Exam 2 - ENT, pulm, cardio Flashcards
What are the main bacteria that cause AOM?
S pneum, H inf, M cat
What is the mainstay of AOM?
High dose Amoxicillin; need higher doses because its hard to reach adequate concentrations to overcome strep pneumo.
If someone has a severe AOM and was given Amoxicillin, but failed therapy or its gotten worse, what do you do?
Step up to amoxicillin-clavulanate; helps expand coverage.
Also good for recurrent AOM.
If amoxicillin is intolerable for whatever reason, what else could you prescribe for AOM?
3rd gen CS = Cefdinir
OR Arithromycin
If kids can’t keep oral meds down for AOM, what do you prescribe?
Ceftriaxone; patient can come into the office for 3 IM doses.
What bacteria causes acute rhinosinusitis?
S aureus, gram negs, and those that cause AOM
How do you determine if acute bacterial rhinosinusitis is bacterial or viral?
Must have symptoms for over ten days.
If its bacterial, symptoms will worsen around 5-6 days.
What treats Acute Bacterial Rhinusitis?
Augmentin (Augmentin for those nose)
Why? Its important to increase your coverage. (B-lactamase influenza, etc).
If a patient has a PCN allergy and Acute Bacterial Rhinusitis; how do you treat it?
Clindamycin has good gram positive coverage, also levofloxacin
What is important when treating acute pharyngitis?
Worried about secondary infection – acute rheumatic fever, endocarditis, heart failure
How do we prevent overprescribing abx for acute pharyngitis?
Rapid strep test
If pos result; do a culture to see if you have to change coverage.
How is acute pharyngitis normally treated?
Amoxicillin
What med can you use to treat acute pharyngitis in children who are nauseous and vomitting?
Benzathine; given IM because its a suspension. One time dose.
What if the kids can’t tolerate PCN? (acute pharyngitis).
Cephalexin
Clindamycin
Azithromycin
What do otic antibiotics have in them?
Anti-infectives: inhibit bacterial growth
Glucocorticoids: decrease production of inflammatory cytokines.
Why don’t otic antibiotics get resistance as easily?
High concentrations are used to eradicate locally.
What are available otic agents?
phoncc
cipro cipro/dex neomycin polymixin b hydrocoritsone ofloxacin
What are main uses of otic antibiotics?
OM and OE
Risks of Neomycin?
Change for hypersensitivity
Contact dermatitis
If a patient has tubes or ruptured TM, what med can’t you use? Why?
Polymixin B (ototoxicity) Leads to cochlear damage and hearing loss
Why is it bad to prescribe cipro/dex?
Its expensive
Alternative: ofloxacin otic and dex opthalmic
EYE can go in EAR.
MOA Ketoconazole
Inhibit fungal cell wall permeability by inhibiting CYP450 from propagating cell wall
Happens in other AZOLES
ADR Ketoconazole
QT prolongation
Inhibit CYP450 in fungus and people! It’s not very selective; if used systemically, can have CYP3A4 interactions.
- statins
- hyperlipidemia meds
CHECK DRUG INTERACTIONS BEFORE PRESCRIBING.
What is a benefit of using nystatin?
Its a nonabsorbable antifungal, no systemic toxicity
When is nystatin used?
Used topically as powder for oral thrush.
Good for I/C pts
Prevent fungus growth
Treat infection
MOA Nystatin?
Binds to sterols in fungal membrane to increase cell wall permeability; opens up for contents to spill out.
What virus is responsible for infection in I/C patients, AIDs, and cancer pts?
CMV - Leads to esophagitis, retinitis, colitis.
What are the antiviral prodrugs?
Famicyclovir
Valacyclovir
Valgancyclovir
What are prodrugs?
Not active in current form, but when metabolized by liver are confirmed to “active compound”
Why are prodrugs prescribed?
A larger portion of drug goes through first pass; increase the bioavailability!
How do antivirals work?
Inhibit viral DNA replication; guanine analogs are incorporated, but they’re missing the sugar backbone so elongation can’t occur.
Triggers cell death.
What are uses for acyclovir and valacyclovir?
Herpes simplex, Shingles, Herpes stomatitis
Which drug has more bioavilability - acyclovir and valacyclovir?
Valacyclovir, because its a prodrug. Has better efficacy.
ADR of cyclovir meds?
Nephrotoxicity - worry about drug crystallizing in renal tubule causing interstitial nephritis.
Bone marrow suppression.
CNS affects - might increase risk of seizures or altered mental status in the elderly.
What do you tell a patient on an antiviral?
Drink a lot of water to prevent crystallization in the kidneys.
What’re uses of pencyclovir and famcyclovir?
Herpes and Shingles
Toxicity is worse so they’re used less frequently than others; used mostly to step up therapy for resistant strains.
Which one is a prodrug - pencyclovir and famcyclovir?
Famicyclovir
Ganciclovir and Valgancyclovir uses? ADR?
CMV for transplant patients and cancer patients.
Can cause thrombocytopenis and CNS toxicity. Patients stop therapy due to side effects.
Monitor CBC
Which one is a prodrug - Ganciclovir and Valgancyclovir?
Valgancyclovir
What’s Foscarnet used for?
Is it a prodrug?
How is it administered and excreted?
Resistant viral strains; there is no pro drug for it.
» CMV retinitis, acyclovir resistant HSV, shingles, ganciclovir resistant CMV
Administered IV only and renally eliminated. Needs dose adjustment.
MOA Foscarnet?
Inhibits DNA polymerase, directly.
ADR Foscarnet?
Chelates cations - can lead to hypocalcemia, hypomagnesaemia, and hypokalemia
What is acetylsalycilic acid?
Aspirin (ASA)
What is aspirin used for?
Has anti-clotting effects and analgesic at higher levels.
Old drug, good absoprtion, hepatically conjugated, and excreted in kidneys.
MOA Aspirin?
Irreversible inhibitor of COX 1, 2, 3 - no selectivity. Used to protect the heart against MI.
Why wouldn’t you use Aspirin?
Inhibits PLT, causes bruising and bleeding.
Do not use in bleeding disorder or pregnancy.
Why is aspirin bad for kids under the age of 16?
In children with fever (esp. viral), there is an increased risk of Reye’s syndrome!
What is Reye’s Syndrome?
Fatty liver encephalopathy that affects children.
Symptoms are similar to viral illness - fever, vomitting, lethargy etc., but can cause CNS damage – can go unnoticed for a long period of time.
Stages of Reye’s syndrome?
1 - rash on hands and feet, vomiting, high fever, lethargy
2 - encephalitis, hyperventilation, fatty liver
3 - coma, cerebral edema
4 - deeper coma
5 - siezures, organ failure, death
What else causes Reye’s syndrome?
Peptobismol (Bismuth salicylate) - Has salicylate and can cause Reye’s Syndrome.
Motrin (ibuprofen)
Inhibits COX 1 and 2, nonselective
Reversible inhibitor! - not as high risk as ASA.
What is motrin used for?
Pain relief
If you have a sprain or inflammation, better drug to use bc it works on the inducable COX.
What is the risk of using motrin?
RISK - COX1 helps prevent erosion with stomach acids, so use can lead to ulcers (since this is the target); can have acute kidney injury, can worsen hypertension
Motrin interactions with other meds?
Decreases antihypertensives (ACEI)
Leads to accumulation of Lithium
Decrease secretion of methotrexate, which can lead to bone marrow suppression.
Don’t give Motrin tooooo…. ???
ASTHMATICS
Patients may have allergy to it that induces their asthma.
MOA Tylenol (acetaminophen)? Indications for Tylenol?
Inhibits COX3, which is located in CNS. Good for fevers!
Not good for a sprain, because it doesn’t target the periphery.
Tylenol puts you at risk for?
Liver toxicity; don’t exceed 4000mg a day!
Good for pain in pregnancy.
Why is histamine important?
Mediates immune reactions.
“Triple Response” -
- redness - vasodilation
- wheal - edema
- flare - redness
Where are H1 receptor antagonists located?
Located on the heart and bronchial smooth muscle.
When activated, will see vasodilation.
H1 receptor FXC?
H1 receptors increase post capillary permeability and vasodilation.
This leads to increased mucus secretion, bronchus constriction, and smooth muscle tone.
H2 receptors FXC?
Stimulate gastric acid secretion.
Used in long-term complications of allergies, i.e. anaphylaxis.
H3 receptors FXC?
Promote sleep and wakefulness.
H1 receptor antagonist - what do you see from their actions?
Block smooth muscle and GI tract vasodilation, lowers edema (less itching).
What is doxylamine?
OTC Sleep Aid
H1 receptor antagonist
H1 receptors antagonists are commonly abused because?
euphoria, hallucinations at high doses
Second generation of H1 anatagonists - benefit?
Why?
Don’t cause sedation
Can’t cross blood-brain barrier
What is used to treat motion sickness, nausea, and vomitting?
Phenergan
Why are H1 receptor antagonists used?
allergic reactions, motion sickness, nausea, OTC sleep remedies.
ADR of H1 receptor antagonists?
Sedation, GI disturbance
Antimuscarinic, so dry mouth and blurred vision
blind as a bat dry as a bone red as a beat mad as a hatter hot as a match
ADR H1
What’s the difference between H1 first generation agents and second generation agents?
Second generation - Not antimuscarinic or antiemetic bc can’t get into CNS
What is azelastine?
Intranasal spray; H1 receptor antagonist.
Used for allergic and vasomotor rhinitis.
ADR Azelastine?
Nose bleeds, bitter taste
No systemic side effects or activity. i.e. Doesn’t help itching and rashes.
Beclomethasone Budesonide Fluticasone Mometasone Triamcinolone
Nasal Corticosteroids
ONES AND IDES
Benefit of nasal corticosteroids?
Can be used over longer period of time, chronically, to decrease nasal allergic reactions.
Do not use for acute allergies.
Why shouldn’t nasal corticosteroids be used for acute allergies?
Decrease transcription from site of nucleus (gene transcription and protein production).
Meds need to be taken consistently. Takes a week or so before effects are seen.
Why is it good to use brand names for corticosteroids?
Don’t want the pharmacist to fill inhaler version (for asthmatics only).
ADR Nasal Corticosteroids?
Epistaxis Septum perf (rare)
Dexamethosone (Decadron)
What is it used for?
Synthetic adrenocortical steroid
Used for drug hypersensitivity, severe rhinitis, asthma exacerbations.
Why are corticosteroids bad when given systemically?
They have glucocorticoid actions and mineralcorticoid actions
GC is anti-inflammatory, while mineralcorticoid does fluid retention, salt retention, etc. to maintain good volume for cardiac status.
MC effects cause worsening of CHF, HTN, fluid retention and weight gain. Can see glucose intolerance, because it can decrease insulin release. Bad for diabetics Can also see cataracts and increased IOP.
Short course use only!
Immunosupressive!
Dexamethosone and other systemic CS are bad, so why do we use them?
They’re very potent anti-inflammatories. Good for asthma exacerbations, anaphylaxis, etc.
Dexamethosone Drug Interactions
Decreased antidiabetic medications. Diabetics don’t mess with dex.
Electrolyte shift to hypokalemia = potassium deficiency.
When is dexamethosone not used?
Fungal infections, because it’ll further depress immune system.
MAJOR RED FLAG OF DEXAMETHOSONE
Adrenal gland insufficiency
Exogenous corticosteroids causes the adrenal glands to secrete less. If on for over a week and stopped, the adrenal glands would be insufficient.
Need to taper over a weeks time to prevent insufficiency.
Prednisone/Prednisolone (active liquid)
key points
ADR: Same as Dex.
Don’t use for fungal infections.
Taper off of it or you’ll have rebound symptoms.
Afrin MOA
Used intranasally
MOA constricts alpha receptor in nose to decrease edema and leaky capillaries.
What is afrin used for?
Local decongestant! Treats nasal congestion, but causes rebound hyperemia.
Receptors are down regulated; none to be activated to reconstrict when off medication.
Whats the name for rebound hyperemia?
Rhinitis medicamentosa
Risks of Afrin?
Worsen HTN
Pseudoephedrine MOA
Systemic decongestant; alpha agonist that constricts blood vessels in mucosa to decrease stuffiness.
Sudafed can make erections go down, because it constricts blood vessels.
Pseudoephedrine warnings
Can have some rebound congestion, but not like that in Afrin
Guaifenesin (Mucinex)
Mucolytic - loosens mucus secretions in airway and decreases viscosity of them.
Needs to be taken with water to decrease viscosity. Increase in drainage.
Pregnancy Category A
Shown in studies to have no fetal harm or harm in animals; totally safe.
Ex: folic acid, water-soluble vitamins.
Pregnancy Category B
Animal studies may show some harm, but shows no harm to human fetus in any trimester.
Ex: Amoxicillin
Pregnancy Category C
“Shrugging your shoulders” - not enough data to determine effect on humans. Majority of drugs!
Ex: Albuterol
Pregnancy Category D
Evidence of risk to the fetus, but benefits of treating mom outweight the protection of fetus. Need to do risk-benefit analysis.
Ex: Lithium
Pregnancy Category X
Definite harm and there’s no case where its beneficial to give it to the mother.
Ex: Teratogens
START OF PULMONOLOGY CARDS
START OF PULMONOLOGY CARDS
How can you stop cough?
Can target brain stem or the stretch receptors of the throat.
Need to reduce number and severity of coughing episodes and prevent complications
What meds can make you cough frequently?
Ace inhibitors
Tessalon pearls MOA?
Uses?
Patient Education ?
Hardest drug to dispense!
Anesthetize stretch receptor in the lungs to prevent cough.
Do NOT chew! Can numb mouth. Maybe not good for kids, might chew and can cause CNS depression.
Dextromethorphan (Robitussin, Delsym) - MOA? Use?
Related to codeine; helps to supress cough center in the brain.
RED FLAGS for Dextromethorpan (Robitussin) use?
Proserotinergic effects - If you’re taking other drugs that block reuptake of serotonin or decrease metabolism you may see tachycardia, altered mental status, hyperthermia.
Too much serotonin in the synapse.
What are viral causes of acute bronchitis?
rhinovirus, coronavirus, influenza, adenovirus
What do you want to avoid in treating bronchitis?
AVOID ANTIHISTAMINES because it’ll dehydrate the bronchial secretions and worsen symptoms.
How do you treat a viral bronchitis?
Usually self-limited, give NSAIDs.
