adv pharm quiz/exam 1 Flashcards
Pharmacokinetics
The study of the absorption (A), distribution (D), metabolism (M), and excretion (E) of drugs
the application of PK principles to the safe and effective therapeutic management of medications in a patient.
pharmacodynamics
study and relationship of the action of a drug in the body over time; relationship between the drug at site of action and resulting effect
half life
time required for serum concentration to decrease by 50% after absorption/distribution
clearance
volume of blood from which drug is removed over a given time
steady state
when drug concentration is considtent after each does- 5 half lives
Emax
maximum response of the system to drug
EC50
concentration of a drug that produces 1/2 maximum response; dose at which 50% of individuals exhibit specified effect
Potency
measure referring to different doses of 2 drugs needed to produce same effect
ADME- A
absorption
movement of drug into bloodstream
bioavailability
how much of the drug is absorbed
Routes for absorption
oral, rectal, IM, percutaneous, transdermal, intraosseous, peritoneal
factors affected absorption
gastric pH (higher in premies)
Gastric emptying time
bile acidand bilirubin excretion
pancreatic enzymes
First Pass metabolism
drug is first metabolized by the liver and therefore decreases the bioavailability of the drug in systemic circulation
only with oral admin (sublingual goes directly into the bs)
IM admin CDC recs- site of admin
0-12 months
vastuls lateralis
IM admin CDC rec- 13-24 months
vastus lateralis, deltoid
IM admin 3-adults
deltoid is preferred
vastus lat
How many mL can you give IM for adults, neonates and children
adults- 2mL
Neonates- 0.5
children- no more than 1
percutaneous absorption in children- physio differences
thinner stratum corneum
high water content in dermis
greater body surface area to body
by 5yo BSA normalizses; (transdermal patches);
pharmacokinetics percutaneous absorption
absorption increased in newborn
ADME- Distribution
1 compartment
2 compartment
movement of a drug from one compartment to another;
1- drug is immediately distrib through body
2- drug is first distributed to central compartment (heart, l lungs, kidney) and then to body (tissues)
factors affecting distribution
Concentration gradient Blood flow Lipophilicity/ hydrophilicity Molecular weight Protein binding only unbound drugs will be able to exert pharmacologic activity Permeability of capillary beds Blood brain barriers
distribution- protein binding
Protein bound drugs pharmacologically inert
Only unbound drugs exert pharmacologic effects
Displacement of protein bound drugs may alter pharmacologic and toxic effects of the drug
Examples of highly protein bound drugs:
Phenytoin (80% in neonates – 95% in adults; requires serum albumin dose adjustment)
Ceftriaxone (85 – 95%)
distribution differences in children - plasma protein binding
Decreased in young infants> increased free drug
Fetal albumin: decreased binding affinity with acidic drugs
Competitive binding
Competitive binding: bilirubin, free fatty acids and drugs competed for albumin binding sites
Highly protein bound drugs displace bilirubin from protein binding sites > kernicterus
BBB
blood brain barrier
Cerebral endothelial cells have tight junctions
Drugs with low lipid solubility unable to cross
Highly lipid soluble drugs cross easily
Inflammation can increase concentrations into the brain
Relative permeability of capillaries
liver, kidney, muscle, fetus (placenta), brain
distribution differences in pediatrics
body composition increasedTBW neonates- 78% premies- 85% fetus- 94%
ADME-M
metabolism
transformation of drug into active formulation to allow for pharmacologic effect
degradation of active chemical compound
not all drugs will undergo metabolism
Phase 1 Metabolism
mixed-function oxididase enzyme system
think CYP enzymes
Inc hydrophilicity of drugs to facilitate elimination of drugs by kidney
phase II Metabolism
conjuguation reactions
enzymes which catalzye the formation of conjugates with the oxidized drug or parent compound
–where you end up with the active component in addition to inactive components
metabolism alterations in children
hepatic clearance: inc during first 3 months of life, exceeds adult clearance by adolescence
