Pharmacokinetics Lecture Notes PDF

Module One Pharmacokinetics Pharmacology is the study of drugs. What is a drug – it’s a chemical agent capable of producing a biological response in the body. That response can be therapeutic (desirable) or adverse (undesirable). A medication is a drug that is then used in the prevention, cure or...

Module One Pharmacokinetics Pharmacology is the study of drugs. What is a drug – it’s a chemical agent capable of producing a biological response in the body. That response can be therapeutic (desirable) or adverse (undesirable). A medication is a drug that is then used in the prevention, cure or treatment of a disease. 2 Many (of the 10,000) drugs available can be prescribed for more than one disease. For example, a calcium channel blocker can be prescribed for treatment of hypertension, angina and dysrhythmias. So, how are we going to study, learn about these 10,000 drugs…you can’t  Instead (as we mentioned in the lecture slides on rational drug selection) we study drug classifications and then learn about the “prototype” drug in that classification. 3 As we go through the semester we will study the drugs based on classification – learning in general the pharmacokinetics and pharmacodynamics of the drug classifications but then select certain “prototype” drugs in that classification. If you know that prototype drug then you can generally predict the action of other drugs in that classification – there may be exceptions to this but we’ll evaluate them as they come up. The other way is their pharmacologic classification  based on how the drug produces its effects or its mechanism of action. When looking at drugs remember that they have three names – we will be dealing with generic and trade names of the drugs. Generic names should be in lowercase and trade names in upper case … which I will try to do – however sometimes WORD doesn’t understand that concept and wants to capitalize everything  ***IMPORTANT*** - while most of the time you will see both generic and trade names on the lectures slides – be aware that ONLY generics will be used in the quizzes. Just as NCLEX (for undergraduates has gone to using just generics) as of 2015 – the NP certification exams are now only using generics. 6 So, now on to the “foundations”… 7 Basically, pharmacokinetics looks at what the body does to the drug. Three applications to clinical practice include: 1. It allows us to understand how the body handles medication 2. It helps us understand the actions and side effects of the drugs 3. It helps us understand obstacles drug faces to reach target cells (site of action)  the drug needs to go to bloodstream, to interstitial fluid, to the organ, to individual cells, then through the cell membrane to reach intracellular organelles (lysosomes, ribosomes) to exert its action. 8 Pharmacokinetics is the study of what actually happens to the drug from the time it’s put into the body until that “parent drug” and all metabolites have left the body. By understanding the principles of pharmacokinetics it allows us to have a better understanding and prediction of the action and side effects of the drug. There are four major components to pharmacokinetics (they are referred to the acronym ADME): A = drug absorption (which permits entry of the drug into plasma) D = drug leaves the bloodstream to distribute into the interstitial and intracellular fluids – getting to where it needs to go M = hepatic metabolism E = renal excretion (through the processes of metabolism and excretion – these cause the drug or its metabolites to be eliminated from the body). In a nutshell, pharmacokinetics is the movement of drugs through the body as they are ADME. It is the movement of drugs into and out of the body 9 Flow map of the concepts and factors associated with each of the components of pharmacokinetics. 10 Absorption is the movement of a drug from it’s site of administration into the circulation Two important concepts as they relate to absorption: rate of absorption and extent of absorption Rate  time it takes for the drug to be absorbed into the systemic circulation. This determines how soon effects will begin Extent  amount of the drug absorbed. This determines how intense these effects will be Rate & extent can vary according to patient and drug variables Bioavailability: is the amount of the drug dose that reaches the systemic circulation (looks at the extent of absorption). With oral medicat ions remember that they have to be absorbed from the intestine and may be metabolized (broken down) or become inactivated before they even reach the bloodstream. So the bioavailability of oral medications is always less than 100%. Need to consider that different formulations of oral medications may have different bioavailability and you need to know what formulation your patient is on or what formulation you want to prescribe. For example, there are several formulations of digoxin. Capsule form is high at 90% bioavailability and the tablet form is 70%. The pediatric is 80%. Why is this important? Consider…Mr. G is on digoxin tablets and runs out of his medication but he knows his neighbor Mrs. T is on digoxin so he goes and borrows some of hers. However, Mrs. T’s dig is capsule form. So, Mr. G goes from have 70% bioavailability of the digoxin to 9 0% meaning more is available to reach systemic circulation