If you suspect a bacterial bronchitis, how do you normally treat?
Bacterial - Those sick 3-5 days with a worsening of symptoms are bacterial: want to focus on atypicals.
Use doxycycline or azithromycin
If you suspect mycoplasma is resistant to macrolides in bronchitis, what medication would be most apropriate?
Doxycycline (teeth stain under 8yo) - treats mycoplasma resistant to macrolides!!
When is it okay to use a resp FQ to treat bronchitis?
Don’t want to use unless you had recent abx exposure; helps to cover for resistant strep pneumo (since they are more at risk for it).
- levofloxacin
- ciprofloxacin
- moxifloxacin
How do you manage CAP patient?
Curb 65
PSI
Guide if patient goes inpatient, outpatient, ICU
What factors increase risk of PCN-resistant Staph pneum?
Over 65yo, had a beta lactam within last three months, alcoholism, immunosupressed, and medical comorbidities.
What factors increase risk of enteric gram negatives?
nursing homes, cardiopulmonary disease, medical comorbidities, recent abx therapy.
What factors increase risk of pseudomonas aeruginosa?
lung disease, corticosteroid use, broad spectrum abx therapy, malnutrition
What is treatment for CAP outpatient when there’s no risk for strep pneum?
1st line is a macrolide like Azithromycin or Clarithromycin
Macrolides inhibit CYP3A4.
What is treatment for CAP outpatient when there is a risk for strep pneum?
Treat with Beta Lactam AND Macrolide
- augmentin, cefuroxim
- -azithromycin or clarithromycin
If can’t have beta-lactam, use resp FQ.
How do you treat CAP in non-ICU inpatient?
IV beta-lactam, ORAL macrolide
Cefotaxime, ampicillin, and macrolide
How do you treat CAP in ICU?
IV treatment only and MRSA coverage (Vanco).
CAP MRSA Pneumonia
Cavity infiltrates and GPC clusters.
Needs vancomycin (or linezolid, if CI to vanco).
Nosocomial Pneumonia
Occurs from nursing homes, hospitals, or other healthcare settings. Infection not present at time of admission.
HCAP is more likely to occur when?
Hospitalized in acute care facility for more than two days in past 90 days.
Nursing home IV antibiotics recently Chemotherapy wound care dialysis patients
What are un-modifiable risk factors of nosocomial pneumonia?
age, lung disease, depressed consciousness, large volume aspiration, hospitalization during winter months
What are modifiable risks of nosocomial pneumonia?
mechanical ventilation, placement of NG tube, or ICP monitor.
Preventing these lowers your risk for resistant bugs!
What bugs are in nosocomial pneumonia?
SPACE bugs
Psuedomonas E coli Klebsiella Acinetobacter Enterobacter
MRSA
strep pneum
If you put a patient with nosocomial infection on apropriate empiric coverage and they aren’t getting better, what do you consider?
Fungal infection
When you suspect nosocomial pneumonia, what do you do?
What should you cover for?
Start therapy as soon as possible; don’t wait for definitive culture!
Initiate broad spectrum abx
- Consider MDR, esp if at risk
- Must cover MRSA and pseudomomas
When cultures come back, you can streamline therapy to target the bug.
A patient was on previous abx 3 months ago. He is now in the hospital for two weeks, undergoing chemotherapy for cancer – what types of drugs does he need to be on for recently contracted nosocomial pneumonia?
He has multiple risk factors for MDR pathogens. – Need to go with 3 drug coverage. 2 for gram negative psuedomonas so on its hit, plus aminoglycoside, and MRSA coverage.
Cefepime - antipseud CS
Imipenem/Meri - antipseud carbapenem
PLUS
Gentamycin - aminoglycoside
or antipseud FQ - levofloxacin.
PLUS vanco (or linezolid).
If your patient has low risk factors for MDR pathogens, what do you prescribe for nosocomial pneumonia?
3rd gen CS = Ceftriaxone
OR levofloxacin
OR ampicillin/sublactam
OR ertapenem
What are antipseud CS?
Ceftazidime and Cefepime!
What are 2 antipseud carbapenems work? Any red flags?
Imipenem - use with caution for patients with seizure history
Meropenem
What are antipseud PCNs?
Piperacillin/tazobactam
Ticarcillin/clavulanate
What are antipseud FQs? Why?
ciprofloxacin
levofloxacin
Have good penetration to the lungs!
What is ADR of FQ?
QT prolongation
Tendon rupture in young patients
- ciprofloxacin
- levofloxacin
Aminoglycosides
- Gentamycin
- Tobramycin
- Amikacin
Nosocomial Uses?
What needs to be monitored?
Once daily dosing, because they’re conc-dependent killer. Also, need higher doses because they have poor lung penetration.
Need TDM; nephrotoxicity and ototoxicity
Vancomycin is used in nosocomial pneumonia for MRSA coverage.
Why do yo uneed higher trough levels for lungs, brain, and bones?
Lungs, brain, and bones are hard to penetrate, so they require higher trough levels.
When is trough drawn?
3-4th dose to make sure you’re at a steady state
What is monitored on vanco?
ototoxicity and nephrotoxicity
What is linezolid used for?
MRSA, VRE
Can penetrate lungs
Used when vanco isn’t tolerated.
NO DOSE ADJUSTMENT FOR RENAL FUNCTION.
What drug isn’t good for pneumonias, bc its inactivated by surfactant?
Daptomycin
Reasons for nosocomial pneumonia failure of tx?
Could be a resistant pathogen and wrong therapy. May have been misdiagnosed. Complications, such as empyema or lung abscess.
How long is nosocomial treatment normally for?
7-8 days, but 10-14 for more resistant bugs
Anaphylaxis Symptoms
Laryngeal and lower airway edema, stridor, wheezing, rhinitis, GI symptoms
What is the first thing you do in anaphylaxis?
Worried about “leaky cappillaries” and intravascular depletion of fluid causing edema.
Start with epinephrine and volume expansion!
What are crystalloids used for?
Crystalloids are salt-based, ex: lactate ringers, NaCl.
Good for intravascular volume replacement in anaphylaxis.
What are choloids used for?
Albumen and starch.
Why is 0.9% NaCl used?
Its a crystalloid isotonic solution - osmolarity is 308, which is isotonic to blood osmolarity (300).
It will stay in intravascular space!
If you’re giving a fluid bolus, what dose is it?
20ml/kg! (20kg patient gets 400ml bolus).
Top off at 1-2 L and reassess. volume status.
What do you do for a fluid bolus with a renal patient?
Might need to give less than regular fluid bolus; also applies to peds patient.
What is the rule when doing maintenance fluids after a fluid bolus?
4:2:1 rule
4ml/kg for first 10kg
2ml/kg for second 10kg
1ml/kg for every kg after 20.
How much fluid should a 60kg patient get for fluid maintenance after bolus?
100ml per hour.
What is the first drug given for anaphylaxis?
Epinephrine
Epinephrine MOA
MOA: activates alpha and beta receptors
Alpha - increases vasoconstriction to prevent the leak
Beta - helps cause smooth muscle relaxation to release airway contraction and improve oxygenation.
Know to relieve pruritus, urticaria, and angioedema.
What do you do if they’re allergic to epinephrine?
Use preservative free product, because of allergy.
If not possible, you treat allergy during tx.
How is epi given?
IM or subQ
Can be given IV for SEVERE reactions, when patient isn’t perfusing.
If a patient is coding, how do you give epi?
IV
They’re not perfusing so it won’t be circulated if IM or subQ. without blood flow to these areas, it wont work well.
1:1000 epi dose
1mg in 1mL
1:10,000 epi dose
1mg in 10mL
If you give too much epinephrine, what happens?
intercranial hemorrhage
MI, pulmonary edema, etc.
What is slammed into a patient when they’re coding?
1 in 10 via IV.
What is adminsitered after epi in anaphylaxis?
Histamine blockers! B/c there’s a huge amount of histamine being released in reaction and these help alleviate itching, etc.
What are H1 blockers?
diphenhydramine and hydroxyzine
Most commonly used!
What are H2 blockers?
Rantidine
Mainly GI drugs; optional add on drugs.
H2 blockers prevent gastric acid in GI tract. They end up increasing pH of stomach so more things can grow and ulcers can occur.
After epi, fluid, histamine – what is administered?
bronchodilators, such as albuterol, which relax bronchial smooth muscle.
What happens in albuterol overdose?
anxiousness, tremors, tachycardia
H1 antagonists - first generation
benadryl
dephenhydramine
H1 antagonists - second generation
zyrtec
allegra
claritin
What are some Inhaled Corticosteroids?
Beclomethasone Budesonide Fluticasone Mometasone Triamcinolone
What’s the benefit of using inhaled corticosteroids rather than systemic ones?
There are less systemic side effects; they work locally in the lungs.
MOA Inhaled Corticosteroids
Inhibiting the anti-inflammatory cascade by working at site of nucleus to decrease transcription of genes that makes inflammatory cytokines.
How long do ICS take before they have an effect?
Inhaled corticosteroids take longer to work. Tell patient to take drug consistently, as prescribed, every single day.
Takes 8 weeks for maximal effects.
What are adverse reactions to ICS? What do you tell patients?
Well tolerated compared to systemic CS.
May develop oral candidasis, because the drug goes to the back of the throat and causes immunosuppression there. Must swish out mouth with water and spit afterward.
Exceedingly high doses may suppress normal growth.
Why do we see combination drugs with ICS?
LABA like formoteral and salmeterol can be combined with ICS.
LABA will provide some control throughout the day while the ICS start to kick in.
What are examples of combination drugs for Asthma with ICS?
Symbicort (Formoterol/budesonide)
Dulera (Formoterol/momentasone)
Advair (Salmeterol/fluticasone)
Frequently, if patients are having mild, persistent symptoms, what can you get away with?
Using ICS by itself. Combination products can be very expensive for patients.
If its severe, do combination initially.
Why are Leukotriene Modifiers used?
Leukotrienes are responsible for the bronchial constriction .
If we get something to block at receptor site, it prevents them from bronchoconstriction in the first place and stops asthmatic symptoms.
What are the Leukotriene modifiers?
Zafirlukast (Accolate)
Montelukast (Singulair)
Montelukast (Singulair)
Primary leukotriene modifier used clinically
Zafirlukast (Accolate)
CYP2C9 and CYP3A4 inhibition, which is hard to use clinically without causing drug interactions.
MOA of leukotriene modifiers
What can it treat?
Block LTD4 receptors to prevent mucus secretion, edema, and inflammation.
Considered a controller medication for asthma. Also works for aspirin induced asthma (non-atopic asthma).
Zileuton MOA?
Directly inhibits lipoxygenase to prevent leukotrienes from being formed in the first place.
Zileuton ADR?
Rarely used, inhibits CYP1A2 and CYP3A4.
Can cause flu, drowsiness, hepatic elevation
COX is inhibited by?
NSAIDs
Lipoxygenase forms leukotrienes.
What blocks receptors?
Montelukast
Lipoxygenase forms leukotrienes.
What will specifically inhibit lipoxygenase from being made?
Zileuton
Works at source - Prevents leukotrienes from being made by inhibiting LOX.
Aspirin-induced asthma
Asthma attacks induced by NSAIDs and aspirin.
Occurs when you block COX from making prostaglandins, it shifts over to the other side forming leukotrienes. Pathway is ramped up and can induce an asthma attack.
If you have a patient with aspirin induced asthma, what do you prescribe?
You can put them on leukotriene receptor antagonists to prevent symptoms from occurring in the first place. - Montelukast
Pt who you wanted on aspirin, you can put on Montelukast as well to help aspirin induced asthma from occurring.
If you have a patient with aspirin-induced asthma, but needed them to take it for cardiac protection, what do you put them on to prevent the asthma attacks from production of leukotrienes?
Put them on montelukast, which will “shunt” the path over to COX production, rather than LOX.
Issues with Zileutin and Zaphrolukast?
Liver Function Decline!
Anorexia, abdominal pain, nausea, jaundice, pruritis
What are side effects of leukotriene modifiers?
Non specific headache or heartburn, but very well tolerated.
Montelukast is mainly used as an?
Adjuvant therapy if asthma symptoms aren’t controlled by corticosteroids.
How do you prevent asthma exacerbations in first place?
Remove trigger and stabilize the mast cells with MCS.
Why are MCS limited use?
They’re for prevention and only block one step of pathway.
They aren’t that effective, which is why they aren’t used as often.
Cromolyn and Nedocromil
Mast cell stabilizers; an inhalation product.
It has to be taken before the insult occurs to be effective against asthma.
MOA not known, but prevent Ca from activating mast cells.
Patient education for MCS?
The drug takes 4 weeks before you see total efficacy.
Tell patient it will take time so they won’t discontinue drug.
Side effects to Cromolyn and Nedocromil?
Bad taste in mouth; well tolerated.
Sore throat, stuffy nose, headache, cough… nothing important
When is Omalizumab (Xolair) used?
Gets used regularly for patients who have significant allergies that are difficult to control and are on other medications.
Used for kids with bad asthma at Nemours.
Suffix -mab
Monoclonal antibody - Used for AI conditions, rheumatology, Crohn’s, and colitis.
Ex: Omalizumab for asthma.
Benefits to use of a monoclonal antibody?
Targets a specific receptor, so these meds won’t have as many side effects since they have one particular target.
Less tissue damage, etc.
Risks when using a Mab?
It is a protein, so any time you inject it into the blood stream, you’re at risk for an immune reaction like anaphylaxis. Monitor patient during infusion.
Also expensive to produce; used when other treatments are failed.
Omalizumab administration
Subcutaneous injection.
Given every two to four weeks at the clinic.
Omalizumab MOA
Specifically targets against IgE.
Requirements of Omalizumab treatment
Requires a
Prior Authorixation, because insurance companies won’t cover unless you have evidence of documented treatment failures.
During administration, you have to monitor the patient for anaphylaxis until you know how they tolerate the treatment.
What’re risks for Omalizumab?
Secondary malignancy like leukemia may pop up, but is exceedingly rare.
Anti IgE Antibody Side Effects
Omalizumab
Urticaria
Anaphylaxis
Injection site pain
Bruising
They’re rare, but concerned about anaphylaxis.
Methylxanthines group
MOA and use?
Theophylline and Aminophyline
Nonspecific phosphodiesterase inhibitor.
Not used frequently, bc they’re less effective and less well tolerated. Controller meds LABA and ICS are better.
