Exam 1
Drug development
- Drugs must be safe and efficacious - Must be proven across racial and ethnic groups and age groups
peak of action
when the drug has its maximal effect in the body
volume of distribution
(talking about blood flow to tissues)- a hypothetical volume of fluid into which the drug is distributed
Older adults and adverse drug effects
- Accidental overdoses often related to pain meds - Four medications cause 2/3 of hospitalizations o Warfarin o Insulin o Oral antiplatelets Oral hypoglycemics
Risk factors for adverse drug effects
- Age > 85 - Low BMI - Cr CL < 50 ml/min - More than 6 co-morbid disorders - More than 9 meds, more than 12 doses a day - Previous adverse drug effects
Drug excretion in the elderly
- Aging can decrease renal function, glomerular filtration, and renal tubule excretion - Creatinine levels may remain normal despite glomerular filtration changes - Muscle mass decreases and less overall creatinine exists
Drug therapy in geriatric patients
- Aging changes: o Blood brain barrier o Baroreceptor responsiveness o Decreased renal/hepatic blood flow o Immunosenescence o Pharmacodynamic aging changes
beers criteria
- American geriatric society: o Five types of criteria- § Medications that are potentially inappropriate § Those that should be avoided in older adults with certain conditions § Drugs to use with caution § Drug-drug interactions § Drug dose adjustments based on kidney function
Potentially inappropriate use (PIMS) in older adults: endocrine
- Androgens - Desiccated thyroid - Estrogen with or without progestin - Growth hormone - Insulin, sliding scale (insulin regimens containing only short or rapid acting insulin dosed according to current blood glucose levels without concurrent use of basal or long-acting insulin) -Megestrol - Sulfonylureas, long acting (chlorpropamide, glimepiride, glyburide)
Potentially inappropriate use (PIMS) in older adults: CNS
- Antidepressants, alone or in combination (amitriptyline, amoxapine, clomipramine, desipramine, doxepin > 6 mg/d, imipramine, nortriptyline, protriptyline, trimipramine) - Antipsychotics, first (conventional) and second (atypical) generation - Barbiturates - Benzodiazepines (short, intermediate, and long-acting) - Meprobamate - Nonbenzodiazepine, benzodiazepine receptor against hypnotics (Z drugs) - Ergoloid mesylates
pediatric excretion
- Neonate or preterm infant has immature kidneys - Monitor drug doses and therapeutic blood levels of medications to prevent toxicity - Reduced gfr and decreased tubular secretion and reabsorption during the first 6 months of life leads to extended half-life - Age 3 months; kidneys concentrate urine at the adult level, but urinary excretion is low until approximately 30 months
Type 3 hypersensitivity response
- Occur when antibodies (IgM & IgG) are formed against soluble antigens. The antigen-antibody complexes are deposited in tissues such as joints and lungs o Cause serum sickness - Ceclor
Type 2 hypersensitivity response
- Occurs when drug binds to cells (RBCs) and is recognized by an antibody, usually IgG o Complement and cytotoxic T cells are activated o This response is rare
orphan drug status
- Pharmaceuticals to treat rare diseases - FDA orphan drug act: the disease that the drug is intended for should affect less than 200,000 people in the US - Fast track review process and market exclusively for 7 years - Direct guidance from the FDA for the design of the clinical plan to further develop the drug - The cost of developing and marketing these drugs will not be covered by expected sales
Chemical starting points
- Plants - Animals - Humans - Lead components are more often sourced from targeted chemical synthesis directed to bind to the unknown structures of receptors and enzymes
Distribution in children
- Plasma proteins reach adult levels by age 1 - Children up to 2 years of age may require higher dosages of water-soluble drugs
acid/basis environment
- the environment of the stomach is more acidic - the environment of the intestines is more basic - the pka of aspirin is 4.5 (weak acid) - where is aspirin more likely to cross the cell membrane? - The stomach
influence of pH and pKa
- the pka of the drug is the ph at which half of the molecules are ionized and the other half are in unionized form (calculated by the Henderson hassle bock equation, do not need to know how to do equation) - most drugs are either weak acids or weak bases - the ionization of the drug determines how the drug will be able to cross the cell membrane - the degree of ionization of drugs is determined by the surrounding ph of the environment the drug molecule is in and the drugs pka - drugs that are weak acids are uncharged in an acidic environment - drugs that are weak basis are uncharged in a basic environment
absorption
- transfer of a drug from its site of administration to the blood stream (most occurs through passive diffusion) - factors affecting absorption- o route of administration o drug properties- lipid solubility, polarity, drug form (tablet, capsule, liquid) o total surface area available for absorption contact time with absorption surface
biliary excretion
- transported by liver cells from blood to bile then enter the GI tract and excreted through feces o Enterohepatic reabsorption
What are the actions and side effects of cholinergic receptor antagonists?