drug interactions in metabolism
Substrate
Substance acted upon by an enzyme
Inducer
Stimulates synthesis of enzyme capacity
Inhibitor
Prevents enzyme from synthesizing drug
ADME-Excretion
The removal of active and inactive drugs
Renal excretion
Biliary excretion
Active or passive
Renal Excretion
Major route by which drugs exit the body
Rate of excretion dependent on:
Pharmacologic properties of the drug
Concentration of drug in the blood
Rate of urine production
estimating renal function
CrCl
Equations
CCG
Schwartz (Original, Modified, Revised)
Limitations
SCr is not a great marker (especially in kids)
Equations can vary and some can overestimate
Estimating Creatinine Clearance- equation
CrCl = K x L/SCr CrCl = Creatinine Clearance (mL/min/1.73m2)
K = constant of proportionality
Age & gender based
L = Length (height) in cm
SCr = serum creatinine (mg/dL)
Biliary Excretion
Drugs in the liver may be secreted along with bile into the duodenum
May also be reabsorbed
excretion alterations in children
Decreased GFR and tubular secretion at birth
Especially during first week of life
Reaches relative adult function at 6 months of age
inc risk of toxicity
ADE associated with PK changes in pediatrics
Increase risk of toxicity Impedes linear growth Acute dystonic reactions Respiratory depression Paradoxical hyperactivity Cognitive impairments Kernicterus
Therapeutic Drug Monitoring
TDM
Indications: any drug with a narrow therapeutic range
inadequate response of medication
suspected toxicities (ie serious or persistent ADE)
target concentrations
peak
trough
Peak – highest concentration that a certain medication reaches in the blood stream
Trough – lowest concentration that a certain medication reaches in the blood stream
pregnancy categories
A
Adequate and well-controlled studies have failed to demonstrate a risk to the fetus during pregnancy
pregnancy-B category
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in humans
pregnancy-C category
Animal studies have shown an adverse effect on the fetus and there are no adequate and well controlled studies in humans
pregnancy- D category
There is positive evidence of human fetal risk based on adverse reaction data
pregnancy-X category
Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data
preload
Ventricular filling pressure or left ventricular end-diastolic volume (LVEDV)
afterload
Left ventricular wall tension or stress during systole
Stroke Volume (SV)
volume of blood ejected during systole
– Dependent on preload, afterload, & contractility
Cardiac Output (CO)
volume of blood ejected
per unit of time
[CO = HR x SV]
Cardiorenal modeling
Na/H20 excess> think diuretics as 1st line
Cardiocirculatory
nadequate contractility think (+) inotropes
Neurohormonal
initial insult activates sympathetic system; but
progression is mediated by neurohormones > modulate hormonal
activation
principles of pharm therapy for systolic HF
– Block the compensatory neurohormonal
activation caused by decreased cardiac output
– Prevent/minimize Na and water retention
– Eliminate/minimize symptoms of HF
– Slow progression of cardiac dysfunction
– Decrease mortality (prolong survival)
– Increase quality of life
diuretics
mechanism of action
– Inhibits reabsorption of sodium and chloride in the renal tubules
• ↑ Na excretion>↑ volume excretion>↓ preload – Rapid improvement in edema
diuretic class: Na excretion
loop
thiazide
k-sparing
loop: 25-30%
Thiazide: 5-10%
k sparing- 2-5%
ADE of diuretics
electrolyte depletion ( dec in Na, K, Mg and Ca and Cl)
hypotension
dizziness
dehydration
Loop: Nephrotoxic sulfa allergy-caution hyperglycemic ototoxic
Sprironolactone-
hyperkalemia is ADE but also is often used for this effect
gynecomastia
Beta Blockers- clinical pearls
clinically stable patients on CE and diuretics
should be fluid stable before starting
symptomatic for first few weeks
start low and then titrate slow
MOA for Aldosterone Antag
blocks effects of aldosterone in kidneys, heart, vasculature
dec K and Mg loss–>dec in ventricular arrhythmias
-dec in Na retention–> dec in fluid retention
-dec in catecholamine potentiation–> dec in BP
-blocks direct fibrotic actions on myocardium
Aldosterone antag– ADE
inc in K
Gynecomastia or breast pain
sexual dysfunction
Why use Spiro in peds?
