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Nursing549: Pharmacology Study Notes
Week 1: Lecture 1
- PharmacoDynamics: what the Drug does to your body o Affected by genetic factors: receptors, transporters, cell signaling pathways, enzymes, metabolic pathways – influences drug efficacy
- Pharmacokinetics: what your body does to the drug o How the body absorbs, distributes, metabolizes, and eliminates the drug o Affected by age, organ function, other meds (concomitant therapy), drug interactions, disease state, o Affected by genetic factors: drug metabolizing enzymes, transporters, targets – influences dose requirements and adverse effects
- Pharmacogenetics: individual variation in drug metabolism and distribution, usually related to a single gene
- Pharmacogenomics : study of complex multi-gene variation among individuals/ how genes interact with environment
- Receptor-Agonist theory : theoretical foundation of pharmacology. explains how drugs work in body. all drugs are either agonists or antagonists o Agonist : compound that binds to cell receptor to cause biological response - Full agonist : produces 100% response - Partial agonist: even when saturates receptor, cannot produce 100% response o Antagonist : bind to cell receptor to block agonist. Has NO biological effect, just blocks the agonist, makes agonist less potent, or reverses the agonist - Competitive : binds to same spot as the agonist, directly blocks agonist (coreg blocks receptor so epi cant bind)
- Non-competitive : binds to a different spot compared to the agonist (naloxone blocks morphine- less effect) o Antagonists and agonists can be endogenous (natural/made by body) or exogenous (made by people) o Receptors may be enzymes, nucleic acids, or membrane bound proteins.
- Efficacy : maximal response that a drug can produce (how effective is the drug), how well drug’s response is. Pain scale
- Potency : how much drug required to produce an effect (how strong is the drug) 4mg of hydromorphine vs 10mg of morphine o Does NOT mean how well it works! Higher potency does NOT mean better drug
- Bioavailability : fraction of drug that reaches circulation in form ready to engage in biological reaction (not protein bound) o Some drug doesn’t reach circulation, some reaches circulation but not active o Influencing factors:
- Route of administration: IV goes directly into bloodstream, IM goes into highly vascular muscle, PO goes through saliva + stomach acid + absorption into intestines + liver metabolism before reaching blood
- GI motility: increased gut motility can increase or decrease absorption of PO meds, depending on the med. (Tylenol/lithium- don’t like acidity, want to get out fast.) (cimetidine, digoxin- need acid breakdown to activate)
- Drug-drug interactions: for example, some drugs require an acidic environment for absorption, and antacids will prevent these drugs from being absorbed
- Drugs that need acidic environment: tetracycline, ketoconazole,phenytoin, theophylline, warfarin, digoxin)
- Protonix (proton pump inhibitor) raises ph in gut, makes acidic loving drugs less effective. - Interactions in the serum: most drugs are active when not protein bound (aka free), if two highly protein-
o CYP450 degradation: oxidation-reduction (add oxygen-add electron)
- CYP450 cascade: primary mechanism of drug metabolism. Responsible for more adverse drug reactions than any other cause. Results in hydrophilic drug ready for excretion.
- Substrate : the drug which is being metabolized by the cascade (2/3 of all drugs) - Common CYP450 substrates: beta blockers, anti-dysrhythmics, SNRIs, SSRIs, macrolide antibiotics, prokinetics, HIV antivirals, antihistamines, steroids, statins, morphine, lidocaine
- Inhibitor : a drug that prevents the cascade from occurring
- Common CYP450 inhibitors: amiodarone, grapefruit juice , ciprofloxacin, clarithromycin, mifepristone, ranitidine
- Inducer : a drug that promotes the cascade **- Substrate + substrate =no significant change
- Substrate +inhibitor = no metabolism occurs, and toxic lvs of drug build** **up in body
- Substrate +inducer= metabolism is induced too quickly, sub-therapeutic** levels in body.
