into more detail with ACE inhibitors As mentioned before, these are typically used in stage 1 and stage 2 hypertension These are also a go to drug with our diabetic patients This can lower the vascular resistance, it does not produce any reflex tachycardia To clarify, when you take thiazide diuretic, you can paraxodically get a reflex tachy from taking tat So these are a really handy tool for improving the oxygenation of the heart muscle Pg 280 has some great details of when you are using ace and arbs for various disease processes 279-283 Notice that it can help improve insulin sensitivity without effecting lipid levels or glucose metabolism The drugs that diaresis and dry you out can increase cholesteral and glucose levels This is why it is a drug of choice for diuretics Captopril was the first drug in the class This leads to breakdown of bradykinin- stimulates nitric oxide release Enalipril is a prodrug- it is broken down in the body and converted into active process after the drug ACEIs improve oxygenation to the heart muscle and decrease inappropiate remodeling of heart muscles after a myocardial infarction or with heart failure, resulting in improved survival it increases vasomotor tone by directly stimulating vascular smooth muscle contraction and through the inhibiation of endothelial nitric oxide and prostaglandin release, raising BP and decreasing blood flow through arteries including the coronary arteries ACEI and ARBs do not affect cardiac output and so do not produce reflex tachyardia they are the first choice for HTN control in the presence of DM DRIs are not to be used in diabetic patients with renal output of less than 60 ml/min ACE has a role in the kinin-kallikrein-bradykinin system ACE facilitates the breakdown of bradykinin into inactive fragments thus reducing the reaction of vasoldation and smooth muscle contraction high levels of bradykinin are thought to be a factor in t

SNRIs (continued_1)

§Pharmacokinetics •Half-life: 8 to 17 hours •Metabolized in liver via CYP1A2 and CYP2D6; forms multiple metabolites •Watch with antibiotics: quinilones §ADRs •Headache, somnolence, dizziness, insomnia, fatigue, dry mouth, constipation, orthostatic hypotension, erectile dysfunction, ejaculation failure There is a whole variety of what the half life would be You may notice the half life of paxil vs fluoxetine is wildly different EMR have protected drug functions on it Be aware of this as well especially when look at older patients who are on 10-12 different medication these drugs are rapidly absorbed after oral intake and metabolized extensively in the liver the time needed to reach maximum plasma concentration is 2 hours for both venlafaxine and duloxetine oral administration of levomilnacipran reaches peak 6-8 hours after oral administration the most common side effects with both venlafaxine and duloxetine include headache, somnolence, dizziness, insomnia, nervousness, nausea, dry mouth, constipation, and abnormal ejaculations appepitie and weight decreases may occur at higher doses both drugs may contribute to elevated blood pressure the most common adverse side effect for milnacipran is nausea other side effects include headache, constipation, hot flashes, dizziness, hyperhydrosis, and palpitations patients can experience decreased libido and ejaculation failure levomilnacipran can most commonly cause nausea!! remember all these cause nausea constipation, hyperhydrosis, tachycardia, erectile dysfunction, urinary hesitation erectile dysfunction and urinary hesitation increase as dose increases

ARB CYP450 Example

§Pharmacokinetics (Losartan) •CYP2C9 ‒Extensive first-pass metabolism resulting in 33% bioavailability ‒Inducers: rifampin, barbiturates ‒Inhibitors: lovastatin, sulfamethoxazole and trimethoprim (SMZ/TMP), fluconazole, fluvastatin, fluvoxamine, sertraline Will see the CYP450 system as we go through a lot of these drugs There is so many medications and different interactions Understand how to look it up and what to look for when you are diagniosis and treating patients Do not want to forget about the CYP450 system It may build up fast in body or may be slow

Angiotensin II Receptor Blockers (ARBs)

§Prevent binding of AT II to receptors in kidney, brain, heart, and arterial walls §Inhibit the renin-angiotensin-aldosterone system (RAAS) and cause fall in peripheral resistance §Evidence supports use in kidney disease until late stage and heart failure, but not all forms are renal protective like ACEI ARBS- artan suffix These don't have a specific effect on the bradykinin levels but have a more complete blockage of the antiotension effect They share similar effects of the ACE inhibitors so this is why this is not an uncommon drug to use for a patient with diabetes Again you can also get a cough on this one It is possible if the patient is on an ACE inhibitor and try valsartan and it wont be as problematic and check in with them if its improvement A combination with an ARB and a hydrochlorizthide

Drugs Affecting the Sympathetic (Adrenergic) Nervous System (continued)

§Primary use: depends on receptors activated •Alpha1 receptors: nasal congestion, hypotension, dilation of pupils for eye examination §Alpha2 receptors: hypertension (HTN) §Beta1 receptors: cardiac arrest, heart failure, shock Beta2 receptors: asthma, premature labor contractions Table 11.1 is a really nice break down of the information and how it affects the organ systems changes in the PNS or the SNS can occur by decreasing the activity of the opposing system should evaluate the risk for adverse drug effects when using any of these drugs drugs such as peripherally acting alpha 1 agonist are used mainly as decongestats, and beta agonist are used mainly for bronchodilating effect The two divisions of the autonomic nervous system are the sympathetic division (SNS) and the parasympathetic division (PNS). The SNS contains alpha and beta receptors, and the PNS contains nicotinic and muscarinic receptors. Each type of receptor has a specific action when stimulated.