primarily for K sparing effect
only tablets are available so it requires compounding pharmacy to prepare suspension
-avoid in combination with both ACE-1 and ARB due to risk of inc. K
benefits of Digoxin
improved symptoms, improved exercise tolerance, dec hospitalizations, no effect on mortality
very minimal use in children
MOA Digoxin
inhibits Na-K ATPase
dec central sympathetic outflow by sensitizing cardiac baroreceptors
dec renal reabsorption of Na
Digoxin ADE
Dig tox
cardiac tox- ventricular arrhythmia, heart blocks, bradycardia
CNS toxicities
Confusion, vision changes
Risk factors for ADE-Dig
low K low Mg High Ca hypothyroidism interacting meds renal insufficiency
Contraindications for Digoxin
2nd or 3rd degree heart block
Cautions for Digoxin
Amiodarone, diuretics, Cholestryamine, spriro, verapamil
Monitoring Digoxin
BMP- SCr, K serum dig levels Ti- 0.8-1.2 HF symptoms Signs and symptoms of dig tox
Digoxin clinical pearls
NOT for acute exacerbations
loading dose not needed in HF
Low starting dose in patients with conduction abnormalities, dec renal fx, low lean body mass
dec dose by 50% for concomitant amiodarone therapy
Nitrates & Hydralazine
MOA
hydralazine- Vasodilator, enhances effect of nitrates
Nitrates- stimulates nitric acid signaling in endothelium, dec. preload
ADE Nitrates/Hydralazine
ADE: Headache, hypotension, dizziness
Hydra: leucopenia, thrombocytopenia, lupus-like syndrome
Nitrate- flu-like symptoms, flushing
what to monitor for nitrates and hydralazine
CBC: WBC/Platelets
Vitals-BP
ANA profile (lupus)
HF symtpoms
Calcium Channel Blockers- benefits
no mortality benefit
tx of htn in patients at target doses of ACE-1, BB and ARB
no observed decompensated HF with amlodipine/felodipine
Anti-Arrhythmics in HF:
the only two that are proven safe:
1) Amiodarone
2) Dofetilde
Aspirin uses
post Norwood/procedures requiring least amount of anticoag.
- IVIG resistent Kawasaki disease for anti-inflamm. and aneurysm clotting
- dose: 5-10mg/kg
- unstable in liquid- crush and dilute w water before admin
- reye’s syndrome- caution
Warfarin/ Coumadin
MOA- inhibits VKORC1, depleting functional Vitamin K reserves
limits amount of vit K dependent coagulation factors needed for clotting
Factors: II, VII, IX, X
Protein C & S- natural anticoag
Fontan- procedures, cardiac devices
Warfarin Dosing
0.2mg/kg starting dose
usually given at night for AM lab draws
may req bridge anticoag for first 304 days until therapeutic INR due to depletion of protein C and S
monitoring Warfarin
Nutrition (vit K)- crucial to eat same amount of vitamin K each week
INR Goal 2-3
reversal options for warfarin
vitamin K and FFP
Enoxaparin/ Lovenox
uses
Procine derived low molecular weight heparin, inhibits factor Xa preventing clots
Use: DVT proph.