- Some people are ultra-metabolizers (too fast, need more drug), extensive metabolizer- normal, intermediate metabolizers (a little too slow, need less drug), poor metabolizers (very slow, need less drug)
- Drug shorthand o RH: shorthand for any drug compound o RH-OH: shorthand for the oxidized form of a drug compound - First-pass effect (applies to PO drugs)- hepatic metabolism o When a drug is taken orally, a large portion is first metabolized by the liver before entering circulation o If a drug is administered in an active form, a lot of it will be metabolized (inactivated) by the liver before even getting a chance to reach its target location
o On the other hand, this first pass through the liver activates pro-drugs (inactive when swallowed, activated when metabolized by the liver) prednisone is inactive- first pass through liver activates it to prednisolone o If hepatic function is impaired, drug bioavailability will be impaired
- Regular drugs: don’t get metabolized, risk of toxicity buildup
- Prodrugs: don’t get activated, risk of sub-therapeutic
- Drug elimination o Routes of elimination include kidney, lungs, skin, GI tract, breast milk o Kidney is major route of excretion
- Need to consider adequate renal blood flow and renal function
- Specifically: glomerular filtration, tubular secretion, tubular reabsorption - Dosing o Goal of dosing: maintain steady state within therapeutic window (ABOVE minimally effective concentration, BELOW minimally toxic concentration) o Serum low must be higher than minimally effective concentration. Serum high must be lower than minimally toxic concentration o 5 half-lives must pass before steady state is maintained Week 1: Lecture 2
- Pediatrics & pharmacokinetics o Adolescence 12- 18 yrs. meds influenced by many hormones. o Birth to one yr and adolescence has most rapid growth, development of body systems o Routes of administration and effect on pharmacokinetics ▪ IM: usually for immunizations, not great for peds drug administration due to decreased muscle mass/ erratic blood flow ▪ Transdermal/topical: peds has increased surface area to volume ratio, increased water content, thinner statum corneum (layer facilitating absorption), occlusive dressings (increase absorption/biovailabilty of drug) Transdermal patches not okay for peds: will absorb more than an adult, also may eat it
bioavailability) ▪ Acidic drugs bind better to albumin, basic drugs bind better to alpha 1 acid glycoprotein and lipoprotein) ▪ Medications such as sulfonamides may compete for protein binding sites with endogenous chemicals such as bilirubin, which increases free bilirubin levels in serum= kernicterus o Drug elimination ▪ Most drugs eliminated by the kidney ▪ Renal function only reaches adult levels at 9-12months, so kids have prolonged metabolism and excretion of drugs. ▪ Result: most monitor therapeutic levels of drugs such as digoxin, vancomycin, phenobarbital as they have higher chance of toxicity.
- Pregnancy & pharmacokinetics o The maternal circulation eliminates the drug o Is a med safe for pregnancy? Depends on if drug can cross the placenta or not o If the med does not cross placenta, it’s ok to take EVEN IF it is unsafe for fetus o If the med does cross, does it impact fetal growth and development?
- Lactation & pharmacokinetics o Does the med appear in breastmilk? If not passed in breast milk, then it cant reach baby so its ok. o If so, is it safe for pediatric use? Then okay to use o If not, then it is NOT okay for mom to use. Once the baby is out, we look at baby not mom.
- Elderly & pharmacokinetics o Decreased renal perfusion o Proportionately less water-soluble body content and more fat content (think of fat old lady) (lipid soluble drugs can stay in system longer -increases half-life of drugs). More likely to have comorbid conditions
- For each med you give or do a med rec on: o What enzyme metabolizes this med?
o Does this med effect an enzyme that metabolizes the other meds? Block vs compete vs induce. Week 2: Lecture 1
- Lipid : any fat-soluble substance o Cholesterol : a building block lipid ▪ Primary structural component of cell membranes ▪ Also a precursor to steroid hormones and bile salts o Triglycerides (fatty acids) ▪ Primary fuel lipid ▪ The smallest component of lipids (as amino acids are to proteins) o Other lipids include: ▪ Glycerophosphlipids & sphingolipids: cell membrane components- hydrophobic barrier bw h20/cholesterol ▪ Eicosanoids: precursors to prostaglandins ▪ Bile salts- emulsify dietary fat, breaks down triglycerides ▪ Steroid hormones: glucocorticoids (cortisol), mineralcorticoids (aldosterone), sex hormones ▪ Fat soluble vitamins (ADEK) E is antioxidant in endogenous form, D is calcium absorption
- Triglycerides and cholesterol both can either be ingested via gut (exogenous) or made by the body in liver (endogenous), both must travel though plasma in hydrophilic molecule, both influence cardiac health
- Triglyceride ingestion: how dietary fat from food gets to muscle or fat stores! o Destination: muscle (as fuel) or adipose (as storage) o Must be packaged in a water-soluble form in order to enable transport through plasma or will form fat emboli
o Step 3: cholesterol travels via chylomicron through the plasma and returns to the liver via the chylomicron remnant ▪ Chylomicron is the transportable form of exogenous cholesterol ▪ Cholesterol gives chylomicron “some weight,” allows it to move- why they go through plasma before going back to liver: (drops off triglycerides in fat or muscle and then travels back to liver) o Step 4: cholesterol enters free cholesterol pool in the liver (returns via chylomicron remnant) o Cholesterol is train conductor, triglycerides are passengers, chylomicron is train.