Treatment: Heart Failure

§Stage A •ACEIs are drug of choice •ARBs are considered but more expensive §Stage B •ACEI in all patients, ARB for those who cannot tolerate an ACEI •BBs in most With heart failure ACE and ARBS are our drugs of choice ARBS are decreasing in expense as we seen over time Stage 2 we will use beta blockers as well Stage 2 is when the cardiac output is inadequet with the oxygen that I needed to be produced by the body The systolic failure is the reduced contractility and ejection fraction The diastolic failure is the stiffening and the loss of the relaxation The ejection fraction is normal but the stroke volume is reduced The treatment is directed specifically at reducing symptoms and managing acute decompensated failure episodes

Treatment: Heart Failure (continued)

§Stage C •ACEI and BBs (nonselective) in all patients •Diuretics, digoxin •Spironolactone §Stage D •Sacubitril/Valsartan (Entresto) in lieu of ACE or ARB •Inotropes: dobutamine •Ventricular assist device, transplantation, hospice As heart disease progresses we will use other medications such as digoxin To manage the rate Spirnolactone is potassium spearing Once we losing lots of fluid we like to balance this out many times Stage D heart failure, going to use combination medication such as entresto We look at managing the contractility and rate with an iontrope Manage this patient with a cardiologist

Treatment of Hypertension With Higher Cardiovascular (CV) Risk

§Stage I: SBP 140 to 159 mm Hg/diastolic blood pressure (DBP) 90 to 99 mm Hg •Diuretics: thiazide-type •May consider angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), calcium channel blocker (CCB), or combination One thing to think about is the stage of the blood pressure and how that is going to effect what we are looking for Standardize treatment is to start with something that is like a diuretic Something like thiazide type diuretic Genetics, environment, race, gender can effect blood pressure When we diagnose blood pressure this is done on two office visits and the appropriate way to diagnosis is when they are sitting down, feet flat on the floor, sitting and resting for 2 minutes At least two office visits and looking at the disease process, this is where we get into stage 1 or stage 2 We look at other comorbidies. are they obese, what is there hem a1c, how is their cholesteral These comorbidies can interact with eachother and make eachother worse Things that we need to consider, what is their diet, is it high fat, a lot of oil, processed foods, are they smoking including raising blood pressure, harden arteries Look at medications that can help and look at skills and life style changes that can help cardiac health Is the patient taking a high dose NSAID that can effect their kidneys Are they on contraceptives- for clots and cardiovascular events Thiazide first line for a stage one lower elevated blood pressure ACE and the ARBS and someone who is diabetic and has proteinuria Protect their kidneys because the elevated sugar in the kidneys can cause renal damage and that is accumulative Taking an angiotension inhibitor will reduce the renin artery pressure and the goal is to change the amount of aldosterone release so then you have an improved lower of the BP For our renin medications we have 3 classes The ACE's ARB;s and renin entiagonist The beta blockers will help decrease the renin secretion, they don't actually antagonize the effects of release renin 3 classes in 13 and continues in chapter 42 For ACE- PRIL is the typical suffix Thiazides will be more appropaite for aferican American population Ask what is there blackground and ask if this is experiencing how th

Treatment of Hypertension With Higher Cardiovascular (CV) Risk (continued)

§Stage II: SBP greater than or equal to 160 mm Hg /DBP greater than or equal to 100 mm Hg •Two-drug combination: thiazide-type and ACEI, ARB, beta blocker (BB), or CCB §With compelling indications: heart failure (HF), DM, stroke, chronic kidney failure, point of maximal impact •Diuretics, ACEI, ARB, BB, CCB, as needed Stage 2 hypertension have to combine with an ACE and thiazide and a beta blocker This is something that needs to be treated Someone with BP of 160/100 on just one medication, typically will jump to a calcium channel blocker if there are no contraindications for it right away People that are at a higher risk Heart failure or diabetes- something to start more quickly

ACEIs (continued)