Tx of thrombis (PE, catheter clot)
Dosing in children: 1-2mg/kg/dose q 12
only - SC inj
antidote for Lovenox
Protamine- minimally useful in reversing though
sinus arrhythmias
normal physiologic variant characterized by inc HR during inspiration and a dec HR in inspiration
-caused by changes in parasympathetic input to heart
Ventricular Premature Beats
(or Premature Ventricular Contractions)
Prem. depolarizations of the ventricles leading to early systolic contractions
usually folloewd by pause resulting in irregular HR and irreg patterns
occur in isolation and generally benign
may cause hemodynamic compromise
Atrial Premature Beats-APBs
early depol. of atrial myocardium leading to propogation of electrical impulses through atrium
results in early systolic ventricular contractions
usually benign and rarely assoc w sustained tachyarrhythmias
goal of therapy for Afib
normalize ventricular rate
Rate Control Drugs
Beta blockers
Non-DHP ca ch bl
Digoxin
Amiodarone
Rhythm Control Drugs
Amiodarone Sotalol Propafenone Procainamide Quinidine Flecainide Dofetilide
Inotrope:
hard vs soft
pos. inotrope forces heart to beat- Hard vs Soft
Chronotrope
ffast vs slow
alters the rate
Pos chrono- inc HR
Neg chrono- Dec HR
Dromotrophic
speed of electrical conduction from either nerve or cardiac muscle
Rate Control Drugs:
Beta Blockers
Non-DHP CCBS
Dig
Amiodarone
Beta Blockers MOA
block effect of sympathetic neurotrans. on heart and vasculature–>decrease ventr. arrythmias, dec impulse transmission, dec AV nodal conduction
Beta Blockers: nonselective
Propranolol
Cautions Beta Blockers
severe bronchospastic disease
(asthma)
symptomatic hypotension
2nd or 3rd degree HB
Non-Dihydropyridine CCBS Moa
dec. influx of Ca on vasculature smoothmuscle nad myocardium; slows conduction and automaticity thru AV node
Dec impulse transmission
ADE- CCBs
hypotension, dec HR, fluid retention, dizziness, flushing, constipation (verapamil)
caution- sick sinus syndrome
wolff-parkinson white synd
2ndor 3rd degree AV block
What is agent of choice for acute rate control?
N-D CCB
Digoxin MOA
direct inhib. of Na/K ATPase pump
Loading dose of Dig mcg/kg/day
maintain. dose
loading dose is based on age, formulation, indication
Maint. Dose- 2.5-10mcg/kg q24
therapeutic Monitoring for HF and Tox
HF: 0.5-.9
Tox: > 2
ADE dig
3rd degree block, cardiac change (PVC, V/Vfib)
rash, N/V, D, abd. pain, anorexia, visual disturbance
INC risk of tox: hypoK, hypoMg, hyPERCa, low body weight
very long T1/2
Digibind
immune antigen binding frag for dig; binds to dig and is elim thru kidneys 20-90 min resolution of symptoms
Dofetilide
Classification- Class III antiarrhythmic
blocks potassium channels to inc action potential due to delayed repolarization
CAUTIONS
ADE- hypotension, dec in HR, QTc prolongation, syncope, dizziness
Caution- QTc >440 msec
CrCl < 20
monitor Defotilide
Vitals-BP,HR
EKG-rhythm, QTC
BMP, ADE
prolonged QTc, req 50% dose reduction, potential for proarrythmic effects
Flecainide
Class 1C antiarrythmic
Blocks Sodium Channels
Dizziness, visual, dyspnea, vent. arrythmias, worsening HF
Caution- 1st or 2nd degree HB, renal disease
Contra- congestive heart failure, post-myocardial infarction
Sotalol
MOA Class II and III antiarrythmic
Beta Blocker- class II effects
B-adrenergic Blocking properties
Class III effects- blocks K+ channels at higher doses
Sotalol ADE
hypotension Dec HR AV block QTc prolongation (dose reduce > 450 QTc) bradycardia dizziness, headache, fatigue
caution- severe bronchial asthma, 2nd or 3rd AV block, HF, renal failure
propafenone
Class Ic antiarrhythmic, blocks Na challens to prolong refractor; exhib. B-Blockade activity
ADE- dec HR, QTC prolong, bronchospasm, HF, edema, arrythmias, impaired Taste, dizziness
cautions with Propafenone
severe bronchial asthma, CHF, liver diseases, ANA titers (elevated) - (?lupus?)