What is Aminophyline?
IV form of Theophylline
Whats a common methylxanthine abused by PA students?
Caffeine; same class as Theophyline
What can be given to neonates to stimulate respiratory drive?
Caffeine
Theophyline MOA?
Nonspecific phosphodiesterase inhibitor – Phosphodiesterase is an enzyme responsible for metabolizing cyclic GMP (secondary messenger), which is responsible for relaxation of smooth muscle.
In asthma attack, bronchial smooth muscle constricts. So giving this drug will relax that muscle.
By inhibiting phosphodiesterase, you see higher cyclic GMP. Which means?
More smooth muscle relaxation.
Viagra MOA?
Phosphodiesterase inhibitor.
If a child has pulmonary hypertension, what can you prescribe?
Viagra. Used bc same enzyme is seen in lungs.
Why are Theophyline and other methylxanthines less frequently used?
Narrow therapeutic index - therapeutic and toxic blood levels are close together.
Need to draw troughs!
ADR Theophyline
Arrhythmia, convulsions, nausea and GI issues.
Its an older drug - will see in old women who physician never changed the drug.
If there’s a child in the PICU with status asthmaticus (prolonged asthma attack) that isn’t responding to anything - What can you use to bronchodilate?
IV Theophyline formulation to have extra bronchodilation.
When is Theophyline commonly used?
COPD patients
What are mechanisms of Theophyline? There’s 3.
Inhibit phosphodiesterase to have higher cGMP/cAMP to help bronchodilate.
Adenosine receptor antagonist
Anti-inflammatory reactions
If you have a patient with supraventricular tachcardia, HR is 180, and ventricles trying to keep up. What can you give?
Adenosine - Give to stop heart and reset the rhythm.
If you block affects of adenosine, you have the tachy arrythmias.
Theophyline can cause this, bc it blocks adenosine.
If you block adenosine in CNS, what happens?
Seizures occur
Theophyline can cause this, bc it blocks adenosine.
ADR Theophyline
GI issues, smooth muscle relax in bronchioles, but also vascular smooth muscle = results in hypotension.
Whats important about Theophyline dosing??
Renally eliminated drug; needs to be adjusted so levels don’t get too high or drug can accumulate and get into CNS causing convulsions and sizures.
Levels over 20mcg/mL are BAD!!!
Theophyline Plasma levels
5-20
15-20
30-40
5-20 is therapeutic
Toxic effects start at 15 - nausea, vomitting, and cardiac effects.
30-40 TOXIC - siezures and arrythmias.
84yo nursing home patient was on theophylline and had decrease in renal function. Why is this bad?
Drug accumulated in the CNS and caused a siezure.
Levels over 20mcg/mL become toxic.
How would you treat this old lady with high CNS levels of Theophyline?
Dialyze drug off.
CNS levels were so high, she ended up in non-convulsive epilepsy and died.
Scary drug, not used frequently
Anticholinergics MOA
Short acting rescue medications; block effects of muscarinic receptors which cause bronchodilation.
Methylcolene
Used in provocative tests that induces an asthma attack.
Ipratropium (Atrovent)
short acting anticholinergic that lasts for eight hours
Tiotropium (Spireva)
Long acting; only used for COPD and lasts 24 hours or more.
When prescribing rescue meds, what do you give?
What about in ER?
Albuterol inhaler
Albuterol and ipratropium can be used synergistically to have more oomph into bronchodilation to see how reversible airflow obstruction is. Tells if you need another therapy.
MDI
Meter dose inhaler
DPI
Dry powder inhaler; comes in a discus where you turn it open and hit a trigger to puncture packet so patient can inhale drug itself. Relies on patient to inhale drug.
May not be good for older or younger patients who dont have faculty to inhale.
Spireva Administration
Comes as a capsule. Capsule goes into inhaler and is punctured for inhalation.
If you accidentally swallow spireva, what happens?
Its not absorbed systemically.
TEll patients not to store with normal medications.
What is HFA?
CFC based propellent which damaged ozone layers, so they switched to HFA which is a new repellent.
Side effects to anticholinergics?
Ipatropium (Atrovent) and Tiotropium (Spiriva)
By giving these drugs in lungs, you’re less likely to see systemic effects.
Midriasis, blurry vision, hallucinations, delirium, memory loss, psychosis, flushing, fever, hyperthermia, dry mouth/eyes, urinary retention, constipation, tachycardia, and hypertension.
Side effects to anticholinergics.
Midriasis, blurry vision, hallucinations, delirium, memory loss, psychosis, flushing, fever, hyperthermia, dry mouth/eyes, urinary retention, constipation, tachycardia, and hypertension.
Anticholinergic
What receptors do they act on?
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system.
Nicotinic receptors - skeletal muscle and nerve conduction through CNS.
Muscarinic receptors - tissues.
Patient is on controller meds, but has attacks and uses SABA often. What do you do?
Use short courses of systemic corticosteroids to decrease the inflammation occurring.
Helps suppress and reverse the airway.
Oral Systemic Corticosteroids
Systemic effect; take time to work, but work more quickly than ICS, bc they’re more potent.
This is why only used for exacerbations and short period of time.
What are the oral systemic corticosteroids?
Predinisone (oral tablet)
Prednisolone (oral liquid)
Methylprednisone (oral or parenteral IV, IM)
Dexamethosone (Oral or parenteral IV, IM).
What are the systemic corticosteroid side effects?
Adrenal suppression - exogenous steroids lower their secretions; start to shut down. If dose is less than a week, you don’t need to taper it off. However, if dosed for longer, you must taper off so the adrenal glands start working again.
Effects seen more with chronic dosing; not short-course therapy.
IMMUNOSUPRESSION - leads to secondary infections.
Growth supression
Dermal thinning
Hypertension
Muscle weakness
Patient in ER for asthma exacerbation, what can you do?
Send them home with 5 days of corticosteroids. Stop at the end, no taper needed.
Dose is less than a week, which is why no taper dosing is needed.
A patient with a bad exacerbation might have 3 to 4 days inpatient and 5 going home. How do you dose this?
Need to taper off this dose to prevent the withdrawal that leads to adrenal insufficiency.
Step 1 Asthma Treatment
SABA PRN
Exercise induced bronchospasm.
They have a known trigger, so use beforehand to prevent from occurring.
Step 2 Asthma Treatment
More symptoms, want to add a controller therapy - ICS.
Step 3 Asthma Treatment
Can add LABA or increase ICS.
Step 4 Asthma Treatment
Med dose ICS and LABA
Step 5 Asthma Treatment
High dose ICS and LABA
May add omaxilizumab.
Keep journal of symptoms and nighttime awakenings.
Spacers
Open tube that extends inhaler away from patients mouth
Valve holding chambers
have a one way valve that do not allow patient to exhale into the device
What does a nebullizer do?
Aerosolizes drug.
Compressor with tubing, put drug into a cup, turn on compressor and the air will cause the aerosolization of albuterol to occur.
Downsides to nebulizer?
In six month old, putting a mask with nebulizer is easy, because they’re passively breathing it in.
Downside: more medicine is absorbed, which causes more systemic side effects.
Nebullizer ADR
2 puffs = 180mcg of albuterol
Neb: inhale for 15 mins = 2.5 to 5 mg
Inhale more, so you get jittery, increased HR, potassium shift inwards.
Benefit: helps noncompliant patient get doses in.
Nebullizer Benefit
Help patient get the dose in.
Particle size is important. If its too big, you end up swallowing it. If its too small, you can exhale it.
“Goldy Lock’s” size to get to lungs where it will work.
If patient inhales inappropriately, too fast or too slow, what can you use?
Spacers and valve holding chambers; removes needs for coordinated activity.
Drug is held in chamber and patient can breathe it in more controlled (if you go too fast, it whistles).
MDI with chamber vs. Nebulizer treatment
Equal efficacy, no additional toxicity with MDI.
Inhaler Technique
Take cap off and shake inhaler to “prime” it (takes 3-4 puffs).
Breathe it all out, when you start to inhale actuate inhaler so you have the best airflow down to lungs for drug to go. Hold for 10s and breathe out as normal.
How do you instruct patient on frequency of inhaler use?
Don’t use multiple puffs in succession, bc puff needs time to work ~30 seconds
First dose opens up smooth muscle of bronchioles, so second dose can penetrate even deeper.
When a patient is on ICS, what do you tell them to do afterwards?
rinse mouth and spit
avoids thrush
COPD
Chronic damage being done to lungs over time; effects aren’t completely reversible like they are with asthma.
Accelerated decline in FEV1 over time. Can be asymptomatic for long period of time as lungs start declining. More symptoms will appear as it progresses (graph).
When not airing, need transplant.
What causes COPD?
smoking
alpha 1 antitrypsin deficiency
pollution
What type of med is used for Acute COPD?
For rescue inhaler, start with b2 agonist to relieve acute symptoms.
What type of med is used for Chronic COPD?
Long acting cholinergic or beta agonist. Spireva.
Why don’t you use LABA on asthmatic by itself?
Increased mortality rate; you need an ICS to start and then add a LABA.
If COPD patient symptoms aren’t controlled with a long acting cholinergic or long acting beta agonist - What do you prescribe?
Consider combination therapy.
May add theophyline or ICS added.
Asthma corticosteroids are initiated more early on than in COPD patients.
In COPD treatment, what else is added in conjunction with the medications?
oxygen therapy
Why do we use drugs for cessation of smoking?
Nicotine is addictive; drugs used will try to replicate components, such as the dopamine pathway or nicotinic receptors itself.
When people cut off nicotine cold turkey, they have withdrawals and lowered receptors. This is why we need drugs to stimulate during process.
What drugs are used with cessation of smoking?
Buproprion (Zyban)
Nicotine transdermal (Patch)
nicotine polacrilex (Gum)
nicotine spray or inhaler
Vareniciline (Chantix)
Nitroglycerin tablets - sublingual.
Buproprion Sustained Release use?
Sustained release; long-acting drug. Stimulates “reward” pathway in the brain, dopamine, to decrease withdrawal effects of smoking.
Buproprion MOA?
Nicotine indirectly activates epinephrine and dopamine in CNS.
Bupropion micmics these effects because it inhibits the uptake of norepinephrine and dopamine; increasing dopamine helps bc nicotine isn’t stimulating the pathway anymore.
Alternative uses of buproprion?
Used for weight loss.
Who do you avoid giving buproprion to?
Patients with seizure disorder - run risk of seizure threshold being decreased and causing seizures.
Don’t want them on other drugs that increase norephineprine; no monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressant (TCA).
Its an antidepressant, so it can interact with antidepressants - usually work by seratonin reuptake inhibitors.
How long does it take buproprion to work?
7 to 12 weeks
What are nicotine replacement agents used for?
Taper the nicotine dose, which is healthy since they’re not inhaling tar or other carcinogens.
Nicotine is activating receptor, so do not want smoking on top of this or increases risk of toxicity!
Patient education about nicotine patch?
Make sure patient removes old patch before putting a new one on; don’t want to experience toxicity.
Leave on for 12 hours and then take off.
Who is nicotine replacements bad for?
Cardio patients, bc it may cause tachyarrythmia or hypertension.
Will affect antihypertensives
Vareniciline (Chantix) MOA
Newest drug
Partial nicotine receptor agonist; it binds to receptor and activates, but not to the same degree (partial).
If you smoke while on drug, it binds more tightly than nicotine and prevents it from activating. Can smoke on this drug and taper off to just this drug.
Vareniciline (Chantix) ADR
Vivid dreams, nausea, sleep disturbance
Black box warning for neuropsychiatric events, like depression and SI. If your patient has a history of that, this isn’t a good drug for them.
What immunizations are important for COPD?
Annual influenza - if they get flu, they’d get a bad bacterial superinfection.
Pneumococcal vaccine - more at risk for pneumococcal infections. Want to avoid.
START OF CARDIOLOGY CARDS
START OF CARDIOLOGY CARDS
Infective Endocarditis - What is it?
Bacterial infection on lining of heart or valve itself. Colonies of bacteria like to settle on valve.
Who is at risk for infective endocarditis??
What happens if you can’t treat it with abx?
Older patients > 60 yrs, male patients, IVDA, those with poor dental hygiene which leads to hematogenous spread, and valvular heart disease.
If you can’t treat with antibiotics, you need a valve replacement.
What is the pathogenesis of infective endocarditis?
A thrombus is formed on an abnormal endothelial surface, where vegetation can start. Bacteria in blood colonizes here and starts proliferating.
Why is it difficult to treat infective endocarditis?
Difficult to penetrate through and get a full kill of all the bacteria. This is a concentrated core of bacteria to penetrate.
6-12 weeks of treatment
What are the most causative bugs of infective endocarditis?
Mainly gram positives!
S aureus
Enterococci
HACEK
Gram negatives in immunocompromised
What is HACEK?
Haemophilus aphrophilus Actinobacillus actinomycetemcomitans Cardiobacaterium hominis Eikennella corrodens Kingella kingae
They live in the mouth. Common bugs of endocarditis.
Endocarditis therapy sequence
Therapy needs to be geared towards culture since you’re treating for several weeks.
Start with empiric coverage and then you scale down.
What does the empiric coverage for infective endocarditis target?
MRSA, MSSA, Streptococci, and Enterococci
Prefer bactericidal abx - leads to a better kill and gets rid of vegetation.
Good initial choice for infective endocarditis empiric therapy?
Vancomycin
Good gram positive and MRSA.
Tx may be needed for six weeks or longer.
Start patient with infective endocarditis on vancomycin, but cultures come back for Viridans streptococci and Streptococcus bovis.
What do you use to treat?
They’re PCN susceptible, so use PCN G 4-6x a day or a 24hr infusion to make sure you’re above MIC.
Alternatives: Ceftriaxone, Vancomycin (if can’t recieve cephalosporin or PCN), and Gentamycin.
Why is gentamycin used for infective endocarditis?
Gram positive synergy - one of the few cases an aminoglycoside is used to kill gram positives.
Giving a cell wall killer like PCN or ceftriaxone loosens up the cell wall so Gentamycin can get in to inhibit protein synthesis at ribosome.
Gentamycin MOA?
Whats it normally used for?
Inhibits protein synthesis at the ribosome. Bactericidal.
Normally used for gram negatives.
What’s a big benefit to using gentamycin in gram positive synergy?
It can shorten the therapy time in half and be very cost effective.