§Strong evidence for CV and cerebrovascular risk reduction, HF, and slowing renal disease •Improves oxygenation to heart muscle, decreases inappropriate remodeling of heart muscle after myocardial infarction (MI) or with heart failure, reduces effects of diabetes on the kidneys §Improves insulin sensitivity, does not affect glucose metabolism or raise serum lipid levels It is converted into analphrolasis Anaprolat is for IV use Plaque deveopement from cholesteralemia- will cause more clots because of foam cells If you do not move, and lay for long periods will get a DVT ACEI and ARBS are renal protective for patients with proteinuria but not as protective in renal patients without proteinuria

New Approach to Targets (continued)

§Targets of below 140 mm Hg SBP remain for patients with diabetes mellitus (DM). §Emphasis on lifestyle changes continues after medications are started. Several iterations for blood pressure control Bullet points are fine Have to look at the current guidelines A lot of these guidelines will change, with J and C 7 and J and C 8 and now we have the 2019 guidelines There was some confusion as some thing were recommended that the BP be 150 systolic Now guidelines is 130 over 80

CCB: Two Classes

§Type I - Non-dihydropyridines: affect conduction through the atrioventricular (AV) node and have negative chronotropic effects •Used in treating supraventricular tachycardia •Diltiazem (Cardizem), verapamil (Calan) §Type II - Dihydropyridines: do not affect conduction through the AV node •Nifedipine (Procardia), amlodipine (Norvasc), felodipine (Plendil) We have dihydropyridines and non dihydropyridines Non-DHP effect the conduction through the AV node and have negative chronotropic effects These are our verapramil- and we use these with our SVT With our DHP they do not effect conduction through the AV node Have seen the most amlopadine used in the outpatient setting If having SVT- should be on the non-DHP Need to be able to teach the material Need to teach the DHP vs the non-DHP Worry about mechanism of action first, then black box warning, and then ask why did we use it!!! CCBs directly block the influx of calcium at the onset of the cycle, like the sodium channel blockade in local anesthetics the result is a marked decrease in transmembrane calcium content and prolonged vascular smooth muscle relaxation the blocking action of CCBs occurs via 3 different receptors, includig diphenylalkylamine-based and benzothiazepine based and dihydropyridine-based all CCBs relax arterial smooth muscle but have little effect on venous beds. this results in significant reduction in afterload but limits effect on cardiac preload

Beta Adrenergic Blockers

§Various types include nonspecific beta antagonists, selective beta-antagonists, and those with or without intrinsic sympathomimetic activity (ISA) •In post-MI patients, cardioselective agents without ISA are preferred. •Some are used as antiarrhythmics. •Drugs with ISA may help avoid a decrease in cardiac output (CO) and HR. May be preferred for patients who experience bradycardia with other BBs. Beta blockers are adrenergic blockers These will reduce mortality after an MI, this is importance to consider in patients that have MI and have heart failure It can help prevent reflex tachy and has a lot of excellent therapeutic effects Beta blockers can a reflex of tachycardia that is significant if you stop it very quickly BBs are generally contraindicated for patients with unstable bronchospastic disorders such as asthma they are used with caution for patients with diabetes who have major blood glucose variation ranges because they decrease insulin secretion and may mask many of the signs of hypoglycemia BB are the gold standard to help reduce the second cardiac event post-MI These tables help discuss the classes of drugs and then which drugs fit into that class Do not menorize drugs and doses, just the drug classes, potientially the drug that fits into the class and then the mechanism of action for the drug Think of the derivation- if you know that an alopril and lisinopril are both ace inhibitors but you don't remember which one of them is the prodrug, think of the action of the drug and think about what is happening iwht the side effects Think of what goal you are trying to achieve HCTZ, calcium channel blocker, ARBS/ACE, thiazides, beta blockers- it takes 3-4 weeks see change, life style changes and diet changes If give them a million things that concern them, then try ot focus on the big thing and also have them come in sooner to focus on these things Have shared decision making Diet, routine, cost, lose weight, belief systems Blood pressure is slient killer because they don't feel it Weight loss is super difficult, if they go through menopause, losing weight is really hard If someone is pregnant then increased estrogen can cause weight Do they think that the drug will work 130/80- consecutaively t

ACEI use

§Younger Caucasian patients •Patients with angina: prevents formation of AT II and decreases pulmonary vascular resistance by decreasing retention of sodium and water and reducing extracellular fluid and preload •Patients with diabetes: prevents or slows nephropathy After MI and HF, for ventricular remodeling Younger patients not uncommon to start them on an ACE inhibitor

Cytochrome Ps

•6 isoenzymes have been determined to be responsible for most metabolism related drug interactions: -CY1A2, CYP2C9 CYP2C19, CYP2D6 CYP2E1, and CYP3A4 - •CYP3A4 - responsible for 40-45% of drug metabolism •CY2D6 - responsible for 20-30% of drug metabolism •CYP2C9 - 10% •CYP2EI and CYP1A2 - each responsible for 5% -Remaining 5-20% is accounted for by several lesser important isoforms There are only 6 isoenzymes that we think about 3a4 is the biggest for 40-45% of all drug metabolism