and possibly cause dig toxicity. Can you think of what route of medication when given would have 100% bioavailability? Yes, the IV (intravenous) route – as the medication is given directly into the bloodstream – the bioavailability is 100% Bioequivalent: These concepts are important when you’re evaluating the characteristics of a generic and trade drug. FDA – absence of a significant difference in the rate & extent to which the active ingredients become available at the site of d rug action when administered at same dose & conditions. Acetaminophen and Tylenol – both 250 mg – will have same rate & extent Drug activity needs to be similar (within a range) to the innovator drug Although, pharmaceutical equivalent drugs contain identical amounts of active drug – the excipients (inactive ingredients) such as buffers, fillings, colorings and flavors may differ widely from company to company. These can cause clinical variations in rate & breakdown of drug  subsequent absorption Generic drugs must be bioequivalent to innovator drug Legally have to show drug activity within a range of 80 % to 125% of innovator drug 11 This slide shows how drug molecules can be taken into a cell. The drug molecules move through the cell membrane by one of four processes: 1. Pinocytosis – process through which larger molecules are transported through cell membrane – the cell cytoplasm surrounds (engulfs) the molecule and draws it into the cell. Fat soluble vitamins are taken in this way. 2. Passive diffusion – this is the process for most of the drugs (moving from area of higher to lower concentration) to get into the cell 3. Facilitated diffusion – the drug molecule diffuses with the help of a carrier (mainly the protein receptors found on cell membranes). 4. Active transport – in this process the drug molecules have to move against a gradient using energy (ATP for transport). Examples of this would include electrolytes and the drug levodopa (anti-parkinson’s medication) 12 Most of the drugs prescribed (especially in primary care practice) are oral medications. And, there are a number of factors that affect drug absorption that the NP needs to be aware of – how do you find this information – these factors can be found in the manufacturer’s information, drug reference or handbooks available. There are a number of factors that affect how well a drug is or isn’t absorbed. Remember that there are three routes for medications: 1. Enteral (GI tract) 2. Parenteral 3. Topical So, a drug’s route of administration affects the rate and extent of absorption of a drug. A drug given by parenteral route will have the fastest absorption. The other routes will have great variation in the rate at which they are absorbed (see next slide). Oral drugs must dissolve in liquid and be available in solution because the body cannot absorb solids. Factors to consider with oral medication: Is the drug better absorbed with or without food? Having food in the stomach increases gastric blood flow and increased blood flow increases absorption of the drug metals in antacids (aluminum, calcium, magnesium) and calcium in milk can interfere with absorption of antibiotics (specially tetracycline) Dosage formulation  the higher the dose the faster the absorption. Also, before a drug can be absorbed it must dissolve. Rate of dissolution determines rate of absorption – differences based on formulation of med –is it a tablet, enteric-coated, sustained released capsules, etc. Blood flow  absorption depends on normal blood flow. Food increases blood flow which increases absorption. Exercise decreases gastric blood flow which decreases absorption of medications. Patients who are septic have decreased blood flow to the GI tract so the absorption of oral medications would be decreased Acidity of the stomach  some drugs are affected by pH and require an acidic environment to achieve greater absorption (for example – calcium carbonate (an antacid) and some antifungals) whereas, other drugs are destroyed by the gastric HCL ( such as penicillin) in this case – tablets may have a waxy coating applied to resist aced and then the tablet dissolves in the small intestine (these are referred to as enteric-coated – important client education for the NP would be to instruct the client  DO NOT crush the tablet) Some medications are designed as slow release so they are absorbed over a prolonged period DO NOT crush or open they formulations  these will allow for rapid absorption of the drug and can result in toxic or adverse effects (again important information to teach your clients). Gut motility – most absorption occurs in the small intestine due to increase surface area secondary to intestinal microvilli. If there is a decrease number of microvilli (whatever the reason – disease, surgery, drugs) there is decreased absorption of the drug. transit time can affect absorption by changing drug contact time with intestinal mucosa for example diarrhea – results in increased transit time – so drug absorption is decreased 13 The slower it takes a drug to dissolve  the slower the absorption rate 14 Distribution is the transport of the drug in the body by the bloodstream to its site of action. There are a number of factors that affect distribution – the simplest factor in determining distribution is the amount of blood flow to the body tissues. Drugs are distributed faster to those areas in which the organs have increased blood flow (such as the heart, liver, kidneys, and brain). Areas of slower distribution are the muscle, skin and fat. Drugs considered water soluble are more protein bound so less will be available to the tissues. Drugs considered fat soluble have poor protein binding and are easily taken into tissues and distributed throughout the body (especially the CNS system). And, a very important concept is that of protein-binding … as only drugs that are unbound (or “free”) are available to produce a response. 