Gentamycin ADR
Don’t want to accumulate too much drug because of renal toxicity and otoxicity.
Start patient with infective endocarditis on vancomycin, but cultures come back for Streptococcal species.
What do you use to treat?
Mostly PCN sensitive. Have to follow cultures.
If susceptible to ceftriaxone and not PCN, treat with ceftriaxone.
Start patient with infective endocarditis on vancomycin, but cultures come back for Enterococci.
What do you use to treat?
Use synergy combination of gentamicin
PLUS penicillin, ampicillin, or vancomycin.
Generally resistant to PCN.
Start patient with infective endocarditis on vancomycin, but cultures come back for MSSA.
What do you use to treat?
MSSA is treated by nafcillin, oxacillin, cefazoline +/- gentamicin.
MRSA is treated with vanco.
What are antistaphyloccocal PCNs?
nafcillin
oxacillin
dicloxacillin
Start patient with infective endocarditis on vancomycin, but cultures come back for HACEK…..
What do you use to treat?
Treated by ceftriaxone, ampicillin-sulbactam, or ciprofloxacin.
How are IVDA different from normal endocarditis cases?
They inject particulate matter which can damage tricuspid valve, introduce skin flora, and use of saliva.
What are the common bugs in endocarditis for an IVDA?
S aureus for more than half the cases.
Followed by streptococci, enterococci, fungi and gram negatives.
First line treatment for IVDA endocarditis?
Vanco for empiric coverage
Why are prosthetic heart valves more difficult to treat?
Antibiotics may fail because they can’t penetrate “foreign body”.
Often requires surgery, esp MRSA
Patient came in with symptoms of endocarditis. You know they have a prosthetic heart valve, what do you use to treat it?
Triple drug regimen - targets staphylococcus!
Vancomycin
Gentamicin
Rifampin - add it as the last agent to avoid resistance
Rifampin ADR
orange-red tears, urine, feces, sweat
Why is Rifampin used for a patient with infective endocarditis and a prosthetic valve patient?
It has a unique ability to kill staph that adheres to foreign material.
Rifampin resistance is possible.
How do we acknowledge this during treatment of infective endocarditis?
Add it as the last agent in the three drug regimen.
If you use it first, resistance develops more quickly.
Rifampin MOA
Inhibits bacterial RNA polymerase by blocking RNA transcription.
Rifampin - other use?
tuberculosis
Rifampin Drug Interaction
SUPER IMPORTANT
It induces CYP enzymes like 3A4 so you see decreased level of other drugs.
CYP3A4 is responsible for metabolism of half of all drugs.
Endocarditis prophylaxis
By giving prophylaxis abx prior to bacteremia, you can prevent it from starting off in first place.
If you have a patient with prosthetic heart valve, history of infective endocarditis, or a structural vulnerability - How can you prevent infective endocarditis?
Prophylaxis beforehand, especially before dental procedures. Broncoscopy, tonsillectomy, etc.
Mouth can spread into the blood stream.
How are endocarditis prophylaxis administered?
30-60 mins prior to procedure
Amoxicillin PO
If PCN allergy, use cephalexin, clindamycin, azithromycin.
What types of patients with infective endocarditis get the triple drug regimen?
Prosthetic Heart Valves
What is acute rheumatic fever?
Nonsuppurative complication of pharyngeal infection. Occurs 2-3 weeks following pharyngitis.
Causes arthritis, carditis, nodules, erythema marginatum.
What bug causes rheumatic fever?
Group A streptococcus
What are three parts of treatment for rheumatic fever?
Antibiotic therapy
HF management
Anti-inflammatory therapy
Patient with Acute Rheumatic Fever, what antibiotics are appropriate?
Amoxicillin and PCN
Eliminate Group A Strep carriage
How do you treat carditis if it develops from ARF?
Aspirin to help deal with anti-inflammatory effect. Helps relieve symptoms.
Treat CHF
Valve surgery
How do you treat arthritis and fever if they occur from ARF?
Continue aspirin until symptoms are resolved.
If it doesn’t work, you can use glucocorticoids to manage inflammation, i.e. prednisone.
Typical American Diet consists of ___ triglycerides and ____ cholesterol.
100g triglycerides a day
250mg of cholestrol
How are triglycerides and cholesterol digested?
Triglycerides and cholesterol are incorporated into chylomicrons.
When chylomicrons are metabolized, the ratio of triglycerides and cholestrol change as we go along.
Dietary cholesterol is ingested in GI tract - how?
Emulsified by bile acids; the bile salts are sent to biliary tract, which contains cholesterol as well. Can reabsorb cholesterol in biliary tract.
Cholesterol is absorbed into GI tract and then hits the liver first.
Drugs work at second site to prevent reabsorption.
Lipase FXC
Hydrolyzes triglycerides in the core of the chylomicron. As time goes on, triglycerides go down as they’re being converted to cholesterol.
Chylomicron - describe triglyceride and cholesterol balance.
A big portion of triglycerides, but as metabolism continues, you have higher cholesterol.
LDL and HDL come from chylomicrons.
Triglycerides FXC
Synthesize cell membranes, hormone synthesis, and are disposed as bile salts.
Enterohepatic recirculation
When things are kicked out of biliary tract and reabsorbed through GI tract.
Birth control, antiepileptics, and other drugs do this to increase their half life.
What’s converted to triglycerides?
Carbohydrates and fatty acids
What’s excreted from liver?
VLDL - higher portion of cholesterol, but made of triglycerides
As metabolism goes on, TG is converted to cholesterol esters.
- lipoprotein
- lipase
LDL
Bad cholestrol, lead to artheriosclerosis and plaque formation.
LDL is removed by?
LDL receptor, found in liver. How we metabolize and get rid of LDL.
More LDL receptors in liver, the more that is cleared from blood stream, which is good.
As triglycerides are more metabolized, what to they turn into?
LDL
Where is cholesterol metabolized?
Liver
ApoB-100
Protein on surface of LDL that interacts with the receptor.
Important for catabolism of LDL.
Low Density Lipoprotein
Main focus for medications.
Have a half life of 1-2 days. ApoB interacts with LDL. Patients might not express LDL receptor or ApoB, which leads to high cholestrol since they can’t metabolize it.
If you have a lot of cholesterol in blood stream, what happens?
Liver gets saturated, LDL receptors down regulate or less expressed.
Lower LDL receptors leads to atherosclerosis. Will start making plaques in arteries.
LDL receptor action
Take LDL into liver to make amino acids, bile salts, and recycles the receptor to put on surface of hepatocyte to take another LDL.
Too much cholesterol in liver or blood, there’s less LDL receptors. Why?
There’s enough choleserol so you don’t want to metabolize anymore.
If you decrease the LDL in liver, you’ll put out more LDL receptors to metabolize.
Too high LDL in liver, you express less receptors.
What is heterozygous or homozygous famlial hypercholesteremia?
Heterozygous familial hypercholesteremia - has half the normal number of LDL receptors. Cholesterol is twice the normal amount.
Homozygous familial hypercholesteremia - No functional LDL receptors. Can be as high as 1000mg/dL.
What’s the typical breakdown of serum cholesterol?
60-70 LDL
20-30 HDL
10-15 VLDL
Statins
Main go to drug for dyslipidemia. Used for cardiovascular protection.
Ezetimibe MOA
inhibits absorption of cholesterol
Statins MOA
HMG-CoA reductase inhibitors
Lovastatin Simvastatin Pravastatin Fluvastatin Atorvastatin Rosuvastatin Pitavastatin
Statins
Statins MOA
HMG-CoA reductase inhibitors
HMG-CoA reductase produces cholesterol. By blocking it, we lower LDL in hte liver. Less cholesterol in the hepatocyte causes a response where more LDL receptors are expressed to metabolize the serum LDL.
Decreased serum VLDL and IDL – Done by increasing number of receptors so more can be taken out of blood stream.
Benefits of statins
Outside of its main use, it has pleiotropic effects which are positive and don’t relate to main mechanism.
You have stabilization of plaques, which have good effects on mortality and cardiovascular death.
Frequently recommended for patients with Cardiovascular Disease - Need to be on a statin unless theres a contraindication.
Statins PK - Does it interact with any major enzymes?
Major enzymes:
CYP3A4 - statins are metabolized by it. If you inhibit CYP3A4 via FQ or macrolide, you’ll see high levels of statins and can lead to toxicity.
If a patient has a pneumonia and is on statins, can you prescribe a macrolide?
Which ones?
Macrolides inhibit CYP3A4, which lead to higher drug levels of statins in blood stream.
Patients on FQ and macrolides should be on Resuvostatin or Pitavastatin to avoid toxicity with CYP inhibition.
Dose Response Curve: Statins
Explain the concept.
Using combination therapy is good because synergism lead to better affects than drugs being used by themselves.
Ex: Statin lowers LDL but is prescribed with resin.
Statin effects on Triglycerides
The higher Triglyceride levels in blood, the better effect statins have on it.
START OF CARDIOLOGY 2 CARDS
START OF CARDIOLOGY 2 CARDS
How do statins work?
Inhibit cholesterol formation in the liver , so you produce less cholesterol in the liver. Makes hepatocytes form more LDL receptors to take it out of the blood and process through liver.
Serum lipids go down. Also have other pleiotropic effects - stabilization of plaques and prevent other cardio events.
Common Side Effects of Statins
Headache, fatigue, GI intolerance
Increase in liver enzymes (AST and ALT can rise). Usually dose dependent.
Increase dose increases risk for toxicity.
If you have a patient on statins with an increase in LFTs, what do you do?
Reduce the dose or switch to a different agent.
Rare to see liver problems by itself.
What do you measure when on statins? When?
LFT.
Beginning of therapy and a month or two after to see how they tolerate the drug.
ADR of Statins
Myalgias and myopathies; rare cases of rhabdomyolysis occur as well.
Muscle pain is a common side effect. When dosing based on cardio risk, try to run up as high as you can until patient can’t tolerate it anymore.
What is rhabdomyolysis?
Muscles are broken down; kidneys take a hit, because myoglobin goes into the blood and causes interstitial damage to their kidneys.
How do you treat rhabdo patients?
Give them fluids to dilute the myoglobin to help the kidney.
Patient ran a marathon but haven’t had any physical activity at all - What is this a sign of?
Sign of rhabdo, urine is ice tea colored.
What do you do when your patient is on statins and is experiencing impaired renal function and myopathy?
Decrease dose and do the best one they can tolerate. Avoid drug interactions.
Major drug reactions of fibrates?
Be very careful when prescribing statins and Gemfibrozil together, because it can lead to increase in statins and toxicity.
Or when you do prescribe them togetehr, lower the dose of the statin.
What statins are not metabolized by CYP3A4?
Resuvostatin or Pitavastatin are not metabolized by CYP3A4.
What happens to statins if you have a CYP3A4 inhibitor on board?
Inhibit enzyme and metabolism, so less drug is metabolized, which increases risk for toxicity. Be cautious of it.
Contraindications of statins
Hepatic disease
Pregnancy - baby needs lipids to make cell membranes. Teratogenic.
What are some things to consider when dosing a statin? Relative CI.
Relative CI - you can get away with adjusting the dose.
Gemifibrozil, niacin, and erythromycin —- all will increase level of statins.
What statin doesn’t get metabolized by CYP3A4?
Rosuvastatin
Potavastatin
What inhibits CYP450 and lead to drug interactions with statins?
Verapimil Amiodarone Niacin Fibric acid derivatives (Gemifibrozil) Grapefruit Juice
P-glycoprotein - What does it do?
Its an efflux transporter; things abosrbed from GI tract and this is responsible for kicking things back out.
Inhibited by grapefruit juice as well. Inhibition of this can cause increase in drug levels.
CNS - blood brain barrier and PGP
Brain wants to keep toxins out, so PGP can help.
Statin - place in therapy?
First line drug for hyperlipidemia, most efficacious.
Not given to those who are pregnant or have hepatic disease.
Cholesterol absorption inhibitors - What drug?
Ezetimibe
How does Ezetimibe work?
Decrease the amount of absorption from cholesterol from your diet.
By decreasing amount of cholesterol absorbed, liver doesn’t think it has enough cholesterol. Starts producing more LDL receptors on the surface to absorb more cholesterol and LDL from the blood.
Efficacy between statins and Ezitimibe - which is more potent?
Statins are more potent and efficacious.
How do you synergistically treat hyperlipidemia?
Ezetimibe can be used in combination with statins - synergistic.
Statins work on directly producing cholesterol in the liver and Ezetimibe protects you from absorbing cholesterol from your diet.
Ezetimibe MOA
Decreases cholesterol absorbed in diet. Less cholesterol is absorbed in the liver so the liver puts out more LDL receptors to lower levels.
What does Ezetimibe do to prolong its half life?
Drugs that undergoes eneterohepatic reabsorption. – Absorbed in GI, spit out through biliary tract, and reabsorbed = gives it a longer half life.
Ezetimibe PK - Does it interact with any major enzymes?
No CYP interactions
Benefits of Ezetimibe
You can have an additional LDL reduction by 15-20% when adding a statin.
Only have to take it once a day. Enterohepatic circulation prolongs half-life.
Ezetimibe ADR
Enterohepatic circulation limits the systemic effects, may see GI upset, but minimal as far as side effects go.
May also see elevation in hepatic transaminases when used with statins!
When is Ezetimibe contraindicated?
Shouldn’t be used in breast feeding, pregnancy, children, hepatic disease, myopathy.
When combined with a statin, you may see myopathy and hepatic disease.
What are important drug interactions with Ezitimibe?
Fibric acid derivatives - increases risk of cholelithiasis and myopathies.
Bile Acid Sequestrants - work only in GI tract, so they can bind to this med and decrease the concentration.
Antacids decrease concentration and cyclosporine increases concentrations.
Fibrates - Name them.
Gemfibrozil (Lopid)
Fenofibrate (Tricor)
Bezafibrate (Bezalip)
Fibrates MOA
Activate PPAR-alpha (nuclear transcription factor), which increases fatty acid oxidation. Leads to less secretion of triglycerides, which means less VLDL is produced and decrease LDL on cell surface (VLDL is precursor). Can see increase in HDL which is protective cholesterol.
Fibrates PK - Do they interact with any enzymes?
Fenofibrate is metabolized by minor pathway in CYP3A4
Fibrates Dosing
Once daily medications lead to greater compliance. – Fenofibrate or Bezafibrate.