Geriatric Pharmacokinetics

•Absorption •Distribution •Metabolism •Excretion -Cockcroft-Gault formula (ages 40-80) CrCl (ml/min) = (140-age) X (weight in Kg) 72* X (serum creatinine in mg/dl) *multiply by 0.85 in women Want to think about formula The pharmacokinetics will be effected by changes

5 Basic Parameters of Pharmacokinetics

•Absorption - -the uptake into the body •Distribution - -distributed from the circulatory system to site of action •Metabolism - -body breaks down (metabolizes) and converts (biotransformation) drugs into inactive substances •Excretion - -the rate drugs are eliminated from the body •Half-life - Metabolism!!! This is where a prodrug is going to get turned on and then escretion how it is eliminated Should know these definition Adni Will almost always ask about pharmokinetics Absoprtion- this is specifically the uptake of the drug into the body Moving things across the tissue Most time is oral or transdermal Distribition- how much should be concentrated in the tissues to get to the site of action Example higher dose of amoxicillin for child with OM compared to someone who has a strep infection Because higher level of drug is needed to medication into middle ear Metabolism- how the body breaks down or converts into active substances Excretion- get rids of drugs Half life- is the time it takes to reach half concentration

pharmokinetics

•Absorption - the movement of a drug from the site of action the blood stream • •Distribution - the movement of a drug for the blood stream to other tissues • •Absorption and Distribution occur through permeation of the drug through various barriers that separate these compartments parenteral nutrition may be administered parenterally by injection, when immediate effect is required, when the active ingredients are destroyed of not absorbed by the GI tract or other routes, or when the patient is unable to take oral medication for IV edications, advtanges of rapid or complete absorption and can have an immediate reaction but disadvantage is that drug absoprtion cannot be slowed once administered oral administration- is the most convient and common route of administration. In contrast to IV administration, oral administration must go through a number of steps to get to the blood stream have to make their way through stomach, and continue into small and large intestines and then the colon oral adinistration is metabolized in the liver where it then goes to the blood stream

drug mechanism of action

•Agonist - activates a receptor or biologic process •Antagonist - inhibits a receptor or biologic process •For a drug to interact optimally with its receptor, it must have the correct: - Size - Electrical charge - Shape - Atomic composition - Ability to be transported to site of action - Ability to be inactivated We then look at is this drug an agonist- is it activating something, is it increasing the process, making it more enhanced Or is it an antagonist- is it inhibiting or blocking something, blocking the action An example of an agnost is albuterol a beta agonist Goal is to active the beta receptors and open up the lungs to breathe easily A beta blocker- atentolol, labatolol goal is to block the activity of beta cell to slow down the heart rate, enhance the filling the compacy and lower the BP

half life of a medication

•Amount of time for plasma concentration of a drug to decrease by 50% after discontinuation of a drug •Need 4-5 half-lives to reach peak •Loading dose-maintenance doses •Peak/trough levels Half life this is an important concept This is generally the amount of time a plasma concentration of a drug will decrease by 50% This is in reference to pharmacogenetics The average you want to think about 5 half lives to reah peak And 5 half lifes to get ride of the drug This is important with loading dose or peaks and troughs

mechanism of drug permiation

•Aquaeous Diffusion - occurs within larger compartments of body, through pores, driven by concentration gradient (Fick's Law) •Lipid Diffusion - separate most aqueous compartments so is the most important limiting factor for drug permeation •Carrier Molecules - protein carrier moves substances that are too large or too lipid-insoluble to diffuse passively Lipid- certain drugs pass the blood brain barrier With metabolism- sometimes it is through simple aqueous diffusion Other times the molecule is too big to get through the phospholipid bilayer like lipid defision or we need active transport The lipid defussion think can this drug get through the blood brain barrier For example antihistamines pass through easily through blood brain barrier Can use bendryl as a sedative or for nausea- it can make us sleepy because they pass through blood brain barrier Second generation antihistamines such as clarition is safe to use with flying, driving because it is harder to pass through blood brain barrier and doesn't make us sleepy We need transport molecules such as ATP to help move large molecules or lipid soluable molecule across or against a concentration gradient

Pharmacogenetics: genes affect the pharmacodynamics and pharmacokinetics of a drug