monitor vitals, EKG, LFTS, CBC, lupus, ADE
clinical pearls Propafenone
Titrate no more than every 4-5 day
reduce dose by 25-50% in aptients with liver disease, HB, QRS widening, immediate release recommended for acute control, sustained release recommended for chronic control
Amiodarone
fits in ALL Vaughan Williams Classifications; place in therapy- multiple arrhythmias, also helpful in retrograde electrical disorders, angina, HF
Amiodarone ADE
dec bp, dec HR, QTc prolong, AV block
N/V, dec appetite, constip.
phlebitis, optic neuropathy/neuritis
dizziness, peripheral neuropathy, coordination, hep, hypo/er thyroid, blue-gray skin discolorations, photosens, pulmonary fib
Amidoarone Caution
iodine allerg, 2nd or third deg HB, hepatic disease, drug interactions, QTc prolong
monitor- Vitals (BP/HR), EKG, pulmonary testing, thyroid testing, opthalmic testing, ade
*prefer IV route in sympt. patients, safe and effective in patients iwth AFIB and HF
FDA requires patients receive drug info patient education packet
QT Interval Prolongation
Duration from early ventricular
depolarization to latest repolarization
• QTc = corrected QT interval accounting for
heart rate
• Standard values
– Normal: < 430 (men) & < 450 (women)
– Borderline: > 450 (men); > 470 (women)
– Prolonged: > 450 (men) & > 470 (women)
• Risk factors for prolonged QT:
– Multiple prolonging agents OR high doses of
1x agent
– HypoK+, hypoCa+, HypoNa+
• So anything that can affect electrolyte balance can
potentiate the risk (ie diuretics)
– Female
– Congenital prolonged QT
QTc =
QTc = QT interval ////
sq route of RR interval (in sec)
TdP: Torsades de Pointes
Life threatening • Requires cardioversion • Crediblemeds.org – Class III anti-arrhythymic drugs – Ondansetron (Zofran®), Granisetron (Kytril®) – Methadone – Fluoroquinolones – Haloperidol
Cystic Fibrosis
life expectancy
life expectancy is now up to 40; used to be 10, 30s
Patho of CF
CFTR dysfunction alters ion permeability of cell membranes
inadequate secretin of fluid, which alters physical chemical properties of secretions
–>imbalance of ions and water in intracellular areas
CFTR gene protein- ATP-binding cassette protein; 2 ATP hydrolysis domains. fx: cAMP- dep and protein kinase C, Cl- channel
==> Loss of function results in epithelial dysfunction
GFTR gene mutations
Class I: defective protein production class II defecive protein processing Class III- defective channel regulation Class IV: defective channel conductance most common mutation is 3-base pare deletion-->loss o phyenylanine at position 508: 508 allele
clinical manifestations lower resp tract
dec FVC, forecd exp vol in 1 sec (FEV1)
bronchiectasis, chronic hypoxia, cough, chronic infection, GERD barrel chest, clubbing
ciliary dysfunction–>mucous, warm, moist environment- infection->decline
most common CF organisms
staphylococcus aureus (mrsa) pseudomonas aeruginosa haemophilus influenzae
other- proteus, klebsiella,etc
Fungal: Aspergillus furnigatus
Cycle of lung disease
CF gene mutation>CFTR dysfx>ion transport defect>altered airway secretions, infection, tissue damage, inflammation
Pancreatic insufficiency and CF
85-90% have pancreatic insuff and need supplemt
variable effects: due to defective Cl- HCO2 exchange; dec NA and HCO3 in panc duc, retention fo enzymes, malabsorption of fat, protein, nutrients
longterm- destruction of panc. tissue: firbrosis, fatty replacement, cyst form, need insulin over time, pancreatitis;
Intestinal tract and CF
10-16% of CF cases are dx with meconium ileus
obstruction–gerd, DIOS: Distal Intestinal obstruction syndrome, rectal prolapse, intussesception, appendiceal abscesses;
chronic constipation
Upper Resp tract and CF-
nasal polyps, sinusitis, URI
p aeruginosa, h influenzae, strept, anaerobes
Sweat glands and CF
Bones and joints, hematologic
high NA and CL concentration, loss of ability of reeabsorb sodium (Na concentrations > 100)
Bones- arthritis, osteopenia, vit D def.