Why do you want to give Gemfibrozil before meals?
When you have ingestion of dietary fats, you produce the most cholesterol. This oxidation of fatty acids lead to less triglycerides being released.
Not as big of an effect as statin, but HDL increases and triglycerides decrease.
Adverse effects of fibrates
Nausea, abdominal pain, diarrhea.
BIG RISK - Cholelithiasis, can affect movement of bile acids. By inhibiting that movement, you can have gallstones.
Myopathy is also a risk. Can have synergistic effects with statins.
When are fibrates contraindicated?
Pregnancy
Hepatic or renal dysfunction
Galbladder disease
Adjust dose based on renal dysfunction.
What could happen if you prescribe fibrates to a patient on warfarin?
Warfarin - see increased anticoagulant effects, could be related to protein binding interaction.
Warfarin binds to albumin. If a fibrate drug is used, it will bind to albumin more tightly and plasma concentrations of warfarin will increase. More drug is available, so increase risks for bleeding.
What happens when you have a patient on HMG CoA reductase inhibitors (statin) and you put them on fibrates?
With gimfibrozil, will see reactions that increase levels of statins, increasing risk for toxicity.
See it in most fibrates, but highest effect in gimfibrozil.
Decrease the statin by half.
Primarily, when are fibrates used?
Primary hypertriglyceridemia
TG>1000mg/dL or low HDL.
Can add it to increase those levels.
What are bile acid sequestrants called?
Resins.
They work in the bile tract and are not systemically absorbed, which is why you can give them to children and pregnant patients :)
Bile Acid Resins MOA
By binding cholesterol and bile salts, they’re bound by resins and will be excreted in the feces.
You absorb less cholesterol from diet and spit out diet tract to prevent that from being absorbed..
Increases LDL receptors to decrease cholesterol in the blood. Not as effective as statins, but are nice bc they’re not absorbed systemically.
Why would you see some GI issues with Resins?
Cholesterol excreted in feces can lead to GI effects.
Who are Resins good for?
Children and pregnant patients!
Children and pregnant women love resins
What are the Bile Acid Sequestrants? 3C
Cholestryamine
Colestipol HCl
Colesevelam
Not absorbed, but bind cholesterol in GI tract to prevent them from being absorbed.
Dosing of bile acid sequestrants
Issues with tolerance that might come up?
Plateau effect?
Most products come as tablets; these come as bulky powders or tablets.
Patient may not tolerate as well, bc of the pulpy taste. Can mix with orange juice to mask flavor.
There’s a “plateau effect” where if you increase dose you get more ADR instead of efficacy from this.
Why should BAS be taken within an hour of meal?
That’s when you have most fat in GI tract. Galbladder is actively secreting bile salts to help emulsify.
Should give more bang for your buck.
Why do you separate bile acid sequestrants from other medications?
They can bind to other medications.
Can give a drug one hour before or two to four hours after to make sure the reaction doesn’t cause binding.
Because you don’t absorb fats in GI tract when using bile acid sequestrants, what can yo feel?
bloating, flatulence, fullness, constipation, nausea.
Because bile acid sequestrants bind to bile sats, what might you see less absorption of? Why?
Less absorption of water soluble vitamins – ADEK and folic acid. Bile salts normally help emulsify these for absorption.
Avoid this by separating medication times to one hour before or four hours after taking BAS.
What drugs can be bound up by bile acid sequestrants?
digoxin, warfarin, thyroxine, beta blockers, and thiazide diuertics
How do you avoid bile acid sequestrants from binding to other medicines?
avoid interaction by adminstering one hour before or four hours after bile acid sequestrant.
What are BAS contraindications?
High levels of triglycerides (can make it worse) and familial dysbetalipoproteinemia.
Bile Acid Sequestrant - Place in therapy
Safest drug, because no systemic side effects. Good for pregnant patient and children.
Poorly tolerated from GI standpoint.
Can use with antilypemics as well since they have a differnt mechanism of action.
Niacin
B complex vitamin; another derivative is nicotinic acid.
Used an an antilipemic.
Amide form is a niacinamide. Can cause flushing.
Why are long acting forms of niacin used?
Less likely to cause side effects and hot flashes.
Niacin products
Immediate release
Niacin supplment and Niacor
Long acting
Niacin Supplement
Extended release
Niaspan
Inositolhexiancinate
Supplements
Not well regulated by FDA.
Niacin MOA
Decreases free fatty acids released from the adipose tissue; will also see changes in synthesis of triglyercides which happen in liver.
Less VLDL released = less LDL being produced, which lowers cholesterol in the blood.
RECAP: Less triglycerides are getting in liver, less VLDL produced, more LDL receptors to clear LDL.
Will see an increase in HDL.
Benefit of Niacin MOA?
Will see an increase in HDL. Extended release has more moderate side effects.
If we get better effects from immediate release, why do we use extended release niacin?
Its more tolerable to patients, i.e. less flushing
How long does nicotinic acid take to work?
Tmax = 30 to 60 mins
What’s Tmax?
How long it takes to get to highest concentration.
What’s another benefit of extended release?
Longer duration of action so they’re given less frequently.
Niacin ADR
Cutaneous flushing
Nausea
Abdominal discomfort
Larger doses - increased LFTs, glucose, uric acid (bad for diabetics and gout), decreased glucose tolerance.
Why does Niacin cause facial flushing?
Too much prostanglandins production
What inhibits prostaglandins?
Aspirin, because it prevents production of prostaglandins by inhibiting COX
Also, ibuprofen.
How can you prevent facial flushing when taking niacin?
Take aspirin or ibuprofen before to decrease production of prostaglandins beforehand.
Or take extended release.
Why is niacin bad for diabetics and those with gout?
Increase in uric acid and decreased glucose tolerance. => Insulin produced isn’t effective, so glucose goes up.
Mitigated by extended release product.
CI Niacin
Liver disease
Symptomatic gout
Type 2 diabetes
Peptic ulcer disease (can get aggravated by it).
Niacin drug interactions
Statins - see mild increase in statin concentration, same thing with bile acid sequestrants (BAS increased).
ETOH - can lead to increased flushing if you take with niacin bc acetaldehyde.
Other herbal supplements can inhibit metabolism of it: kava-kava, germander, pennyroyal, comfrey, chaparral.
What inhibits niacin metabolism?
Other herbal supplements can inhibit metabolism of it: kava-kava, germander, pennyroyal, comfrey, chaparral.
WHere is niacin place in therapy?
Good for atherogenic dyslipidemia. Useful to lower LDL and increase HDL.
Combination of statin and niacin example?
Lovastatin/Niaspan (Advicor)
Reduces LDL, increaes HDL. Good effects on triglycerides.
Lovastatin/Niaspan (Advicor) ADR??
hepatotoxicity, myopathy, and flushing
What drugs lower LDL?
Statins
Resins can a little, but limited by side effects.
What drugs will increase HDL?
Niacin and fibrates
What drugs will decrease triglycericdes?
fibrates and nicotinic acids
What will increase triglycerides?
Resins; don’t give to those who already have high triglycerides.
ATP 3 Goals (Old model) - Not used anymore; now patients are assessed on cardiac risk.
LDL less than 100.
HDL to be high, bc protective of cardio disease.
TC less than 200
TG less than 150
New AHA/ACC guildelines
treat blood choelsterol to reduce atherosclerotic cardio risk in adults, which is leadin cause of death and disability in US.
How are patients assessed for these meds?
Statins can be moderate intensity or high intensity.
Based on cardiovascular risk.
Who are the four types of people that benefit from statins?
Individuals with ASCVD- stent placement, angina patients
Individuals with LDL > 190 which means you are at risk for developing plaques and CAD
Individuals with diabetes, 40 - 75 years old, that have LDL 70-189.
Patients LDL 70-189 and estimated risk of ASCVD.
If I have a patient who has diabetes, history of MI, and LDL is 200 - What therapy should he be on?
Moderate to high intensity statin
If a patient has ASCVD at less than 75 years of age. What therapy should they be on?
High intensity statins. They’re at a big risk for developing more ASCVD.
If a patient has ASCVD at over 75 years of age. What therapy should they be on?
Moderate intensity, bc they’re older and at higher risk for toxicity.
If you have diabetes, you have a higher risk of CVD. If risk is high, what therapy?
High intensity statins
How do you determine risk of how likely you’re to have CVD in 10 years?
Gender, age, race, cholesterol, systolic BP, diabetes, smokers
If over 7.5%, you get put on statins.
What are the two more potent statins?
Atorvastatin and rasuvastatin; dosed to how well patient can tolerate it.
If you put a patient on rasuvastatin and patient has myopathies, what do you do?
Decrease the dose.
If you have too high of a salt balance in the body, what happens? To little?
Too much = volume overload and pulmonary edema.
Too little = volume depletion and cardiovascular collapse.
How do kidneys regulated blood pressure?
Kidneys receive 22% of cardiac output and regulate BP in the body. If there’s not enough pressure, they try to get more pressure going into them.
Drop in BP will decrease ANP, increase ADH to counteract the drop, and increase BP. Can lead to renal cell hypertrophy.
Do you want afferent arteriole to be dilated or constricted to get blood to go to the glomerulus?
Vasodilated - more blood can flow.
What’s responsible for dilating afferent arteriole?
Prostaglandins
What happens when a patient takes an NSAID?
Decreases production of prostaglandins, so the afferent arteriole will have a smaller diameter. Less blood can get to the glomerulus.
What’s responsible for constricting the efferent arteriole?
Angiotensin 2!! Squeezes efferent arterioles, increases pressure on glomerulus, and causes more filtration to occur.
Patient has an injury and BP goes down, what do kidneys do?
Reflexively decide to increase angiotensin 2 and prostaglandins.
This dilates afferent arteriole and squeezes efferent arteriole to get as much blood to the kidneys as possible.
Map of kidney from Bowman’s Capsule
Where blood enters kidney and is filtered to proximal convoluted tubule…. to loop of henle, distal convoluted tubule, and collecting duct out to the urinary tract.
How many liters are filtered a day and how many are excreted in the urine?
150-180 L filtered a day
1 - 2 L excreted
Proximal Convoluted Tubule
First sight hit after glomerulus where 60-70% of filtrate is reabsorbed.
There’s reabsorption of glucose, organic solutes, and amino acids.
What happens if you inhibit reabsorption of electrolytes?
There will be more water in the nephron (following electrolyte concentration) and more fluid will be excreted.
What happens in the Loop of Henle?
Reabsorbs sodium. Site where loop diuretics work!
Sodium is reabsorbed in ascending loop and is impermeable to water. Descending loop, water will leave to follow the sodium that was leeched out.
What happens in distal convoluted tubule?
Na is reabsorbed here; site of thiazide diuretics.
What happens in collecting duct?
Water movement is modified by aldosterone and antidiuretic hormone in collecting duct. Site of potassium sparing diuretics.
What does ADH do?
Helps absorb more water. ANTI diuretic.
Gets turned off when drinking alcohol.
Loop diuretics MOA
Work by inhibiting Na-2Cl-K carrier on the membrane in lumenal membrane of the thick Ascending Loop of Henle
Inhibiting this transporter causes Na, Cl, and K to remain in lumen of renal tubule. Water flows and is excreted with them.
.What are the 4 loop diuretics?
Furosemide
Bumetanide
Torsemide
Ethacrynic acid
-IDE
Which loop diuretic has the LEAST potency?
Furosemide
What loop diuretic has the highest potency?
Bumetanide and Torsemide
Dosage is less, bc they’re more potent.
What is IC50?
Concentration you have to achieve to inhibit 50% of transporters.
Which loop diuretic is useful for patient with sulfa allergies?
Ethacrynic acid.
Furosemide and Bumetanide have sulfa moiety’s in molecules.
By inhibiting the transporter on the thick ascending Loop of Henle (lumen side), where urine is colecting; what happens?
By inhibiting transporter, you have more sodium, potassium, and chloride on lumenal side. More water flows in that direction to be excreted.
This can lower sodium, chloride, and potassium concentrations! Its important for patients on high-dose loop diuretics to look at potassium because they’re excreting a lot of it.
Why is it important for patients on high dose loop diuretics to monitor potassium levels?
Inhibiting the transporter, a lot of sodium, potassium, and chloride are excreted. Levels can become dangerously low.
What are the major actions of Loop Diuretics?
Inhibit sodium chloride reabsorption by 20-25%, so can see big increases in urine output 4L a day. Also will see potassium, calcium, and magnesium excreted.
If you have a patient prone to an arrythmia or have an anti-arrythmics on board; how do loop diuretics affect them?
By losing more electrolytes, like potassium and magnesium, they’re more prone to having arrythmias.
Be aware of electrolyte shifts by giving these drugs.
By decreasing potassium levels in the blood from loop diuretics, what happens?
Explain the reflex mediated catelcholamine release that occurs and how it affects the a2 and b2 receptors?
The resulting hypokalemia can impair insulin release leading to high blood glucose levels (hyperglycemia).
Because you’re decreasing the pressure in the kidneys from diuretic, it activates SNS; releasing NE and dopamine.
Catelcholamines:
Activate a2 receptors = decrease insulin release. Activates B2 = increases glycogenolysis to produce more glucose. Leads to liver producing more glucose and see hyperglycemia from these drugs. Can worsen diabetes.
Why is it bad to put a diabetic patient on loop diuretics?
Hypokalemia (low K) impairs insulin release, which leads to high glucose levels and activation of A2, which further decreases insulin release and B2 which increases glycogenolysis.
Leads to very high sugars and worsens diabetes.
What is another important action of loop diuretics?
Reflexive systemic vasodilation – Prostaglandins will open up the afferent arteriole and have a direct relaxant effect on muscles.
Opening up the smooth muscle and allowing more volume to hit the glomerulus.
Prostaglandins dilate the afferent arteriole, but can be blocked by which type of drugs?
NSAIDs
How do the kidneys respond to loop diuretics increase in volume depletion?
It tries to counteract the drop in BP - Increase in the renin angiotensin system, aldosterone secretion, and ADH hormone.
Kidneys say too much volume is lost, so trying to keep as much as they can. Reflex mechanisms like this can lead to medications being less effective.
Why don’t you want to use loop diuretics long term or chronically?
If you give these chronically - Patient can have same dose of loop diuretic, which can be good in the beginning, but drop off over time and become a closer to normal output.