-(sympathetic system)- blocking the parasympathetic nervous system. These drugs compete with acetylcholine at receptor sites and the cholinergic system. Mostly work at muscarinic receptors. Side effects- red as a beet, dry as a bone, mad as a hatter, blind as a bat, hot as a hair, full as a flask. Headache, decreased memory and cognitive function, anxiety, prolbems with behavior, insomnia. Hyperthermia, hydrosis, tachycardia, constipation, reduced saliva, urinary retention, pupil dilation. med ex: atropine, benztropine mesylate
phase 1 metabolism
Phase 1 - metabolite either active or inactive. non synthetic reactions - Oxidation- most important drug metabolizing reaction that involves adding of oxygen or a charged radical. Involves the CYP 450 isoenzymes. - Reduction - Hydrolysis
receptor interactions
drugs bind to receptors on cells to produce a response. Receptors are typically proteins. Responsible for getting the drug from the outside of the cell into the intracellular environment
beta 3 receptor agonist
relaxation of the smooth muscle of the bladder occur. Example: mirabegron for overactive bladder.
pharmacodynamics
the action of the drug on the body
steady state
the amount of drug going into the body equals the amount being eliminated (usually about 5 half lives per 1 steady state)
duration of action
the length of time the drug shows any effect in the body
drug half life
used to decide dosing schedules. The length of time required for the concentration of the drug to decrease to half of its starting concentration. Once it reaches steady how much of half of the drug to be eliminated from the body. After one half life has passed, 50% of the drug is removed from the body.
prior to prescribing medications
- Take a thorough patient history - Perform a physical examination
Medication safety in older adults
- Elders take 34% of all prescription medication - Most mediations for older adults are for: o HTN o CAD o Analgesics/anti-inflammatories o Sedatives o GI meds
process for prescribing medications
- Assess →Diagnose → Review pathophysiology/pharmacotherapeutics/possible drug interactions → select 1st line of therapy (nonpharmacologic vs pharmacologic) → need to set goals for therapy and evaluate the patient's response to therapy → if successful maintain current regimen, if unsuccessful move to second line of therapy → evaluate response → if successful maintain current regimen, if unsuccessful move to third line of therapy (ex: diabetes or htn may require multiple medications for management)
pediatric phase 1 metabolism
- CYP 450 3A plays an important role in drug metabolism - The earliest isoenzyme to show activity is the CYP3A7 and is present in utero - CYP3A7 declines rapidly after birth - The rate of decline of CYP3A7 decreases throughout the first 6 months with and increase in CYP3A4 and CYP3A5 - Adult levels of these isozymes will not be reached for several years
Drug therapy and the geriatric patient
- Causes of adverse drug effects in older adults: o Medication factors o Physiologic aging changes o Patient errors o System errors o Provider errors
pediatric prescribing
- Children differ from adults regarding the following: o Drug absorption o Distribution o Biotransformation/metabolism o Excretion/elimination
Excretion in children
- Children over 12 months of age are able to excrete drugs effectively
phase 4 clinical trials
- Date is submitted to the regulatory agencies (several months; targeting certain regions) - New drug application takes approximately 15 months to review - Process is expedited for oncology and HIV - Phase 4 begins with post marketing or safety surveillance trials - Harmful effects are discovered that can lead to the withdrawal of the drug
Drug absorption in the elderly
- Decrease gastric acid: o Drugs requiring an acidic environment to dissolve will take longer to be absorbed o Decreases the systemic availability of the drug - Reduced blood flow to organs decreasing drug absorption - Decreased drug absorption with IM or subq route due to decreased blood flow at the injection site - Overall slowed drug absorption related to decreased GI motility, decreased gastric acidity, and reduced blood flow