- Triglyceride synthesis: made in liver from glucose/ or its larger form: sucrose. NOT INGESTED. Made by body o Liver makes fatty acids (triglyceride precursor) from dietary glucose – triglyceride then has to get to target destination (muscle and fat) from the liver o Step 1: triglyceride is packaged with apoproteins, phospholipids, cholesterol to create VLDL very low density lipoprotein (water-soluble “bag” to hold the triglycerides). Not called a chylomicron when body makes its own! ▪ VLDL is the transportable form of endogenous (body makes its own) triglyceride o Step 2: VLDL enters the bloodstream o Step 3: HDL gives “destination tag” to VLDL o Step 4: at target destination, LPL enzyme in capillary endothelial cells digests the triglycerides from VLDL. Once TGS is dropped off, the bag is no longer very low density. o Step 5: some free fatty acids are used for energy while others are stored ▪ Fed state : most free fatty acids convert to triglycerides and stored in adipose tissue ▪ Fasting state : adipose tissue releases free fatty acids and triglycerides into bloodstream as fuel
▪ Free fatty acids and glycerol are released in bloodstream and serve as predominant fuel in body.
- Cholesterol synthesis (NOT INGESTED, made by body) MOST CHOLESTEROL MADE THIS WAY. o Step 1: cholesterol is made in the liver from its precursor: acetyl CoA ▪ 2 acetyl CoAs join with another acetyl CoA (facilitated by HMG-CoA synthase, not rate-limiting) to form HMG-CoA ▪ HMG CoA reductase converts HMG-CoA to mevalonate, then more reactions occur, and cholesterol is formed - This reaction (HMG-CoA reductase) is the rate-limiting step in cholesterol synthesis - High levels of cholesterol (ingested or in plasma) inhibits HMG-CoA reductase o Step 2: cholesterol is packaged with triglycerides and protein to form VLDL ▪ VLDL is the transportable form of endogenous (body makes own) cholesterol o Step 3: VLDL enters bloodstream, goes to target destination o Step 4: LPL digests the triglycerides in the VLDL, causing the remaining substance to become denser (less low- density triglyceride, more high-density cholesterol) – the resulting substance is IDL o Step 5: IDL is unstable and converts to an LDL ▪ LDL is analogous to the chylomicron remnant (what is left after triglycerides gone) ▪ LDL has both cholesterol and triglycerides (more cholesterol than triglycerides) ▪ VLDL---IDL- LDL o Step 6: liver takes in LDL from bloodstream via endocytosis into hepatocytes, breaks it down, and recycles it – cholesterol from the LDL is sent to the free cholesterol pool
o Synthesized cholesterol is returned via LDL o HMG-CoA reductase pathway: Intracellular synthesis of cholesterol – responsible for 75% of serum cholesterol
- Glossary- o Triglycerides: lipid fuel source o Cholesterol: lipid structural compound- building block o Chylomicron: water-soluble transport for ingested lipids o VLDL: water-soluble transport for synthesized lipids (more triglycerides than cholesterol) o IDL: unstable breakdown product of VLDL o LDL: stable breakdown product of IDL (more cholesterol than triglycerides). HDL synthesis: NOT DEGRADATION OF VLDL o HDL is made in the liver and gut, then enters bloodstream o HDL tags chylomicrons and VLDL with apoproteins (“location tags”) o HDL also picks up cholesterol and transports it to the free cholesterol pool Bile acids o Bile acids are made (from cholesterol) by the liver and stored in the gallbladder o They are released into the gut in response to incoming food o They emulsify dietary lipids, then reabsorbed into the gut and recycled ▪ Bile acid bindings drugs bind to bile acids in the gut and prevent them from being reabsorbed and recycled - this forces the liver to keep having to make new bile acids out of cholesterol and use up more cholesterol, which also causes the liver to upregulate LDL absorption **Week 2: Lecture 2
- Statins: HMG-CoA reductase inhibitors o** Mechanism
o Labs to follow ▪ Liver function tests at start of treatment, no need for routine monitoring. o 2013 AHA guidelines on treatment of blood cholesterol ( TREATMENT )
- Some people have genetic lipid disorders causing high serum lipids; most do not but have high serum lipids due to lifestyle factors (diet, weight, exercise)
- Statins come in high intensity (50% reduction in LDL) and medium intensity (30-49% reduction in LDL) – all doses are daily. Low intensity- 30% reduction not really used. o High: 40-80 mg atorvastatin, 20-40 mg rosuvastatin o Moderate: 10-20 mg atorvastatin, 10-20 mg rosuvastatin, 20- 40 mg simvastatin, 40-80 mg pravastatin, 40 mg lovastatin The guidelines list 4 different groups who should receive statins Group 1
- Anyone age 21-75 years old with atherosclerotic vascular disease ( high intensity ) o Can get moderate intensity if over age 75 or can’t tolerate high intensity Group 2
- Anyone over 40 with LDL over 190 mg/dL ( high intensity if 75+, otherwise moderate) Group 3
- Anyone age 40-75 with diabetes mellitus ( moderate intensity ) - Anyone with a 10-year ASCVD risk over 7.5% ( high intensity) Group 4 - Anyone 40-75 with a pooled risk for ASCVD over 7.5% ( moderate or high) Statin’s pleotropic effects: uncertain. Improved endothelial cell function, halting atheroma or plaques development, reducing inflammation, and antithrombotic effects.