•CYP450 enzyme genetic variability (polymorphism) •'poor, extensive, ultra-' metabolizers of meds •Variations in drug response •Genotype testing •Medication can inhibit or enhance CYP450 activity •Disease states alter activity -Cystic Fibrosis (CF) alters CYP 2D9 They can be slow metabolisers so it will take a longer time to eliminate Sally put on paxal for depression, developed hypertension and put on metapropol- and the two together were metabolized together When its an inhibitor it is induced together Inducer eating less- gets rid of it When its an inhibitor it is eating more of the drug- adds more Grape fruit is CA4 and CA5 There can be variations in the metabolism, some can be poor or ultra metabolizers Cystic fibrois can alter cyp2D9 metabolism If they are an ultra metabolismer may need to alter the medication because wont be able to get to theraputic level

drug metabolism

•Chemically changing drug to metabolite-less active form than 'parent compound' •Some drugs active and have active metabolites •PRO-drugs -Inactive form must be metabolized to an active metabolite state to have any effect -First pass metabolism (in liver), lungs, kidney, gut can also metabolize drug into active metabolite Want to think of pro-drugs Pro-drugs are drugs that are given in the inactive form and be metabolism to an active metabolit to have any effect They go through first pass and then turned into active form prodrugs are inactive compounds that rely on metabolism to become active. prodrugs have advantages and disadvantages. the advantage may be in terms of their absoprtion or distribution L-DOPA is a prodrug used to treat parkinsons, parkinsons is a lack of dopamine in the striatum of the brain dopamine cannot pass through the blood-brain barrier, so it is ineffective when used to treat the neurotransmitter shortage in the brain

Pharmacokinetics

•Drug absorption •From pill to systemic system to site of action •Metabolism in liver before travel to site of action (first pass) or after they visit the site of action Most elimination is via kidneys Important to remember metabolism almost always happens in the liver especially if its an oral mediation Think about this when thinking about other things going on like problem with kidney and liver the way that medications are presented to the body affects the speed, extent, and duration of drug absoprtion the route of administration will affect patients adherence

dose potiency and efficacy

•Efficacy: maximum effect that can be achieved •Potency: compare 2 meds/doses measure for same effect -Influenced by Pharmacokinetics: absorption, distribution, metabolism, excretion of a med •Consider maximum effectiveness and the ability to reach receptors The guidelines, people who are older, when we do geri rotation will do renal dosing to make sure the patient is not doing too much Clearing the drug through kidneys When look at the different medication for cholesteral there can be wide differences in which medication has how many miligrams and that is because there are different potiencies among the same class of medication And why you would pick one medication over the other

Geriatric Pharmacology

•Elderly" over 65 (society) •"Geriatric" over 75 (medicine) •Functional capacity of most organ systems show a decline at young adulthood •1/3 of healthy people have no age related decline in creatinine up to age 75 We have an aging population Have a lot of people who are elderly The organ criteria start to decline We will see beers criteria patients over 65 include taking more medications and taking them more often than younger patients older patients have decreased renal and hepatic function, resulting in decreased metabolism and clearence, which can cause drug accumulation and toxicity treating geratric populations has been demonstrated that patients over age 65 require hospitlizations for treatment of ADR more than patients younger than 65 years old

Cytochrome P450 (CYP450)

•Enzyme acts as catalyst to metabolize a drug •Bound to membrane within the cell (cyto), contain heme pigment (chrome), absorbs light at wavelength 450nm •~50 enzymes, 6 metabolize 90% of meds -CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 •Potential drug-drug interaction, adverse effects, or therapeutic failures 2c19, ca4, and ca5 this is where you find interactions, This will be a board and exam question If you give a pathway on the CYP2D6 and the CYP3A4 this is different pathways These different subsystem If you have a substraight that is one part of the puzzle and then what is an inducor CYP450 acts as a catalyst to metabolise the drug If give someone a CYp450 a cyp3a4 substrate and then give a second medication that is on the cyp450 and cypa4 inhibitor, it is inhibiting the metabolism of the other cyp450 drug When they are inhibiting the metabolism they are slowing down the break down of the drug If you have a substrate and an inhibitor, you will have more of the substrate Contrastingly if you have a substrate and an inducer then will have less of that drug because inducing the metabolism of the drug They will munch munch munch with the drug the most thoughly studied drug metabolism reaction is the CYp450 mixed function oxidase reaction this reaction catalyzes the metabolism of a large number of diverse, highly lipid-soluable drugs and chemicals CYP transfer electrons from the oxidation of drugs to the electron transport system of the endoplasmic reticulum, a cell organelle CYPs are organized into numbered families, based on their function CYP1, CYP2, CYP3 families metabolize a variety of drugs and steriods the CYP3As are the major subfamilies expressed in the human liver and consist of three forms: CYP3A4, CY3A5 and CYP3A7 the CYP3A7 enzyme is present in fetuses and appears to be discontinued after birth