15 Some drugs bind t… o pornoltyeifnrseeinlythceirbcluoloadtisntrgeaum nb(o thuenydum suoallelycb uilneds tcoatnheca aulbsuemainre psropto einns).eAin ndtiasssuloensg a s the drug is bound tio mpproortteainn…t citocnacnenpott *p*a**ss into the tissues to cause a drug response. as tissues use the free molecules – the bound drug molecules are released into the bloodstream to be released. Drugs more than 89% protein bound – are referred to as highly bound Drugs less than 30% protein bound – are referred to as having low protein binding So, why is this important: If two drugs are protein bound – the drugs can compete for the protein binding sites. One drug can then displace the other – causing more free drug to be available – which can increase the risk of toxic effects An example of this is Coumadin (an anticoagulant given to prevent clots) and aspirin (ASA) both are protein bound. When ASA is given it displaces Coumadin from protein and the unbound Coumadin increases the patient’s risk for bleeding as more of the Coumadin is available in the bloodstream. Increase unbound drug in elderly d/t to decrease plasma protein In infants – protein bound drugs will displace bilirubin increasing the risk for developing kernicterus Patients who are suffering from long-term malnutrition (for example patients with liver disease) – have decrease plasma proteins in their blood stream – if there are decreased proteins then it means more drug is free to circulate in the bloodstream (unbound) than if the same dose were given to a patient with normal protein levels … as a result, the drug will have a stronger effect 16 The next step after absorption and distribution is metabolism (also referred to as biotransformation). And the liver is the main organ responsible for metabolism of drugs. Most drugs are degraded (detoxified) by the liver enzymes. Metabolism results in one of three things: 1. The drug is inactivated (inactive form) 2. Changed to a more water soluble form for excretion  One of the most important aspects 3. Or, changed into a more potent (active) metabolite codeine to morphine; theophylline to caffeine 17 There are two phases of metabolism – some drugs undergo just one - some undergo both – and there are drugs that require no metabolism and are excreted basically unchanged. Phase I is known as oxidation in which an oxygen atom is inserted into the drug molecule to achieve the above effects. Oxidation phase of metabolism is where the cytochrome P-450 molecules come into play. It is the most important and commonest type of metabolic reaction Reduction  removal of oxygen or addition of hydrogen to drug molecule Hydrolysis  splitting of drug molecule by addition of water Most drugs metabolized in phase I may be converted to a metabolite of lessor or metabolite stronger than the parent drug Phase II is known as conjugation or glucuronidaton in which there is the attachment of another chemical group to the drug making it more water soluble for easier excretion. 18  The most important conjugation reaction is with glucuronic acid to form a glucuronide Basically metabolites are converted to inactive compounds 18 Read slide 19 Hepatic metabolism involves the use of a number of microsomal enzymes known as cytochrome P-450 enzyme system (not a single entity but a group of 57 families). Of these 57 there are ~ 15 families involved in the metabolism of drugs Of these 15 only 6 are involved in 95% in drug metabolism 20 Essential fact to master re: the P450 is that while there are 6 primary enzymes that account for metabolism of nearly all clinically important drugs (2 of these 6 are critically important**). **CYP 3A4 enzymes needed for metabolism of many drugs – metabolize about 50% of all drugs Antihistamines, antibiotics, antilipidemics, antihypertensives **CYP 2D6  metabolize SSRI’s, pain relievers, beta-blockers Metabolizes ~30% of clinically useful med 2nd most abundant enzyme Participates in conversion of codeine to morphine CYP 2C19 PPI, NSAIDs, BB CYP 2C9  NSAIDS, Viagra, warfarin, sulfonylureas CYP1A2  acetaminophen, theophylline, caffeine, diazepines, verapamil CYP 2E1  acetaminophen, ethanol 21 Genetically determined differences also influence the biotransformation of drugs. The differences may be evident in one group of individuals or marginally present or completely absent in another group. One of the most prevalent alterations involves acetylation, a phase II reaction. Half of the U.S. population are slow acetylators, an autosomal recessive trait. These persons biotransform drugs more slowly than the rest of the population. As a result, they are more likely to develop toxicity and often require lower dosages A syndrome resembling lupus erythematosus (characterized by joint pain, arthritis, and pleuritic pain) is more likely to develop in patients who are slow acetylators who are taking drugs such as hydralazine, procainamide, or isoniazid. 