o United States Preventive Services task force recommendations ( PREVENTION ) ▪ Adults age 40-75 with no history of cardiovascular disease, 1+ risk factors, and 10-year ASCVD risk over 10% should receive low to moderate intensity statins (strong evidence, level B) ▪ Adults age 40-75 with no history of cardiovascular disease, 1+ risk factors, and 10-year ASCVD risk 7.5- 10% should consider low to moderate intensity statin (less strong evidence, level C) ▪ Adults age 75+ and no history of cardiovascular disease – insufficient evidence to recommend statins o Updates/take-home messages (2018) ▪ 2. Patients with clinical atherosclerotic cardiovascular disease (ASCVD), use maximum tolerated statin ▪ 3. In high risk ASCVD , aim for LDL under 70 mg/dL , add ezetimibe first, then PCSK9 inhibitor as needed ▪ 4. If severe primary hypercholesterolemia, start high intensity statins regardless of ASCVD risk, goal LDL under 100 mg/dL , add first ezetimibe, then PCSK9 inhibitor as needed ▪ 5. If age 40-75 with diabetes and LDL over 70 , start moderate intensity statin regardless of ASCVD risk ▪ 6. If age 40-75 and only seeking primary prevention, discuss risks before starting statins ▪ 7. If age 40-75 with LDL > 70 mg/dL and 10-year ASCVD risk > 7.5% start moderate statin ▪ 8. If age 40-75 with 10-year ASCVD risk 7.5-19.9%, start statins if risk factors present too ▪ 9. If age 40-75 with LDL 70-189 mg/dL and 10-year ASCVD risk 7.5- 19.9%, measure a coronary artery calcium if unsure if needs to start statins ▪ 10. After starting statins, measure lipids 4-12 weeks after starting and
o Adverse effects: URI, back pain, injection site reactions- most common one Omega-3-acid ethyl esters: icosapent ethyl o Indicated if triglycerides > 500 mg/dL, demonstrated risk reduction for cardiac events o Mechanism: reduces hepatic VLDL synthesis (thus leads to decreased LDL), fish oil derivative o According to ADA- American diabetes association: Should be considered when patients on statins still have triglycerides 135-499 mg/dL
- Fibric acid derivatives : gemfibrozil –lopid, fenofibric acid, fenofibrate (Tricor) o Mechanism: increase LPL activity, promotes breakdown (via LPL) of triglycerides and VLDL, blocks lipolysis of triglycerides stored in adipose tissue (harder to remove TGS from fat cells)– reduces triglyceride levels but not LDL o Adverse effects: Similar to statins (HMG-CoA Reductase inhibitors) since they inhibit same hepatic synthesis pathway: cholelithiasis (gallstones), dyspepsia, diarrhea, myositis, LFT abnormalities, headache, dizziness, impotence o Not really used, old drug. Trilipix (fenofibric acid) is only one really used o Labs to monitor: liver and renal function before starting, may decrease serum glucose and uric acid **o Causes HYPO-glycemia and low serum uric acid= treatment for GOUT.
- Bile acid sequestrant: Welchol** o Mechanism: binds bile acids in gut, prevents reabsorption of bile acid (which is made of cholesterol), this causes the liver to have to make more cholesterol to
make more bile, must uptake more LDL from serum in order to make more cholesterol, reduces LDL by 15-30% o Side effects: constipation, GI bleeding and irritation, LFT abnormalities, bile duct obstruction, high triglycerides, prevents absorption of fat soluble vitamins, blocks absorption of many meds (PO anticoagulants, digoxin, penicillin, thyroid, tetracycline, iron) o Often used to treat diarrhea, short-gut Week 3: Lecture 1
- Diuretics 1. Mechanism: inhibit transportation of ions NOT WATER. Water simply follows electrolytes and this side effect is why its used to remove water off people. Traps electrolytes in urine and water follows into urine as well. ▪ Goal is to reduce blood volume (water follows solutes). Diuretics block re- absorption of electrolytes 2. Dosing: all available PO, thiazide diuretics and loop diuretics available IV 3. Loop diuretics: most effective, act at ascending loop of Henle (water most permeable here). Cause more dryness than thiazides since they take more H out. ▪ Does not require adequate renal perfusion because it acts on the outer surface of the tubule 4. Thiazide diuretics: most commonly used. act at distal convoluted tubule (near loop of Henle) ▪ Requires adequate renal perfusion (GFR of atleast 30) because it acts on the inner surface of the tubule ▪ Promotes excretion of sodium, hyponatremia, hypochloremia risk and HYPER-kalemia