Age-Related Pharmacokinetic Differences in Children Compared to Adults

•Factors which impact absorption: -Decreased gastric acidity, emptying time, and GI motility -Little muscle mass and decreased peripheral absorption -Decreased pancreatic enzyme activity -Increased GI surface area -Increased skin permeability Toddlers have metabolic rate and GFR which exceeds adult values. •Factors which impact distribution: -Decreased blood brain barrier -Decreased plasma proteins -Neonate 70-75% water -Less body fat •Factors which impact metabolism: -Decreased liver function and P450's 50-70% lower (prolonged T ½) •Factors which impact elimination: -Decreased renal blood flow GFR and tubular function Toddlers have a very fast metabolism There renal blood flow can exceed adult values So looking at the whole picture one pearl to know is and never forget!! Never exceed the adult dose in a child So when prescribe for children you will be looking at their weight you will be looking at the whole picture it will be dosed base on weight But keep in mind never exceed the adult dose children and older adults are at a higher risk of experience ADR. children are at a high risk primarily because medication dosages must be tailored to their specific weight or body mass index. inatention to weight based dosing may cause harm. The very young may additionally have immature organ function, which further complicates dosing and increases the risk for an ADR

Theraputic Index (TI)

•Fine line between therapeutic effects and ADVERSE effects of a medication •Ratio of dose required to produce serious toxicity or death in 50% of subjects compared with doses for effective treatment of 50% of subjects •Wide or narrow TI: measure level of a med You need enough dose to cover More is not always better This describes a therapeutic index So there is a line between both the therapeutic effect and contrastingly an adverse effect of the medication This can also be effected by the patient themselves, are they metabolizing the drug quicker then expected Are they getting less of the therapeutic effect because metabolizing more Thing of this graph when giving the medication as specified intervals because we can keep it at a more steady state The down side is that when we dose medication multiple times a day that can be difficult for patient to adhere too 5x a day may be too much for them Might try something less frequent, this is where delayed release or extended release meds come in handy the therapeutic impact of the drug is reviewed in the literature and observed in the individual patient. an NP assess the evidence of the theraputic impact of a selected drug using clinical trials, clinical practice guidelines, and systemic review. the effect of the drug on decreasing morbidity and morality and hospitalizations is examined, as well as the drugs ability to relieve symptoms and treat the disease process.

Teratogenicity

•From the Greek 'teras' meaning monster •Ability of an exogenous agent to cause the dysgenesis of fetal organs as evidenced either structurally or functionally •FDA categorized drugs according to fetal risk Here we have a teratogen effect of methomercery

variation in drug metabolism

•Genetics/ethnicity •Neonates, older adults: reduced drug metabolism •Pregnancy: increased or decreased •Liver disease: rate of elimination may be decreased •Time of day: circadian rhythm •Environment: smoke, pollution, chemicals •Diet: food-drug interactions •Alcohol/cigarettes: increase drug metabolism •Drug interaction Different medications Need to see what this person needs and their safe in life There is a lot of things that effect variation Diets, drugs interaction Pregnancy can also cause an increase or decrease drug metabolism

protein binding

•In circulation, drugs are bound to protein •Drugs bound to proteins cannot cross plasma membrane=inactive and cannot bind at receptor site, has no therapeutic activity •Unbound drug is free! Free drug=active drug •Bound drug can free itself to help restore equilibrium Drugs are bound to protein If its bound to protein it is not free If you have a heavy protein bound drug like warfarin We need to get albumin level to see how much protein Protien bound drugs are not free If something else that is protein bound then their INR will go up They are taking another drug that will change how much protein is available Free drug is active drug Protein binding is important to look at when we need to determine how much of the drug will be free Warfarin- is only 1 percent free, 99% is bound A patient on warfarin INR is good 2.2- (2-3 is good range), he starts taking more asprin and still on warfarin and the INR is high The asparin is in competition with the warfarin so he managed to increase the effect of the warfarin from 1% to 2% but the effect exerted is doubled Keep in mind the whole list that is taken Look at prescribed, over the counter, all of them

drug distribution

•Initial phase: distributes to high-flow areas: heart, liver, kidneys, and brain •Second phase: fat, bone, skin •Affected by body composition, cardiac output, blood flow, binding properties, and lipid solubility By defussion things will progress When you distribute drugs it will go to the watery area first and then solid The body starts to break down as we get old We cannot give a 20 year old the same dose to an 80 year old Distribution will move to high flow areas from the blood stream, heart, kidney brain The second phase is if we need to get drugs into the fat, the bone, the skin, the nail bed How to treat someone who has severe tinea umgium- toe nail infection Pt that had a infection that was so deep in the toe nails and had to go one for 6 months