Drug metabolism in the elderly
- Decreased blood flow results in less drug clearance - The liver size declines o Decrease in hepatocytes o First pass effect can be reduced - Aging affects the efficiency of phase 1 metabolism o Slowed metabolism o Reduced oxidation o Increase drug blood levels o Extended half-lives - Phase 2 metabolism is not affected
drug distribution in the elderly
- Decreased drug distribution: o Decreased body mass o Reduced albumin o Less effective blood brain barrier o Decreased cardiac output o Changes in body weight o Poor nutrition o Dehydration o Inactivity Bedrest
Type 4 hypersensitivity response
- Delayed type sensitivity - cytotoxic T cells are activated o Well known type 4 responses are allergies to poison ivy and latex o Contact dermatitis With repeated exposure to drugs, a "cytokine storm" can be triggered
Cognitive and psychosocial developmental considerations
- Developmental age is the functioning level of the child - Strategies consistent with child's developmental age are needed to ensure safe and effective medication administration - Assessing the child's temperament can lead to determining the best method of administering a medication
pediatric distribution
- Differences in body water and fat - Immature liver function o Age 0-6 months less albumin and fewer proteins o Fewer binding sites in the pediatric patients results in higher blood concentrations of two or more drugs or less affinity for one of the drugs - Immature blood brain barrier o Birth: the blood brain barrier is not developed leading to greater risk of CNS toxicity; drug enters the CNS
Basic calculation steps
- Dosage recommendations will be mg/kg - Convert the patient's weight to kg by dividing the weight in pounds by 2.2 o Example: 74 lbs divided by 2.2 = 33.63 Round to the tenths place = 33.6 kg
Calculate liquid medications
- Dose desired: o Dose on hand X quantity in mL = volume to be administered
Pharmacokinetics in children
- Doses based on weight: o Mg/kg - Physiologic differences: o Infants have more water, less fat o Immature liver makes fewer serum proteins, is less able to metabolize drugs o Blood brain barrier less well-developed in infants o Renal function not fully developed until 30 months - Phase of development important - Drugs known to be dangerous to children are not given
Dosing in pediatric populations
- Drug dosing in infants and children: o Recommended doses for FDA approved drugs must be computed based on the individual child's weight. - Accurate drug dose is critical since infants/children do not have the mature physiological responses to compensate for drug errors
writing a prescription
- Drug name and strength - Signa (patient directions) - Signature - First part (date, name, address, DOB) - Prescription components (prescribers name, address, phone #, name of the drug, dosage, dosage regimen, route of administration, allowable subs, prescribers' signature, and license number)
pregnant or breastfeeding women
- Drug therapy in pregnant women: o Treat pre-existing medical condition o Treat pregnancy related complications - Drug therapy during lactation: o Drugs are used only if necessary and treatment cannot be delayed until after the infant is weaned o Breastfeeding mothers should take drugs immediately after breastfeeding to lower the drug concentration at the next feeding
Metabolism in infants
- Drug-metabolizing enzymes in the liver of infants is immature - More drugs in circulatory system may increase the potential for drug toxicity - Drug dosages for infants must be carefully calculated and drug levels and clinical responses closely monitored
Drug distribution during lactation
- Drugs with increased lipid solubility and low protein binding such as CNS agents pass easily into breast milk - Drugs of low molecular weight pass into the breast milk - Low pH produces high concentrations
Phase 1 clinical trials