How do you avoid the “plateau effect” in loop diuretics?
Put patient on loop diuretic and an ace inhibitor.
What should you be concerned about when putting a patient with arthritis on loop diuretics?
Increases in uric acid levels occur, because of fluid loss creates a more concentrated build up in plasma uric acid levels.
By decreasing fluid volume, everything gets more concentrated to some degree. Increased risk for precipitating out.
By causing fluid depletion from a loop diuretic, what type of acid-base disorder can occur?
Contraction metabolic alkalosis.
Volume depletion leads to an increase in bicarbonate reabsorption, which is alkalosis response. You also excrete more hydrogen ions, contributing to this.
What effect do loop diuretics have on lipids?
Mild increase in lipids; bad for patients who have uncontrolled lipids already.
Can you give loop diuretics to someone with end stage renal disease or poor renal function?
Loop diuretics remain effective in patients with poor creatinine clearance and poor renal function ~ Even if 5ml/min.
End stage renal disease, can still have increases in urine output with a loop diuretic. May not be true with other diuretics.
What are therapeutic indications of loop diuretics?
Used to manage fluid overload in pulmonary edema, nephrotic syndrome, ascites, hypercalcemia, renal failure, and heart failure.
NOT used by itself to manage hypertension. If HTN pt is on loop diuretic, usually for something else.
Why are loop diuretics poor in controlling hypertension?
Bodies tries to compensate and raises blood pressure when dosed chronically.
What is nephrotic syndrome?
They have protein loss and can’t regulate plasma fluid volume, which leads to fluid overload.
Why are loop diuretics good at treating hypercalcemia?
By blocking channel, you lose more calcium, causing you to go back to a normal level.
ADR of loop diuretics
9
- Volume depletion - reflex mechanism associated to keep volumes up.
- Hypokalemia leads to cardiac arrythmias.
- Hyperglycemia - diabetogenic effects.
- Contraction alkalosis may occur.
- Hyperuricemia can exacerbate gout.
- Ototoxicity damages hair cells in cochlea. Occurs in high doses and other ototoxic meds, like vanco and aminoglycosides.
- Hyponatremia leads to seizures.
- Allergic reactions (Sulfa allergies to all except E. acid).
- Azotemic due to increase in BUN (and uric acid). Azotemia is an increase in nitrogen containing elements in the blood.
If you have a nursing home patient with nosocomial pneumonia and you put them on vanco and aminoglycosides.
Why is it bad to prescribe loop diuretics as well for fluid overload?
These drugs can synergistically cause ototoxicity.
Vanco, aminoglycosides, and loop diuretics.
Drug interactions of loop diuretics?
4
NSAIDs - will oppose prostaglandin synthesis and blunt the diuretic response.
Warfarin protein binding interactions - more warfarin in the blood will have increased anticoagulation.
Lithium - body will want to retain sodium (lithium looks like sodium), and it will retain lithium as well. Can see increased levels in the blood = toxicity.
Digitalis (antiarrythmic) - have increased risk for arrythmias when electrolytes are manipulated (K and Mg).
What are the two thiazide diuretics?
Chlorothiazide
Hydrochlorothiazide (HCTZ)
-THIAZIDE
What are thiazide-like diuretics?
Chlorthalidone
Metolazone
Indapamide
Have some calcium channel blocking activity, but less elevation in lipids, less hypokalemia, and less hyperglycemia.
Is Indapamide (Lozol) used frequently?
Haven’t seen used clinically
What is the importance of Metolazone compared to the other thiazide diuretics?
Interesting, because, as a class, thiazide diuretics lose activity when Cr clearance is below 30ml/min.
Loop diuretics stay active no matter what.
Thiazides lose their activity when under 30ml/min or less, except for Metolazone, which still remains active.
Frequently you get patients that become “loop resistant”, why?
You decrease sodium reabsorbed in ascending Loop of Henle, but there’s an increased amount absorbed in distal convoluted tubule later on.
DCT increases it, which is a blunting from loop diuretics.
How do you overcome “loop resistance”?
By giving a thiazide with a loop diuretic you can overcome resistance and prevent DCT from reabsorbing as much.
Loop diuretic and high dose IV and still not working, what do you add?
Thiazide - Metozolone is usually used for that.
Metolozone can make a rock pee!
Where do thiazides work?
The distal convoluted tubule to inhibit sodium and chloride reabsoprtion.
Thiazide diuretics MOA
Instead of working on Na-2Cl-K channel like loop diuretics, it specifically works on a NaCl channel to inhibit reabsorption. Want it excreted.
Not as potent as a loop diuretic.
Major actions of thiazide diuretics?
5
Increased NaCl excretion (not as potent as a loop diuretic.), but has increase in fluid output. Will also see a lot of K and Mg being released.
Has decreased calcium excretion, which causes it to be reabsorbed in the blood by PCT and DCT. More Calcium is reabsorbed in blood! IMPORTANT.
Hyperglycemia
Increases in uric acid levels, acutely.
Decreased GFR - seen acutely with fluid loss, but chronically they adapt to maintain GFR.
Why are thiazide diuretics preferred for patients with nephrolisthiasis?
Patients with kidney stones have kidneys precipitating calcium out in nephrons.
By increasing reabsorption of Ca, it could have more in the blood and less in the urine - prevents stones from being formed in the first place!
What are therapeutic indications of thiazide diuretics?
Primarily used for HTN and for hypercalcemia (renal calcium stones).
May also be used with other loop diuretics, etc. to get fluid off the body for renal failure, ascites, and CHF.
Who should we use thiazide diuretics in for HTN?
Elderly, obese, african americans, and those in Na retentive state.
Work best in patients who are SALT SENSITIVE hypertensives - have a decreased ability to manage sodium in the body. Sodium can get stuck in interstitium of vessels causing “water logged” blood vessels. They can’t dilate as well, so they have HTN.
How do thiazide diuretics reduce water logged vessels?
Acutely, there’s an increase in urine output, which causes a decrease in volume and cardiac output. The body uses Ang 2 to increase total peripheral resistance to squeeze down, but BP still drops. Over time, volume and CO will go back to normal, but BP will stay low because vessels are no longer water logged. :)
Decreased wall thickness, increased diameter for flow , and decreasing response for vasopressors cause BP to go back to normal.
How do thiazide diuretics work, both acutely and chronically on the body?
Acute - Start of thiazide diuretic decreases plasma volume and cardiac output immediately, from increased urine output. Body response by increasing total peripheral resistance, because you have less volume and want to maintain the same pressure so “squeeze down”.
Chronically -Want to increase cardiac output and plasma volume. Plasma goes back to normal and CO will increase. Systolic and diastolic may go down because there’s decreased water logging effect. Chronically why these work better than loop diuretics.
In loop diuretics, PV decreases, but they produce more ADH and it goes back to normal.
Main adverse effects of thiazide diuretics (similar to loop diuretics).
7
Hyperglycemia - Increases in glucose due to a decrease in insulin release. Hypokalemia Metabolic alkalosis Hyperuricemia hypercalcemia hyperlipidemia photosensitivity
Why are older patients more prone to orthostatic hypotension on these diuretics?
More prone because body can’t regulate hemodynamics as well.
Sitting to standing, their blood pressure isn’t as elastic to clamp down and maintain blood flow to the head.
Why is it bad to give an elderly person an antihypertensive, when they’re already at risk for orthostatic hypotension?
When is it recommended to dose this?
When you give them an antihypertensive, it exacerbates further. Can see changes in mental status, dizziness, headaches.
Dose at night time so they can sleep through that.
What is a benefit of thiazide diuretics over loop diuretics?
Do NOT have sulfa in them, so no allergies like you have with loop diuretics.
Loop diuretics - all have sulfa, except for Ethacrynic acid.
What are some issues with Thiazide diuretics?
Are they affected by GFR?
Sexual dysfunction
Constipation
Thiazides are only effective above 30-40ml/min Cr clearance, but metolazone is a thiazide diuretic effective at lower clearance rates!
Drug interactions of thiazides
2
NSAIDs block PGs and blunt the effects of thiazide diuretics.
Increase digitalis toxicity due to potassium excretion; the body wants to hold onto digoxin.
Loop Diuretics vs. Thiazide Diuretics
With loop diuretics, you can increase the dose and keep having more urine output. Ex: Start a patient on IV furosemide and you can drive dose up high.
Thiazides, you hit a ceiling. HCTZ may only be 15-25mg; above that you don’t see more increase on BP. You just see more ADR.
How do you dose Thiazides for HTN?
Low dose thiazides are preferred for hypertension, bc there will be fewer ADR.
Mechanism for diuretic therapy in general (chart)
Volume depletion leads to increase in Renin and Angiotensin 2, also increase ADH secretion and sodium/water reabsorption.
Chronically, leads to decrease in BP especially in salt sensitive patients.
Where do potassium sparing diuretics work?
Work in the collecting duct.
Can work to decrease aldosterone or decrease water channels, to have less water reabsorbed into the lumen.
Potassium sparing diuretics MOA
Work by blocking luminal Na channels, inhibit Na Ca antiporters, and inhibit Na H ion antiporters. By blocking water channels in collecting duct, water can’t be reabsorbed, so it is secreted.
Has more sodium in lumen, so more urine outflow happens.
Where do potassium sparing diuretics fall in the scheme of therapy?
Potassium sparing diuretics are less potent than thiazide diuretics, so are given to patients on other therapies, but are used because they secrete less potassium.
Raises potassium levels in the blood.
What are the potassium sparing diuretics?
Amiloride (Midamor)
Triamterene (Dyrenium)
Frequently seen in combination with hydrochlorothiazide.
Indications of potassium sparing diuretics?
Same as others, just less potent - HTN, renal failure, CHF, ascites, edema.
Frequently used with other antihypertensives
ADR potassium sparing diuretics
Hyperkalemia - Can be affected by ACE inhibitors and angiotensin blockers; also caution with potassium supplements, too high potassium can lead to arrythmias.
Diabetics may have glucose intolerance.
Red flag of Triamterene?
Can have megaloblastic anemia.
Red flag for amiloride?
Azotemia - medical condition characterized by abnormally high levels of nitrogen-containing compounds
What’s another variety of potassium sparing diuretics?
Aldosterone antagonists
What’s aldosterone?
Hormone you secrete to regulate fluid volume in the body. Binds to receptor in nucleus and works to increase production of certain ion channels in sodium membrane to reabsorb more sodium and water.
If anything, helps to increase BP by fluid volume. To block effects you’ll get more water and salt excretion of kidneys.
Where does aldosterone work?
DCT, but primarily in collecting duct
Aldosterone MOA
Works at the steroid receptors within the nucleus of the renal cells. Have increased number of sodium channels, which leads to sodium and water being reabsorbed.
What two drugs block aldosterone at the receptor?
Spironolactone (Aldactone)
Eplerenone (Inspra)
Spirnolactone
More frequently used; older, generic available, cheaper
Aldosterone antagonists MOA
Bind to the steroid receptor to prevent it from being activated. Prevents aldosterone from coming in and activating it.
Good for patients with high circulating aldosterone levels, will have the most effect from these drugs.
Inhibit channels on lumenal side to have less sodium reabsorption. Also has less potassium being excreted than other diuretics.
Diuretics cause potassium to be excreted. What can prevent potassium from getting too low?
Potassium sparing diuretics and aldosterone antagonists
How do aldosterone antagonists effect lipids, glucose, and uric acid levels?
Modest effect on lipid, glucose, and uric acid levels.
Where are aldosterone antagonists used?
Primary aldosteronism - hyper secretion of aldosterone. HTN CHF - class three or four
Edematous conditions like cirrhosis and nephrotic syndrome.
ADR of aldosterone antagonists
Hyperkalemia, esp. for patients with poor kidneys that can’t manage potassium normally.
What’s an ADR specific to Spirinolactone?
Spirinolactone has weak androgenic effects, which means it interacts with testosterone receptors, but not as tightly as testosterone.
It will interact, but not to the same degree. Can block those receptors and prevent testosterone from working on them, which causes testicular atrophy and gynecomastia.
Woman may get abnormal hair growth or irregular periods.
How do you avoid effects of Spirinolactone? Like gynecomastia, testicular atrophy, or menstrual irregularities.
Switch to Eplerenone
Carbonic anhydrase inhibitors MOA
Work in PCT, earlier end of neprhon, and increase amount of bicarbonate excreted within the kidneys. More excreted and water goes with that as well.
Increased release of sodium and potassium, but is a poor diuretic. Won’t have a good chronic antihypertensive effect from this.
What other disease states are carbonic anhydrase inhibitors used?
Glaucoma for the eyes to decrease aqueous humor production.
What are the carbonic anhydrase inhibitors?
Acetazolamide* main one used.
Dichlorphenamide
Methazolamide
How does carbonic anhydrases affect pH?
What else is it used for?
Should acidify pH.
Can prevent altitude sickness.
Activity of Carbonic Anhydrase Inhibitors
PCT - Inhibit carbonic anhydrase on outside of cell, so less is broken down to CO2 and water and is less likely to be reabsorbed.
Bicarbonate will be excreted in the kidneys, which causes more water to go with it.
When are carbonic anhydrase inhibitors used?
5
Glaucoma, by decreasing aq humor production.
Epilepsy - because metabolic acidosis causes seizure threshold to be higher.
Altitude sickness
Treats metabolic alkalosis by inducing acidosis.
Head injury to decrease the swelling; decreased production of CSF.
Carbonic anhydrase ADR
metabolic acidosis
potassium depletion
drowsiness
Osmotic diuretics
Increase amount of solute in kidneys, so more water will flow there.
By inhibiting H2O reabsorption, esp in PCT allows for more fluid and water to be released. Can increase urine outflow.
What are the osmotic diuretics?
Mannitol
Glycerin
Isosorbide
Urea
What osmotic diuretics are for increased intercranial pressure?
Mannitol
Given for head injury, can use to draw water out of CSF and decrease pressure.
When else are osmotic diuretics used?
Acute renal failure, acute tubular necrosis - questionable efficacy. Increased outflow but kidneys aren’t working better.
START OF CARDIOLOGY 3 CARDS
START OF CARDIOLOGY 3 CARDS
Responsibilities of Renin Angiotensin System
Responsible for blood pressure regulation, secretion of aldosterone - retains sodium and fluid, affect renalblood flow and sodium excretion.
Will be lookiing at drugs to inhibit pathway.