General Guidelines for Prescribing Rx During Lactation

•Is it necessary? (risk vs benefit) •Molecular weight? •Prodrug? •Half-life? •Schedule drug to be taken immediately after breast feeding •Antibiotics have higher concentrations in breast milk (TCN can cause permanent tooth staining. Isoniazid can cause pyridoxine deficiency in the neonate) There is no longer a lot of medications for pump and dumb So if working with breast feeding moms it is a great idea to look at the lactation consultions and the half life It is looking at the whole picture of the patient What is happening medically and what is going on with her physicially and what will be the safest for her

Perinatal Pharmacokinetics

•Lipid Solubility -A more highly ionized drug crosses slower -Impermeability to polar compounds is relative, not absolute •Molecular Size -250-500 cross easily if other characteristics are favorable -500-1000 cross with some difficulty >1000 cross very poorly (ex. Heparin) The idea because more highly ionized drugs are going to cross slower As mentioned before something that is really really big or something that is a big molecule wil not move across easily It will move much more easily via diffusion if it is a smaller molecule

Perinatal Pharmacokinetics

•Lipid Solubility •Molecular Size •Protein Binding Placental Transporters This is going to be effected by lipid solutability, molecular size protein binding and placenta transporters if I have a pregnant women who gets a blood clot I don't want to prescribe her Eliquis, I want to give heparin because it is a massive molecule and it is not going to get through the placenta pregnant patients pose a challenge to the prescriber. Early in pregnancy, there is a risk for drugs being tetrogenic to the fetus the FDA rated the drugs as a pregnancy C, D, or X, is suspected to cause harm or damage to the fetus later in pregnancy, drugs may cause fetal adverse effects such as tachycardia, stroke, or may cause the fetus to abort during premature labor

Perinatal Pharmacodynamics

•Maternal Drug Actions -Effects of drugs can be altered by the endocrine environment for the stage of pregnancy •Particularly effects the reproductive tissues Not as significant in other maternal tissues -Maternal Physiology is Altered •Increased cardiac output and renal blood flow This can also be affected by the endocrine environment by the stages of pregnancy You may notice that the endocrine enviorment you may need to give more of the medication because the metabolism is so high, that lets say treated a mom with hypothyroid, she may need more of her medication in that third trimester They may need more insulin in the third trimester because the metabolic affect is so fast

Pediatric Drug Dosage

•Most drugs approved for use in children have recommended doses -Usually expressed in mg/kg -Approximations can be made based upon age, weight, or body surface area •Youngs rule (age) dose=adult dose X age/age +12 •Clarks rule (weight) dose = adult dose X kg wt/70 -Calculated doses should NEVER exceed the adult dose These are youngs rules and clarks rule Mg/kg the idea that we look at the child and look whats going on with them 11 year old that is 175 pd but still do not exceed adult dose

drugs that are inducers vs inhibitors

•Patient on paroxetine (Paxil). Developed unrelated HTN, placed on metoprolol (Toprol) •ER orthostatic. Metoprolol metabolized by CYP2D6, Paxil CYP2D6 inhibitor=metoprolol was not metabolized leading to adverse effects Ex. Sally is on paxel with depression, then she develops hypertension Then she had severe orthostasis with metroprolol and paxil What was happening is the metroprolol was metabolized by the CYP2D6 pathway and paxil Is also a CYP2d6 inhibitor This means that the metoprolol is not metabolised and got high toxic dose in the body cause orthostasis and low heart rate and syncope competition occurs when two drugs are metabolized a the same enzyme. often the enzyme can metabolize both drugs, but sometimes one drug will be preferentially metabolized, delaying the metabolism and extending the half life of the competing drug

kids are different

•Peds patients differ from adults anatomically and physiologically •àNeed to recognize the potential for different pharmacokinetics in pediatric patients as opposed to adults. •The differences are based on developing body tissues and organs which affect a drug's absorption, distribution, metabolism , and excretion. -Recall that by the end of the first year of life, an infant's weight triples, whereas body surface area and length double. •Children are different than adults •They are not little adults •The body is changing rapidly organ systems are developing rapidly •The childs brain is still really developing through that first year and year in half of life

Chemical Reactions in drug metabolism

•Phase I: oxidation, reduction, hydrolysis -Oxidation (O2 atom is inserted into drug molecule) •Clinically significant Oxidation Enzymes -Cytochrome P450 (CYP 450) •Phase 2: synthetic/conjugation reactions -Attachment of another chemical group, greater water solubility for renal excretion •Drugs may undergo 1 or both processes to produce a metabolite that will be easily excreted ADME Metabolism- first is oxidation or hydrolysis Will also have clinically significant ***things are metabolism often under Cytochrome P450- some drugs like 2d6 They are called a substrait Some will be inhibitors, some will be inducors The protein will depend on how much of the drug will be in the system Phase 2 is when you are getting ready to eliminate There is 50 different enzymes Want to think about phase 1 reaction, this is significant when talking out cytochrome P450, this pathway is important when looking at how drugs interact with eachother They can interact that they either are turning off one of the drugs or creating a super therapeutic toxicity level Phase 2 make it more water solutable to make it easier to pass through the kidneys