- First administration of the new medicinal product to humans - Healthy volunteers - Purpose: o Evaluate safety o Evaluate tolerability o Evaluate pharmacodynamic effect (effect of the drug on the body, e.g., heart rate, bp, ECG) o Evaluate absorption, distribution, metabolism, excretion - Investigation new drug application summarizes the established preclinical manufacturing information along with the investigator guidance - The trial will be stopped if the half-life is too short or too long or poor bioavailability - The trial is stopped if significant ECG changes and severe adverse effects - Phase 1 studies start with sub-pharmacological doses that are escalated following multiple doses
Potentially inappropriate use (PIMS) in older adults: anticholinergics
- First generation antihistamines - Anti-parkinsonian agents (benztropine, trihexyphenidyl) - Antispasmodics
Pediatric Absorption
- Gastric pH does not reach adult levels until age 1 - Thus, if an acidic environment is needed to absorb the medication less medication will be absorbed by infants - Children have greater body surface area and will have greater absorption of topical medications - Infants skin is also more permeable leading to greater absorption of topical medications - Immature peripheral circulation will prevent the absorption of IM or subcutaneous medications
Absorption in children
- Gastric pH is equal to adult by 2 to 3 years of age - Gastric emptying rates are faster than in infants - Skin and blood-brain barrier become more effective
Adverse drug reactions
- Harmful or unintended response - Common - range from mild to life threatening - Some ADRs can occur in anyone o Overdose o Excessive effects o Drug interactions - Some ADRs occur in susceptible individuals: o Intolerance o Idosyncracy Allergy
Distribution and metabolism in pregnancy
- Heart rate increases by 10-15 bpm - 50% increase in blood volume causes hemodilution of plasma albumin to potentiate drug distribution - Plasma lipid levels increase altering drug transport and distribution - Drugs compete for receptor sites occupied by hormones resulting in more unbound and free drug - Drugs that are not lipophilic enter the fetal circulation - Drug metabolism is not altered by pregnancy or lactation
General guidelines for medication administration
- Honesty is always a priority - Careful attention to vocabulary should be used when giving explanations, so as not to frighten the child - Take developmental stages into account
Idiosyncratic reactions/allergic reactions
- Idiosyncratic ADRs- adverse effects that appear unpredictably - Allergic reactions- hypersensitivity responses o Small drugs are not direct immunogens o These drugs act as haptens - bind covalently with a protein to trigger an immune response o Four types of hypersensitivity responses
Other distribution concerns in the elderly
- Increased body fat o Lipophilic meds will have greater time to excretion - Less water in the body o Might have increased levels of hydrophilic meds
Excretion in infants
- Infant kidneys have higher resistance to blood flow and lower GFR with a decreased ability to concentrate urine - Infants may secrete drugs more slowly, increasing the risk of drug accumulation
Metabolism (biotransformation)
- Irreversible biochemical transformation of drug into metabolites to increase excretion from the body via the kidney o Occurs mainly in the liver o Metabolite usually more ionized and less lipid soluble - so that it will not be reabsorbed in the renal tubule
questions to address prior to prescribing
- Is there a need for the drug in treating the presenting problem? - Is this the best drug for the presenting problem? - Are there contraindications to this drug? - Is the dosage correct? - Does the patient have sensitivities or allergies to the drug? - What drug treatment is the patient already being administered? Will these drugs interact? - Is there a problem with storage with the drug? - Does the dosage regimen interfere with the patient's lifestyle? - Is the route of administration the most appropriate? - Is the proposed duration of treatment too short or too long? - Has the patient been informed of possible side effects? - Is there a genetic component to consider? - What is the cost of the medication? - Does the patient have a prescription drug plan?