22 So, meds subject to phase II metabolism are preferred in older patients as metabolites are not active and will not accumulate 23 There are chemicals or drugs that play various roles in metabolism of drugs Substrate  when a drug is metabolized by a CYP – it is said to be a substrate of that There are also chemicals or drugs that can increase metabolism (inducers). If metabolism of a drug is increased then there is the possibility that there will be decreased therapeutic effect. Stimulating (inducing) drug metabolism causes  diminished pharmacologic effects Phenobarbital  increases enzyme production in liver – this increases speed of metabolism of other drugs and possibly decreasing their effects. And, then there are drugs that decrease (inhibit) – slowing the metabolism of drugs. Decreased metabolism can result in the drug accumulating and therefore the risk of adverse effects (or toxicity) increase. The important concept to remember is that delayed drug metabolism results in: 1. Accumulation of drugs 2. Prolonged action of the drugs 3. Increased risk for adverse effects 24 Another important concept is that of First-pass effect – this is the metabolism of a drug by the liver before its systemic availability. It is a mechanism that can decrease the bioavailability of a drug. Some drugs do not directly go into the systemic circulation following oral absorption but instead pass from the intestine to the liver via the portal vein ( this is known as first-pass). If a drug undergoes high first-pass effect the drug may be metabolized and become ineffective. For example if you have one drug that is available in pill form (but has high first-pass effect) and the drug can also be given IV…you will find that the dose for the oral form is higher than the IV dose. 25 :B;.. "'"'ꞏ' M ꞏꞏ First-Pass Effect }; Routes that bypass the liver: - Sublingual Transdermal - Buccal Vaginal -Rectal* Intramuscular - Intravenous Subcutaneous - Intranasal Inhalation - Rectal route undergoes a higher degree of first-pass effects than the other routes listed 26 Most of the drugs by the time they reach the kidney have been extensively metabolized. All drugs whether the “parent drug,” or active or inactive metabolites of the drug eventually have to be removed from the body. The kidney is the main organ for excretion. Any dysfunction in the renal system can affect excretion – with decreased ability to excrete the drug there is the potential for prolonged action and/or accumulation of the drug (thereby increasing the risk of adverse effects and toxicity). Drugs can also be excreted by the bowel through biliary excretion and feces. 27 You will need to become familiar with terms used to describe drug effects. The graph you see above is referred to as drug response curve: Onset  time it takes for the drug to elicit a therapeutic effect Peak  the time it takes for the drug to reach maximum therapeutic response. This is when the drug reaches it’s highest blood concentration Duration  length of time drug concentration is sufficient to elicit a therapeutic effect. MEC (minimal effect concentration)  amount of drug needed to elicit a minimal therapeutic effect. For example if a nursing student has a headache and takes one aspirin (instead of the 2 aspirin that is recommended as the standard dose)…will her headache go away…probably not…as the drug level (with one instead of two) will not have reached the minimum level to elicit a response. Now, perhaps there’s another student who thinks – well if two are good then four is even better – my headache will go away sooner…. What have they done in regards to drug levels…they will have gone over the therapeutic range and could now be in the toxic range and start noticing some adverse effects, such as tinnitus (ringing in the ears) and prolonged oozing. 28 Half-life is the time required for one half of a given amount of a drug in the body to be eliminated from the body. Half-life helps the health care provider determine how frequent to dose the drug. If you stop giving a medication then it takes about 4 to 5 half-lives before most of the drug is considered removed from the body. In the same respect, if you start a drug and continue to give it – it takes about 4 to 5 half-lives to reach steady state. Steady-sate refers to a physiologic state in which the amount of drug removed via elimination is equal to the amount of drug absorbed with each dose. 29  Loading Dose - Higher amount of drug given - Plateau reached faster - Quickly produces therapeutic response Maintenance Dose o, - Keeps plasma-drug concentration in g oo n oo 100 11 r ome (hours) therapeutic range 31  Need to think- how does my client's disease alter the mechanisms of pharmacokinetics of the drug I want to prescribe... - What if drug elimination is impaired? - What if there is liver impairment? If there is impairment- then you will see that basically the drug will need to be given at a lower dose or longer frequency (instead of q 12 hrs - you may need to go to daily dosing). As we go through the different drug classifications we will look at this and look at the recommendations for that classification 32 Take a break…take a deep breath…then scream!!! Doesn’t that feel good…now on to pharmacodynamics next weeK. 33