Perinatal Pharmacokinetics

•Placental and Fetal Drug Metabolism -Placenta acts not only as a barrier, but also an organ of metabolism for some drugs (Phenobarbital) -Makes metabolites (some still toxic) of others (ETOH) -Drugs that cross the placenta enter fetal circulation via umbilical vein and 40-60% enter the fetal liver and undergo first pass metabolism The placetenta is a barrier but it can also be an organ of metabolism Most specifically thinking about the use of alcohol because alcohol will aways create a toxic effect in the body even in a healthy non-pregnant human It will make metabolites that are toxic, it will create formaldehyde and this can also happen when we are exposing the placenta and the fetus to the alcohol So again that comes through the placenta and then to the fetus and then to the umbilical vein and then to the fetus liver Again the fetus is affected by everything the pregnant person takes

Perinatal Pharmacokinetics

•Placental and Fetal Drug Metabolism -Placenta acts not only as a barrier, but also an organ of metabolism of some drugs •Detoxifies some drugs (ex. Phenobarbital) •Makes toxic metabolites of others (ex. EtOH) -Drugs that cross the placenta enter fetal circulation via the Umbilical vein •40-60% of Umbilical vein circulation enters the fetal liver (fetal first-pass metabolism) The placenta is not just a barrier it is an organ of metabolism for a lot of drugs

Perinatal Pharmacokinetics

•Protein Binding -Albumin-bound drugs do NOT cross placenta easily -Very lipid-soluble drugs CROSS EASILY •Transfer of these drugs are dependent on placental blood flow -Some drugs have greater protein-binding to maternal plasma proteins than fetal plasma proteins •Sulfonamides, Barbiturates, Phenytoin, some Local Anesthetics Notie a lot of this is going to happen in specific stages of fetal development We also want to look at protein binding concept again, they do not cross the placent easily Protein bound drugs are not active drugs Where as lipid soluable drugs can cross very easily This is where we want to think about what we are using because lipid soluable drugs can cross through the placenta easily

drug clearence

•The rate of elimination of a drug in relation to drug plasma concentration -Elimination of a drug from the body may involve processes in the kidney, liver, lung and other organs. -The two major site of drug elimination are the liver and kidneys Some of the drugs reduce hepatic function Renal dosing do on patients with renal issues Drug clearance is how we get ride of the medication Two major sites of elimination is the liver and the kidneys

Placental Transfer of Medications

•Until the 1960s, it was widely believed that the womb provided a secure and protected environment. •After the thalidomide tragedy the government required testing of drugs before human use •It is now know that by the fifth week of fetal development virtually every drug has the ability to cross the placenta When we talk about the history of what is safe and what is not safe Until the nineteen sixties we though that the womb was a completely protected environment We did not know that the placenta would be metabolizing drugs or anything like that Now some of you may be familiar with the thalidomide tragedy What happened in the UK thaidamide was approved as a drug to women during the first trimester of pregnancy and it was to treat nausea There were massive defects that happen to the limbs of the infant and harmed a lot of children Since that trategy there was a lot of testing of drugs before human use Now we know by 5th week vertically every drug has the ability to cross the placenta

volume of distribution

•Water-soluble •Fat-soluble •Different among patient types -Infants-have more body water -Obese-more body fat •Volume of distribution indicates dose size to achieve target concentration •Some meds cannot cross into (distribute) to abscesses or blood/brain barrier Water soluable vs fat soluable The infants are balls of water, the volume of distribution will be different because of this Volume of distibrution Children are small balls of water Toddlers metabolic weight is high Slide refers to something are more free and some things are more protein bound after a drug is absorbed, it still must reach its site of action to produce an effect. the process of drugs moving throughout the body is called distribution distribution of drugs can occur by transfer through the bloodstream and passive diffusion diffussion can influence the action of drugs because drugs can be effective only if they reach their site of action in adequet concentrations before they are metabolized

Geriatric Pharmacodynamics

•↓ Cardiac output •↑ BP •↑ Postprandial blood sugar •↓ Temperature regulation •↓ respiratory function •↓ renal function Decreased cardiac output, decreased renal function, BP will go up as we age, this Is expected This can greatly effect how medication effect our body One of the most important things in elderly patients is looking at the whole list of medications Bring everything in that they take "the brown bag" They may have a lot of polypharmacy and may be taking multiple beta blockers, ace They may have trouble reading So simply the regimine Med boxes that come up with packages that tell them the time of day Make sure that you educate the patient and the care giver and reconcile all the medications See if they really need to be on that or if they can be taken off