Hematologic- anemia, dec erythropoitin
CF and liver
STFR located on apical surfaces of cells lining the bile ducts; results in bile duct obstruction, ult leads to biliary cirrhosis, dx w inc liver enzymes
long term- cholelithiasis, cirrohosis, cholestatis, hypersplenism
Inhaled Agents, CF
mucolytics- Recominant human DNAse, dornase alfa
airway obstruction- B2- Agonist
airway clearance hypertonic saline (irritating cough)
inhaled antibiotics - Tobramycin, aztreonam, colistimethate
Mechanical devices
PEP- Pos exp pressure
High Freq Chest wall oscillation- chest vest
PT (draining, percussion, vibration, coughing)
endocrine tx- pancreatic enzymes
Panc Enzymes Lipase, Protease, amylase
dosing: based on lipase content (max 2500 units/kg/meal)
take with meals and snacks
capsules opened and mixed w food/liq
avail: pancreaze, creon, zenpep
Insulin: CFRD Do not crush or chew DAW dont allow prolonged exposure to alkaline foods like pudding give w meals
anti-inflamm. tx for CF
oral: FE1 > 60%, patients 6+ to slow los of lung fx decline
Oral ibuprofen- dose; 15-30 mg/kg q 12 ADE: abd pain, epitax
Other are not usuallly rec; oral corticosteroids - inhaled corticosteroids
inc side effects
Antibiotics for CF
IV: tx based on suspected org and sensitivities from sputum culture; also consider antifungals
ORAL- Macrolide antibiotics (pesudomonas)
Recommended fo anti inflam and antibiotic propertieis; studies have shown significant improvement in FEV1
Azithromycin- 500 mg TIW
Bactrim
Minocycline
GI Tx for CF
DIOS- distral intestinal obst. syndroem
Polyethylene glycol 3350
Gastrograffin enemas
liver- Ursodiol reduces cholesterol, possibly reduced cytotocicity of bile and improves LFTs
lung transplant- immunosupressants
Nasal congestion- saline irrigation; saline spray OTC products
nasal corticosteroids, surgery
Vitamin Supp Tx
Fat Sol- Vit ADEK
other: Ca, Fe, Zinc, Beta carotene
CFTR gene potentiators
only effective in certain mutations- Kalydeco, Orkambi
other Tx CF
Lung transplant, nasal congestion (saline irrig, nasal cortico, surgery)
CF Exacerbation background precip. factors & TX
infection
S aureus, p aeurigoa, B capecia, h influenzia, h influenzae
TX: Maintenance therapy, continue pulm tx, pancreatic enzymes, PT; inc time and freq to 2-4x daily
*CF exac. are important marker for disease severity; they inc w age,
clinical features- dec FEV1, cough, hemopytsis, inc sputum, SOB, feber, ano, wt loss
TX Exacerbation Tx- antib
pulm infections
IV for admission
S aureus, vanco, base tx on suscpeptibility
P aeruginosa, duration of therapy 14-21 days
pseudomonas always 2 drugs
Lyophilized Aztreonam- dosing 75mg q6hx28days
req unique nebulizer system; most common ADE- cough, congestion, wheezing, pyrexia, pharyngeal pain
lung tx: inhaled Tobramycin- approved in CF pts w p aeriguniosa- 300mg q 12hr
needs specific neb ulizer and air compressor
ADE- tinnitus bronchospasm