Metabolism in children
- Liver enzymes are more effective at metabolizing drugs - Due to elevated BMR, some drugs are metabolized more rapidly - Drug dosages relative to body weight may need to be higher - Drugs may need to be closely monitored
Distribution in infants
- Low concentration of plasma proteins and diminished protein-binding capacity allow drugs to be more available in the circulation. - Greater permeability of the blood-brain barrier allows for rapid access of drugs to the CNS. - Total body water is 80% compared to the adult's 50%. Higher doses of water-soluble drugs may be needed to achieve therapeutic effects
phase 3 clinical trials
- Minimum of two trials - Several thousand patients - Confirms clinical doses, frequency, and timing of administration for approval - Designed to test the hypothesis of efficacy - Adverse effects are collected to assess benefit-risk potential - Studies that use mortality and morbidity end points are very large and can take several years to complete - Data safety monitoring board are used with mortality and morbidity studies: clinician with expertise in the disease area and a biostatistician - All phase 3 trials must: ensure appropriate patient recruitment and timely completion of the study - Drop out rate must be monitored, if the rate is too high additional study sites will be recruited to ensure adequacy - Oncology studies do not take that long to complete and are limited to a few hundred patients
Synthetic chemicals
- Most drugs used today are either partially or wholly synthetic chemical compounds - A partially synthetic agent contains a derivative of natural substance combined with a pure chemical - Synthetic drugs are pure chemicals
What are the issues in pediatric prescribing
- Potential for adverse drug events within the pediatric inpatient population is 3 times as high among hospitalized adults. o What are the reasons? -Most medications used in the care of children are formulated and packaged primarily for adults. Those medications have not been tested for side effects or actions on the pediatric population. -Children especially young small sick children are usually less able to physiologically tolerate a medication error due to still developing renal, immune, and hepatic functions. This makes them more at risk for adverse drug reactions
drug absorption in pregnancy
- Progesterone decreases gastric tone and motility; prolonging stomach emptying time o Alters pharmacokinetics of oral medications - Progesterone promotes respiratory changes o Increase tidal volume o Increase pulmonary vasodilation o Inhaled drug absorption is increased
the prescription drug marketing act
- Protects the American consumer from ineffective drugs - Affects the receipt and dispensing of drugs - Forbids foreign countries from reimporting prescription drugs - Bans the sale, trade, and purchase of drug samples - Must have clear instructions/directions if dispensed to a patient from the office
Absorption in infants
- Rates of drug absorption in the infant are lower than absorption rates in children and adults. - Prolonged gastric transit time and variable gastric pH lead to diminished absorption. - Frequent feeding may impede drug absorption. - Low levels of intestinal flora and reduced enzyme function can lead to decreased absorption. Low peripheral perfusion and immature heat regulation can decrease absorption of IV, IM, or SC medications
Type 1 hypersensitivity response
- Results from production of IgE after exposure to an antigen o Urticaria o Wheezing, rhinitis Anaphylaxis
STOPP and START criteria
- STOPP criteria: o Screening tool of older persons' potentially inappropriate - START criteria: o Screening tool to alert doctors to right treatment
phase 2 clinical trials
- Testing efficacy and safety on the target po - Phase 2 a is the proof of concept: (drug is limited to a single/maximal tolerated dose level) tested on 12-100 patients - Phase 2 b follows the proof of the concept: several dose levels are tested on the target population (dose-ranging studies) - Progression to phase 3 will depend on: o Drug efficacy relative to competitors o Safety profile o Probability of technical and regulatory success o Remaining patent life of the drug o Cost of goods to produce the drug o Market share o Price o Reimbursement
excretion
- The elimination of drugs from the body unchanged or as a metabolite o Kidney - urine (most common) o Liver - bile (first pass metabolism) o Skin o Lungs o Breast milk
Preclinical trials
- The first step is in the discovery of a potential new drug molecule - Preclinical trials are designed to provide basic safety, bioavailability, pharmacokinetic, and initial efficacy data about the drug - Development of a suitable formulation for clinical use - Reproduction toxicology - Long-term carcinogenic testing
Animals
- Traditionally, drugs from animal sources include agents such as insulin - Today, genetically engineered hormones are rapidly replacing animal-based drugs
drug receptor interaction: affinity
- ability of the drug to bind to the receptor
passive diffusion
- drugs dissolve and cross the cell membrane following a concentration gradient - characteristics of drugs- small, lipid soluble, unionized form - only the unionized forms of drugs can pass through the membrane by passive diffusion - unionized/lipid soluble drugs can pass the cell membrane by passive diffusion - ionized (charged)/less lipid soluble drugs are not going to readily cross the cell membrane by passive diffusion
onset of action
- first point at which we see medication working
plasma protein binding
- free drug is the only form that is pharmacologically active and able to cross the cell membrane. Protein bound drugs are not pharmacologically active o Albumin - primary protein responsible for protein binding (strongest affinity for weak acid and hydrophobic drugs. Any condition that can lead to hypoalbuminemia such as cancer, liver failure there could be more free drug concentration o Alpha-1-glycoprotein (affinity only for basic drugs)
renal excretion
- most common method of excretion o Usually removes a drug that is unbound and free in the plasma o Glomerular filtration - depends on plasma protein binding and renal blood flow o Tubular secretion and reabsorption- changes the urinary pH which can change the polarity of drugs
Active transport (also known as carrier mediated transport)
- moves against the concentration gradient and requires energy (energy most often in the form of ATP) - needs carrier proteins that are specific for each molecule
How does hypoalbuminemia affect the process of prescribing?