Physiology of Renin Angiotensin System
Renin is released from the kidneys in response to a drop in BP to regulate more flow to kidneys.
Angio 1 converts to Angio 2 (drugs may work on angiotensin converting enzyme), which is responsible for metabolizing bradykinin.
When Angio 2 is formed, it affects adrenal cortex to stimulate more aldosterone release to stimulate fluid retention and vasoconstriction to cause increase in BP.
Rate of renin release is controlled by?
renin baroreceptor
macula densa
SNS
If you have decreased renal perfusion, what happens?
Increased renin release, because baroreceptors aren’t being stretched enough.
Baroreceptors can recalibrate their baseline to be higher in HTN patients.
How does macula densa control renin release?
Macula densa responds to changes in sodium and chloride.
Decrease in that from diuretics can stimulate renin release.
How does SNS stimulate renin release?
Renal nerve activity controls release of NE and epi to innervate juxtoglomerular cells to activate B1 receptors, whihc stimulate renin release.
Angiotensin 2
Byproduct of renin release. Its a vasoconstrictor to stimulate aldosterone secretion.
Causes renal vasoconstriction on efferent arteriole.
Why are prostaglandins important?
Vasodilator of afferent arteriole
Why is angiotensin 2 important?
Constricts the efferent arteriole, which is important to cause that pressure for flow to occur through nephrons.
What are some roles of angiotensin 2?
Causes a negative feedback loop to inhibit further renin release.
Increases NE release to stimulate thirst, sodium appetite, and ADH secretion to increase BP and fluid retention.
Also helps with cell/tissue hypertrophy and cardiac remodeling after MI.
Why are ace inhibitors and ARBs so important for patients post-MI?
Patients with CHF and post MI are undergoing cell adn tissue hypertrophy and cardiac remodeling after MI.
ACEI and ARBs help stop this remodeling. By blocking process, you slow disease progression of the heart.
What does over activity of RAS lead to?
Over activity of RAS leads to HTN, CHF, and diabetic nephropathy – esp. when they have high pressures and sugars that push on glomerulus, which causes shredding.
Myocardial remodeling.
Why are ACEI important for diabetics with overactive RAS?
Helps diabetics to protect the kidney from nephropathy.
What happens when agents affects RAS system?
effects on morbidity and mortality.
What physiological actions occur with ACE inhibitors, what happens?
Decreased Ang 2 vasoconstriction bc less is made = decreased renal vasoconstriction, less synthesis of aldosterone = less sodium reabsorbed, less NE being send out, and less bradykinin metabolism.
All decrease blood pressure on the system. Will inhibit the negative feedback loop. May release renin, but won’t see much of an issue there.
Why do you have to be careful with patients on ACEI with renal insufficiency?
If you give them a full dose of ACEI at once, it makes a large dilation, which can decrease pressure of kidneys causing an acute kidney injury.
Even though its renal protective, want to start low and go slow so you don’t have a dramatic effect on the kidneys.
How are ace inhibitors used?
How are they eliminated?
Most are prodrugs. Must be metabolized by liver.
Active form is eliminated through kidneys, except fosinopril.
What ace inhibitor is not renally eliminated?
Fosinopril, eliminated throught the liver
What ace inhibitor doesn’t need to be activated by the liver?
Captopril and Lisinopril
What are the ACE inhibitors?
END IN --PRIL Lisinopril Captoppril Enalapril > Enalaprilat Benazepril > Benazeprilat Fosinopril > Fosinoprilat Trandolapril > Trandolaprilat Quinapril > Quinaprilat Ramipril > Ramiprilat Perindopril > Perindoprilat Moexipril > Moexiprilat Perindopril
Which ACE inhibitor comes in IV form?
Enalaprilat; already active so you inject into the vein and it works.
Benefits of ACE inhibitors?
Once daily dosing; good half life
What ACE inhibitor has a shorter half life?
Captopril; may be given twice a day
What do you do with shorter acting ACE inhibitors to get full 24 hour coverage?
Shorter acting agents may lose some effectiveness towards end of the day and you may need to give it twice a day to get full 24 hour coverage.
Ex: Lisinopril is usually given once a day, but might need it given twice a day for full coverage.
What’s the dose response trend of Ace Inhibitors?
Steep dose response at lower doses, which flatten out the higher you get.
Lower doses 5-10mg a day, you have a good decrease in BP, where 20-40 mg a day, you don’t see as big of a decrease in hypertension.
What are the therapeutic uses of Ace Inhibitors?
Hypertension to decrease TPR, systolic, and diastolic pressures.
Decrease LVH by relieving pressure and remodeling.
Post MI - decrease remodeling and decrease in mortality when given post MI.
Diabetic nephrophaty - decreases glomerular pressure and remodeling to prevent or delay progression of renal disease in diabetics. Also slows progression of renal disease in other nephropathies. Good for declining kidney function.
Why are ACE inhibitors preferred for diabetics?
preferred in diabetics, bc of kidney protective effect - helps slow the diabetic nephropathy for longer periods of time.
Why is it recommended for CHF and those with left ventricle dysfunction?
Decreases remodeling that occurs with hypertrophy.
Has decreased afterload by decreasing peripheral vascular resistance.
Decreased preload and cardiac ouput, which will delay progression of CHF.
How is CHF staged?
Based on symptoms - how much activity you can perform efore symptoms occur and function of heart activity.
By decreasing remodeling, you prolong the amount of time it takes to go to stage two, three, and four.
Decrease incidence of MI and hospitalizations.
Who should all receive an ACE inhibitor unless its contraindicated?
Those with left ventricular hypertrophy
What’s the cyclical process of Heart Failure?
Heart failure is from reduced CO, which leads to further SNS activity and vasoconstriction.
To respond to decreased CO, blood vessels want to clamp down to keep perfusion high. All lead to cardiac remodeling and increased Renin release.
ALL cyclical and feed into one another. Renin increases remodeling to keep cardiac function as good as you can for as long as you can.
What are the side effects of Ace Inhibitors?
Dry cough
Hyperkalemia
Orthostatic hypotension
Renal function impairment
What are more rare side effects of ACE inhibitors?
Angioedema - swelling in nose, throat, mouth, larynx, lips, and tongue. Causes airway closure. Due to bradykinin accumulation.
One third occur in first week, some first six months, or some years down road. Just cause on for two years, doesn’t mean that it can’t happen to them. Red flag is inspiratory wheeze!
Fetal morbidity and mortality - CI for pregnant patients bc it can lead to birth defects and fetal death.
Why do ACEI cause a dry cough?
Dry cough - due to inhibit of ACE which increases bradykinin in body, which attacks cough receptors in lungs. Starts a week to six months after therapy, but not related to the dose or the agent. Women are more susceptible. No chronic ailments, but affects quality of life.
Why do ACEI cause hypokalemia?
Hyperkalemia - bad for patients iwth poor kidney function. See reliable increase in potassium in patients, more pronounced when they have renal disease or are taking potassium sparing diuretics. Also done with aldosterone antagonists. Bad for potassium supplmenets, bc can have dangerous increase in it.
Why do ACEI cause orthostatic hypotension in elderly?
Orthostatic hypotension in elderly, especially with the first dose or upward titration. Give at night to sleep through bout and get used to over time. Also with CHF its more pronounced.
How do ACEI cause renal function impairment?
Renal function impairment - patients with renal disease whose blood flow is dependent on Ang 2. Giving tfull dose can drop GFR rapidly. Start low and titrate up with tolerance.
What meds decrease effects of ACEI?
NSAIDs can decrease effects of ACEI, because if you have ACEI work to decrease constriction on efferent arteriole, kidneys try to vasodilate on afferent arteriole.
ACEI decrease constriction on efferent arteriole and vasodilate afferent arteriole.
NSAIDs block, which makes kidneys take a hit in the middle.
Patients who can’t tolerate ACEI, have another group of drug with similar effects. What are they?
Angiotensin receptor blocker (ARBs).
Why are angiotensin receptor blockers used?
Ace Inhibitors block effects of ACE, but there’s other pathways for Ang 2 to be produced — by trypsin, cathepsin, and chymase.
Ang 2 works on ang receptors - AT1 and AT2.
Continues to increase BP.
What are the Ang 2 receptors and where are they located?
AT1 is expressed WIDELY in heart, endothelium, vascular smooth muscle and kidneys.
AT2 is expressed during development in fetuses.
Angiotensin Receptor Blockers MOA
When Ang 2 is made, it affects AT1 and AT2. ARBs have high affinity binding and slow dissociation = have good sustained blockade of AT1 receptors.
Will see vasodilation and renal vasodilation. Less aldosterone = less sodium reabsorption and less NE release to all lower the BP.
Similar affects that you see with ACEI.
What’s the difference between ARB and ACEI?
ARB reduce ang 2 at AT1 receptors and indirectly activate AT2 by increasing Ang 2 levels - By blocking receptors, body thinks its needs more Ang 2 and releases renin. Clinically, AT2 are stimulated, but may not be important.
ARBs don’t inhibit breakdown of bradykinin, which is a disadvantage for antihypertensives. Bradykinin cough might be a problem with ARB.
ACEI renal elimination, while ARB is bile and renal elimination.
What are the angiotensin receptor blockers?
Do not need to know prodrugs vs not, just be able to distinguish from ACEI.
ARB ends in -SARTAN
PRODRUGS - Candesartan, Olmesartan, Losartan, Azilsartan
NON - Eprosartan, Irbesartan, Telmisartan, Valsartan.
What are therapeutic uses of ARBs?
Mainly for HTN and in combination products with HCTZ (hydrochlorathiazide).
Who are thiazide diuretics good for?
Salt sensitive HTN patients
ACEI and ARBs are not as effective for salt sensitive patients. They can be mixed with thiazides for additional benefits.
Therapeutic uses of ARBs?
Left ventricular dysfunction, post MI, CHF, and diabetic nephropathy prevention.
Common side effects of ARBs?
Hyperkalemia in renal disease or K+ sparing diuretics.
Hypotension from first dose effect.
Acute decrease in renal function from drop in GFR.
Fetal morbidity or mortality – Do not give in pregnancy! 2nd or 3rd trimesters
Angiotensin Receptor Blocker key points!
Use low doses and titrate up to avoid acute renal failure from drop in GFR.
Do not cause cough (Main reason why you switch from ACEI to ARBs).
Angioedema has a lower incidence in patients with ARBs. (May switch from ACEI to ARBs - won’t have cross reactivity, bc there’s no build up of bradykinin with ARBs).
Why don’t you use ARB on pregnant woman?
Pregnant patient - Mom has AT1 and fetus has AT2, eventually there will be no AT1 to affect so it will continue to effect AT2.
Selectivity is never absolute and will see cross reactvity with receptors.
Where are L type calcium channels located?
L type - Found in sarcolemma within vascular smooth muscle of the heart, cardiac myocytes, and cardiac nodal tissue (SA and AV nodes). Important to cause muscle contraction.
By blocking L type, see decrease in smooth muscle and myocyte contraction.
What are the groups of ligands for L-type calcium channels?
Dihydropiridines
Nondihydropiridines (phenylakylamines and benzothiazepines).
Heart physiology
SA node and AV node are primary pacemakers in heart.
By blocking Ca channels, you decrease automaticitiy, which will cause heart rate and contractility to go down.
What is the role of calcium in SA node and AV node?
SA and AV nodes are slow response cells that have a “natural leak” to allow sodium to come in.
Big influx of calcium occurs at action potential. By decreasing amount of calcium to get into the heart, you have a decreased peak of contractility and automaticity.
What is the role of calcium in myocytes?
Non-pacemaker cells (or fast response cells) - By blocking calcium, there’s less influx into cell. Calcium enters myocytes, which is important to interact with sarcoplasmic reticulum to initiate muscle contraction.
Blocking the Ca influx will decrease contractility of the heart.
How do calcium channels in myocytes lead to a muscle contraction?
Fast response cells - When action potential comes along, it opens L type calcium channels, to activate the sarcoplasmic reticulum, which releases calcium and allows contraction to occur.
During recovery, calcium goes back to SR and heart has channels to reset (get calcium out of cell).
When you block calcium channel from SR, not as much gets out so the contraction isn’t as strong.
Blocking Ca in Myocytes
Less calcium from SR = less Ca gets to myocyte, so less contraction occurs. Contraction not as hard.
How do calcium channels work in the vascular smooth muscle?
What happens when calcium channels are blocked in the blood vessels?
Smooth muscle surrounds blood vessel - Calcium comes in and is released from SR to cause vasoconstriction.
Inhibiting Ca influx causes vasodilation instead (antihypertensive effect)
What do CCB do to veins?
At therapeutic doses, they’re ineffective at decreasing venous tone. Not a lot of effect on vein.
Because they can affect arteries - they decrease the afterload (afterload = arteries), which is the amount of pressure the heart is pumping against.
Won’t have an effect on preload with therapeutic doses.
Why do you avoid CCB in heart failure patients?
Avoid, because CCB is a cardio depressant.
What is the main difference in calcium in arterial blood vessels vs. myocytes?
Myocardial cells depend on exogenous calcium from L type channels to come out and recirculating internal pool of calcium to be released from sarcoplasmic reticulum.
Arterial blood vessels depend on exogenous calcium from L type channel, but they are three to ten times more sensitive to actions of CCBs than myocardial cells.
Divide between DHP and Non-DHP - DHP work on blood vessels, but not directy depressant effects. Non-DHP work on heart and blood vessels.
Non-DHP
Reduce slow inward current and decrease rate of recovery to slow AV conduction. Work on the heart.
DHP
Reduces slow inward current, but does not affect nodal tissue; works on blood vessels.
What are therapeutic uses of CCBs?
Angina, HTN, supraventricular arrythmias, diastolic heart failure, and rare cases of cerebral ischemia and migraine prophylaxis.
What are the non-DHP drugs and what do they do?
Non-DHP - Dilitiazem and Verapimil
Okay affect on vasodilation, but primarily depress automaticity in AV and SA nodes.
What are the DHP drugs and what do they do?
DHP - work on vasodilation and have negligible affects in cardiac cells.
Dilitiazen
Non-DHP; available IV or PO.
Controls supraventricular arrythmia, Afib, angina, HTN and supraventricular tachycardias.
Dilitiazen PK
Metabolized by CYP3A4 and will inhibit CYP3A4.
Short half life, so when given IV it has to be a CONTINUOUS infusion or an extended release product PO.