Albumin is the main protein carrier for drugs in the body. In states of low albumin, there is going to be more free drug. Certain disease states such as patients with cancer, liver disease, malnourished, infectious states cause low serum albumin and more free drug, may need to decrease dosage of drugs. If drugs are bound to the protein, they tend to stay in the plasma in circulation to get to where they need to go but will not be able to bind to receptor if still bound to protein.
prescribing medicatioins
All prescriptions shall conform to all applicable state and federal statues, rules, and regulations. Always stay within your scope of practice.
define drug efficacy
How well a drug works to exert its therapeutic effects.
explain first pass metabolism
Drugs are routed to the liver before their sites of action and when they get to the liver they are metabolized and excreted before being able to exert their effects. To overcome this effect, drugs require higher doses.
define drug affinity
How much or how well a drug binds to its receptors.
What are the criteria for choosing an effective drug?
Is the therapy likely to help the patient? Is it efficacious? What is the patient's presenting problem? What is the goal of therapy for the patient? Choose the right drug. Is there any non-pharmacologic adjunctive therapy? Patient education on disease process that is being treated, contraindications of medication, what to look for while taking medication, how to take medication. Follow up with the patient on a regular basis. Drug cost.
phase 2 metabolism
Metabolite inactive only. Synthetic reactions. - Glucuronidation
Potentially inappropriate use (PIMS) in older adults: anti-infective
Nitrofurantoin
distribution
Passage of a drug from the circulation to the tissue and its site of action
Describe the process of passive diffusion and the factors that affect a drug's ability to passively diffuse across a cell membrane.
Passive diffusion the drug is moving passively (no energy required) from a higher to a lower concentration area until equilibrium is achieved. Drugs are smaller, unionized, lipid soluble.
What factors affect a drug's absorption?
Ph, drugs solubility (lipid or water), sites and route of administration, conditions of site of administration (ex: patient with edema and giving subq injections the drug is not likely to reach site of action, formulation (sustained or delayed release)
dose response phenomena
Potency is a measure of drug activity expressed in terms of the amount of drug required to produce an effect of given intensity
Describe drug metabolism and the role of the isoenzymes of the cytochrome P450 system.
The main goal of the CYP p450 they convert drugs to a water-soluble form so then they can be excreted by the kidneys. Phase 1 and phase 2 reactions, phase 1 most common is oxidation which is catalyzed by the CYP P450 system. For example, if you are giving two drugs and metabolism is induced there will a decreased level of the drug that is affected and less chance for a therapeutic effect. If the metabolism is inhibited, there will be an increase level of the drug which is an increased chance of toxicity (staggering the dose can help avoid). Sites of metabolism - liver, kidneys, lung, intestinal wall, and plasma. How drugs can be excreted from the body, kidney is the main site.
What factors are associated with clinical judgment when prescribing medications?
There are federal and state laws to follow and depending on the practice there might be other rules to follow. State boards of nursing regulate the states practice law. A thorough assessment of the patient needs to be done, history and physical (comprehensive or focused), obtain diagnostics (labs/imaging), prescribe a medication, and follow up to evaluate effectiveness. Non-pharmacologic therapy can be given alone.
partial agonist
a drug that has affinity but less intrinsic activity, binds to receptor and produces less of a pharmacological response
agonist
a drug that has affinity plus intrinsic activity, binds to receptor, and produces a pharmacological response
antagonist
a drug that has affinity, but no intrinsic activity, binds to receptor but produces no pharmacological response
efficacy or intrinsic activity
ability of the drug to produce a pharmacological response after attaching to the receptor
alpha 1 blockers antagonists
aciton: block postsynaptic alpha 1 receptors and blood vessels, results in a decrease in vasoconstriction in both arteriole and venous beds, which decreases peripheral resistance and decreases blood pressure. Also blocks alpha 1 receptors block postsynaptic alpha 1 receptors in the smooth muscle of the bladder neck and prostate; the smooth muscle relaxes in the bladder neck and prostate gland which decreases the urethral resistance and BPH, pt will have less urinary obstruction symptoms and better urinary flow. Side effects: hypotension, fluid retention, nasal congestion, blurred vision, orthostatic hypotension, dizziness, nausea, fatigue, tachycardia. 1st dose phenomenon of orthostatic hypotension, have patient take the 1st dose of these medications at bedtime and arise slowly only after dangling legs while still in bed to avoid passing out. Start the dose low, and increase slowly (watch for phenomenon to occur again). med ex: prazosin, doxazosin
Beta Receptor Antagonists
action: block the binding of epinephrine and norepinephrine to beta 1 receptors in the heart and elsewhere, happens at the SA node which results in decreased heart rate, at the atrial ventricles decreased contractility occurs, at the AV node there is slowed conduction. Within the vascular system, the beta receptors will block beta 2 mediated vasodilation which has a rise peripheral vascular resistance, but usually resolves. Beta receptors reduce the release of renin, there is a decrease in angiotensin 2 vasoconstriction and less aldosterone cause less plasma volume expansion, a decrease in bp. In the respiratory system, the beta receptor in the lungs are blocked so that bronchoconstriction can occur. Beta blockers are usually contraindicated for patients with reactive airway disease such as asthma. In the liver, may increase triglycerides and decreasing HDL so they may need to be avoided. Beta blockers inhibit gluconeogenesis, be cautious with diabetics. Side effects: bradycardia, hypotension, fatigue, weakness, depression, nausea, confusion, insomnia, hypo/hyper glycemic, constipation, diarrhea. Beta blockers can mask hypoglycemic symptoms. Need to be tapered off beta blockers. med example: LOL's
alpha 1 receptors
alpha 1 receptors are in the eyes, salivary glands, arterioles, post capillary venules, gastrointestinal, genitourinary sphincters. An agonist action- example would be phenylephrine, which is a decongestant, vasoconstriction of vascular smooth muscle, cause pupil dilation in the eye, cause glycogenolysis which is the breakdown of glycogen to glucose from the liver, cause contraction of urinary sphincters and urinary retention, inhibit renin release at the kidney. Side effects include HTN. med ex: methoxamine or midodrine
alpha/beta blockers
bind to block alpha 1 adrenergic (selective alpha 1, non selective beta). Decreased blood pressure- carvedilol (peripheral vasodilation, the heart has decreased workload, less myocardial oxygen demand, also reduces renal vascular effects. Side effects- same as beta blockers, orthostatic hypotension more risk. cervedilol
What are the actions and side effects of cholinergic receptor agonists?
involve either nicotinic or muscarinic receptors in the parasympathetic nervous system. They copy the work of acetylcholine. They either bind at receptors sites with acetylcholine as agonists or they will prevent the breakdown of acetylcholine by the enzyme acetylinosterase. Direct muscarinic agonists- they have actions in glaucoma, improve GI and bladder tone, increase salivary gland secretion. Side effects- increased GI acid (not used with gerd or gi/gu obstruction), bronchoconstriction, hypotension, bradycardia, hyperthyroidism. -cholinsterase blocks the enzyme that breaks down acetylcholine, so acetylcholine has more activity at adrenergic receptors. Side effects- gi/gu obstruction, uterine irritability to pregnancy, generalized seizures, bronchoconstriction (almost same as other) med ex: acetylcholine, methacholine, carbachol, bethanechol
pharmacokinetics
is the study of drug movement into, within, and out of the body. Also, what the body does to the drug. Includes the processes of absorption, distribution, metabolism (also called biotransformation), and excretion.
alpha 2 agonists
located in presynaptic nerve endings of smooth muscles, the eyelet cells of the pancreas, salivary glands, skin and mucosa. When they act centrally, they cause decreased production of intracellular cyclic ANP, results in a decreased release of norepinephrine, less norepinephrine to the peripheral tissues, less peripheral resistance, less renal vascular resistance (slow the heart rate and lower blood pressure). Side effects include hypotension, drowsiness, dry mouth, confusion in elderly, bradycardia, constipation, urinary retention, ED, fluid retention, rash (caution with using with patients with cardiovascular disease, renal insufficiency, bradycardia). Methyldopa might cause hemolytic anemia. If you suddenly withdrawal these, you might get rebound hypertension, need to be tapered. med ex: clonidine, methyldopa, guanficine.
beta 2 receptor agonist
located in the lungs and bronchial smooth muscle. The action is bronchodilation. Other locations such as vascular smooth muscle - causes vasodilation. Also located in the arteries of skeletal muscle- causes vasodilation. Also located in the smooth muscle of the uterus and GI tract - cause smooth muscle relaxation and slows down peristalsis and inhibit uterine contractions. Also located in the pancreas- increase in insulin secretion. Side effects: tremors, tachycardia, palpitations, and anxiety. (ex: albuterol inhaler).
beta 1 receptors
main location in the heart. When receptors are activated, increased hr, increased contractility, AV nodal and SA nodal will be quicker and stroke volume improves, which increases cardiac output. When beta 1 receptors act at sites on the kidneys, they cause an increase in renin release which increases the blood pressure due to effects of angiotensin 2 and aldosterone. Examples: epinephrine, norepinephrine, dopamine. Used for cardiogenic shock. Side effects include tachycardia, palpitations, arrythmias, bp elevated, pt can feel anxious. med ex: dobutamine
3 mechanisms of metabolism
o Active drug → inactive metabolite (most common) o Inactive drug → active drug (prodrug such as Codeine, Acyclovir) o Active drug → active metabolite
factors affecting biotransformation
o Age o Genetics- acetylation (some individual metabolizes drugs faster) o Gender o Diet and environmental factors o Disease states
distribution: specialized barriers
o Blood brain barrier- drug penetration related to lipid solubility and ionization (highly lipid soluble and nonionized drugs are able to cross the barrier) o Placental membrane- drug penetration related to lipid solubility (only have to pass simple diffusion if lipid soluble)
Potentially inappropriate use (PIMS) in older adults: GU
o Desmopressin
Potentially inappropriate use (PIMS) in older adults: antithrombotic
o Dipyridamole
factors affecting distribution
o Lipid solubility o Drug pH (pKa) o Blood flow to tissues o Plasma protein binding o Specialized barriers o Disease state
Potentially inappropriate use (PIMS) in older adults: pain medications
o Meperidine o COX nonselective NSAIDS, oral o Indomethacin, ketorolac, includes parenteral o Skeletal muscle relaxants
Potentially inappropriate use (PIMS) in older adults: GI
o Metoclopramide o Mineral oil, given orally o PPIs
Potentially inappropriate use (PIMS) in older adults: cardiovascular
o Peripheral alpha 1 blockers for treatment of HTN o Central alpha agonists - Clonidine, guanabenz, guanfacine, methyldopa, reserpine o Disopyramide o Dronedarone o Digoxin for first-line treatment of atrial fibrillation or heart failure o Nifedipine, immediate release Amiodarone
CYP 450
o Primarily located in the endoplasmic reticulum of the liver cells. Also located in the intestine and kidney o enzyme induction means that some drugs can induce or stimulate the production of one or more iso forms of the enzymes to increase drug metabolism or decrease the amount of one of the drugs - would need to decrease the therapeutic effect of the drug some drugs will inhibit the production of CYP-450 enzymes and decrease drug metabolism, so there is an increase plasma concentration of concurrently used drugs, this is where the drug-to-drug interactions occur
key points for absorption
o route of administration- when a medication is given through intravenous route, no need for absorption because medication goes right into blood stream. Route will affect the speed and predictability of absorption, example if medication given subq or IM there is greater predictability of absorption versus given orally o first pass metabolism- before the drug reaches the systemic circulation, sometimes significant portions of the drug can be metabolized by the liver which causes the concentration of the drug in the systemic circulation to be decreased. This occurs through the portal vein then goes to the liver which will automatically take off a certain amount of the drug that is available or bioavailable to the body for distribution and metabolism. The sublingual, buccal, rectal route bypass first metabolism o Bioavailability- it's a measure of amount of administered dose of a drug that actually reaches the systemic circulation in the unchanged form