Dilitiazem ADR
Lots of bad affects which is why they aren’t first line for HTN management.
Vasodilation = Flushing, headache, hypotension, peripheral edema. Negative inotropic of Non-DHP effect can cause first degree, AV block, bradycardia, and exacerbations of CHF.
GI - Can lead to constipation and affects smooth muscle by slowing down. More related to decrease perfusion, esp. in older patients. Drowsy, dizzy, depression.
May have sexual dysfunction, gynecomastia, and GINGIVAL HYPERPLASIA.
What medicine causes gingival hyperplasia?
Dilitiazem
Contraindication to using dilitiazem
Advanced heart block, hypotension, heart failure, liver disease, GERD
GERD - esophageal sphincter isn’t tight enough and meds relax smooth muscle and make it loser and worse.
Dilitiazem (and Verapimil) Drug RXNs
CYP3A4 inhibitor, which affects statins, carbamazepine, propanolol, tacrolimus, and cyclosporine.
Also a CYP3A4 substrate, so can be affected by other 3A4 inhibitors - atazanavir (HIV med) that inhibits CYP3A4 and increases levels of Dilitiazem.
What drugs affect Dilitiazem?
Ritonavir, Indinavir, Saquinavir, and Atanzavir.
-AVIR
Other antihypertensives or cardio depressives could affect as well, synergistically.
What is Verapimil used for?
Available IV or PO and sustained release for longer duration of action – used for angina, HTN, Afib, and paroxysmal supraventricular tachycardia.
Exact same as Dilitiazem!!! But may have more vasodilation and suppression in automaticity of SA node and AV node.
Verapimil PK
Inhibit CYP3A4 and substrate for it as well.
Can see reactivity with CYP2C9, but not as often as CYP3A4 inhibitions do.
Verapimil ADR
Constipation is more pronounced, other side effects similar to dilitazen.
Peripheral vasodilation, negative inotropic effects, nausea, vommiting, dyspepsia, abdominal pain, elevation in liver function tests, CNS effects, gynecomastia, sexual dysfunction, GINGIVAL HYPERPLASIA, skin reactions.
Contraindication of Verapimil
Advanced heart block, hypotension, heart failure, liver disease and GERD
Same as dilitiazen as well.
Verapimil Drug Interactions
Substrate and inhibitor of CYP3A4.
PGP - drug efflux pump in GI tract to kick out and prevent absoprtion. By inhbiting PGP there’s increased levels of the drug being absorbed into system.
What drugs affect Verapimil?
Indinavir, Ritonavir, Saquinavir, Atazanavir, Itraconazole, Cimetidine
Similar to Dilitazen.
What are the commonly used DHP? Which is IV form?
Amlodipine (long half life) Nifedipine (short half life) Nicardipine (few available IV form) Felodipine Isradipine Nisoldipine
DHP end in –IPINE
What are DHP used to treat?
Dihydropyridines treat angina and HTN; not used for supraventricular arrythmias, because they DO NOT AFFECT NODAL TISSUE. Only the vasodilation of vasculature.
What is used to treat subarachnoid hemorrhage?
Nimodipine (DHP) - help prevent vasospasm in CNS after hemorrhage.
Why do you avoid short acting formulations of DHP drugs?
Drugs are so potent, you want to avoid short acting formulations. Blood pressure will drop fast and rebound back up. Use extended release prep or drugs with longer half lives.
What’s the primary activity of DHP drugs?
Vasodilation is primary activity of DHP drugs!
How are DHP metabolized?
Metabolized by CYP3A4, but DO NOT inhibit CYP3A4 like Verapimil and Dilitiazem. DHP will not cause increase in other drugs bc it doesn’t inhibit CYP.
Metabolism can be decreased by grapefruit juice.
How do pharmacokinetics vary between DHP drugs?
Half life changes widely in DHP drugs.
Nifedipine is a poor short acting agent, bc it has short half life and duration of action ~1.8 hrs.
Amlodipine is good once daily, bc it has a longer half life ~35 to 50 hrs.
DHP adverse effects?
Vasodilation is more potent.
Worsened peripheral edema (esp in CHF or PVD), gynecomastia being worse with Nifedipine, gingival hyperplasia.
**Reflux tachycardia from heart wanting to pump harder from vasodilation.
Patient overdosed on unknown cardiac agent. If HR is 140 and hypotensive, what did they overdose on?
Tachycardic and hypotensive - CCB like DHP.
Bradycardic and hypotensive – Dilitiazem.
What drug causes really bad gynecomastia?
Nifedipine - worst drug for that. Worse than Dilitiazem.
Who do you not want to give DHP drugs to?
Severe aortic stenosis, unstable angina, or recent MI. Immediate release can lead to huge drop in blood pressure leading to ischemia of the heart.
What drugs with DHP might synergistically lower BP?
Amiodarone, Digoxin, and Beta blockers can have a synergistic drop in BP.
Won’t see cardiodepressant effects, bc not working on heart as much.
What drugs affect DHP drugs? Why?
Can be affected by CYP3A4 inhibitors, which can cause toxicity, but do NOT inhibit themselves.
Indinavir, Ritonavir, Saquinavir, Atazanavir, Itraconazole, Cimetidine ~~ can cause increased levels of DHP.
-AVIR drugs.
Beta blockers MOA
Competitive inhibitors, primarily see their effects on B1 receptors of the heart. They block normal substances that activate beta receptors (Epinephrine, Norepinephrine, Dopamine).
Block will decrease cardiac output and an acute increase total peripheral resistance as they acclimate to decreased CO.
Can also see impaired exercise tolerance. Blocking receptors, when you run, body can’t pick up heart rate bc NE won’t bind.
How do Beta Blockers affect renin release and Angiotensin 2?
Can see competitive blockade of receptors that mediate renin release, which lower ang 2 and blood pressure.
What happens if Beta Blockers block B2 receptors in lungs?
In lungs, non selective BB could have competitive blockade of B2 receptors, which will increase bronchoconstriction. Bad for asthmatics!
What affects do Beta Blockers have on CNS?
CNS activity when lipid soluble - depresses SNS; may cause depression and migraines.
Altered baro-reflex response.- can develop orthostatic hypotension.
How do beta blockers affect presynaptic B2 receptors?
Nonselective - Blockade of presynaptic B2 receptors decreases NE release.
How do Beta Blockers differ in selectivity, metabolism, and dosing?
Beta blockers can be selective to B1, B2, or can be nonselective affecting both.
Metabolized by liver and kidney, but don’t normally need a dose adjustment.
Beta blockers have intrinsic sympathomimetic (ISI) activity. What does this mean?
A partial agonist affect, which can lead to seizures, asthma exacerbations, heart failure, and bradycardia.
What does membrane stabilizing beta blocker do?
Membrane stabilizing activity stabilizes the myocardium of the heart to stop reentrant rhythms.
First Generation BB
Non-selective
Second Generation BB
B1 selective
Third Generation BB
Grab bag of misc effects.
Cause direct vasodilation by blocking A1, making NO, B2 agonist, calcium blockade, etc.
Non-selective Beta Blockers (First Generation)
Affect B1 and B2 receptors;
Nadolol, Penbutolol, Pindolol, Propranolol, Sotolol, Timolol
Selective (A-M)
Non-selective Beta Blockers (N-Z)
KNOW EXCEPTIONS
Propranolol
High lipid solubility; want to avoid in elderly so you avoid altered mental status.
Prevents stage fright and anxiety.
Selective B1 Blockers (Second Generation)
Affect B1; acebutolol, atenolol, bisoprolol, esmolol, metoprolol.
Esmolol
IV only
Good short acting antihypertensive used in ER.
Metabolism of B1 Blockers: Acebutolol Atenolol Bisoprolol Metoprolol
Acebutolol - Both
Atenolol - Renal
Bisoprolol - Hepatic
Metoprolol - Hepatic
3rd generation B Blockers
Carteolol
Carvedilol
Labetalol
Betaxolol
What 3rd generation BB used in glaucoma?
Carteolol and Betaxolol
What BB are used for systemic HTN? Why?
Carvedilol - has additional affects; a1 blockade. By blocking, cause vasodilation and decrease BP.
Labetalol - IV for BP management; blocks a1 and activates B2 - relax bronchi and vasodilate vessels.
Who do Beta Blockers work best on?
HTN (not first line) - First line = ACEI or thiazide diuretics.
Works best in younger patients with increased catelcholamines, tachycardia, etc. Can cause fatigue and limit exercise tolerance.
»Not a first line agent for elderly.
Mean arterial pressure
(1/3 * sytole) + (2/3 * diastole)
How do beta blockers work long term?
Acutely, there’s a decrease in CO, which leads to compensatory increase in TPR.
Chronically, you decrease Ang 2 and NE release. Over time, altering baroreceptor reflex, you have a decrease in MAP, sustained decrease in CO, and long term decrease in TPR.
What B blockers are used to treat glaucoma?
Timolol, Betaxolol, Carteolol
Decrease AQ humor
What B blockers are used to treat migraine prophylaxis?
Propranolol and Timolol
Low dose to help vasospasms.
What B Blocker treats hyperthyroidism (thyrotoxicosis)?
Propranolol; inhibits conversion of T4 to T3.
Used to reduce tachycardia, tremor, anxiety.
Main Clinical Uses of BB?
Glaucoma, migraines, hyperthyroidism, angina pectoris (myocardial ischemia), acute MI, supraventricular arrythmias, panic attacks, tremors
Why does myocardial ischemia occur?
Ischemia is due to too much oxygen demand from myocardium and not enough supply.
Decrease CO and work heart is doing to allow for more blood flow to get to the ischemic areas.
When treating acute myocardial infarction with beta blockers, what should you avoid?
Beta blockers with ISA activity; don’t want to activate those receptors.
Protects myocardium from NE/EPI. Protects ischemic myocardium by blocking receptors. Decreases mortality.
How do beta blockers treat supraventricular arrythmias?
Afib, PAT, PSVT, PVC
Block the AV node to slow transmission.
How do you treat a benign essential tremor?
Blockade of B2 receptors on skeletal muscle.
Non-selective Beta Blocker. Selective won’t affect B2 receptors.
What beta blockers treat CHF, specifically?
Start in hospital and titrate up slowly as they tolerate it.
Carvedilol
Metoprolol
Bisoprolol
Don’t give a cardiodepressant or DHP.
They have impaired left ventricular function, so by slowing the heart down, you can fill better and have a more controlled squeeze.
How do beta blockers affect asthma and COPD?
Bronchoconstriction is a concern with nonselective BB, can lead to asthma exacerbation and COPD pts. Less likely with B1 selective blocker for asthmatics.
Cardiodepressive actions, which worsen negative inotropy, bradycardia.
How do beta blockers affect Type 1 Diabetics?
Type 1 - When there is decreased glucose in blood stream, body increases EPI to have glycogenolysis. Allows gluconeogenesis to take place and increase glucose in blood.
Beta blockers will block B receptors in liver, which block glycogenolysis, prolonging hypoglycemic episode.
Responses are masked by BB. Might not notice for a while.
How do beta blockers affect Type 2 Diabetics?
Type 2 - Have decrease insulin release leads to increased glucose in blood stream.
When hypoglycemic, signs are masked.
How do BB cause impaired peripheral circulation?
BB blocks B2 receptors in blood vessels that are normally vasodilatory, cause constriction, which can lead to raynauds, muscle fatigue, and worsening of peripheral arterial disease.
Also cause elevated triglycerides.
If on BB, why do you never want to have an acute withdrawal of drug?
If you block B receptors, they start to upregulate.
If there’s more receptors and you takeaway drug, EPI affects more receptors leading to increased cardio effects.
— Acute angina, MI, increased BP.
High CNS solubility of BB leads to?
Chance for depression, nightmares, vivid dreams, hallucinations, fatigue.
> > Propranolol
More lipid soluble, worse it will be.
What happens when you give CCB with beta blocker?
Mix with CCB, both have cardiodepressive affects.
What happens when you give clonidine with BB?
Clonidine, leads to decreases in BP and withdrawl.
A1 adrenergic antagonists MOA
Block A1 to cause vasodilation and hypotension. Decreases TPR and get reflex increase in HR.
What do A1 receptors normally do?
Normally constrict vasculature.
When you block cause vasodilation and hypotension.
Prazosin
A1 antagonist
Not used frequently; added as third or forth agent to BB and diuretics or when CI to BB, CCB, etc.
Prazosin ADR
Orthostatic HTN
Postural dizziness
Mild reflex tachycardia - related to decreased TPR.
Increased renin, increase sodium and water retention.
Blocking alpha receptors leads to impotence in males.
Interactions with Prazosin
NSAIDs reduce the response.
BB may worsen postural hypotension.
Be careful with cardiac and renal failure. Can worsen bc of the vasodilation.
Terazosin
Doxazosin
A1 selective agents used as antihypertensives and to help with benign prostatic hyperplasia.
Less alpha constriction leads to relaxation and better urine outflow in BPH.
Longer half life, once daily dosing.
-ZOSIN
Tamsulosin (Flowmax)
A1A selective antagonist, which is expressed on prostate. More specific and limits vasodilation.
Better agent for BPH.
Labetalol
Carvedilol
Can block A1 effects, which is an additive to antiHTN effects.
Central Sympatholytics
By stimulating post synaptic A2 receptors and imidazoline receptors; they cut amount of NE and EPI being released by CNS.
Works on HTN from top down.
What sites do central sympatholytics work?
Nucleus of solitary tract and ventral lateral medulla.
By activating receptors decreases sympathetic nerve activity.
What is clonidine? How does it work?
Clonidine is central sympatholytic.
By decreasing SNS effect; also decreases CO and vascular smooth muscle to lead to hypotension.
What hemodynamic effects are seen in central sympatholytics?
Decreased TPR
Decreased HR
Decreased CO
Advantages of Central Sympatholytics
Decreased TPR and modest decrease in CO (no reflx cardio output like DHP).
Efficacy independent of age, race, gender
Works well in elderly
No negative effects on lipids
Side effects of central sympatholytics
Drowsiness, sexual dysfunction
Narrow therapeutic index so dose change can lead to big changes in BP and CO. Kids are sensitive.
Abrupt withdrawal syndrome - by blocking release of those catelcholamines, you uprgulate receptor which has big increase in HR.
Clonidine
Central Sympatholytic
What does it do?
A2A agonist, imidazoline agonist - Acute increase in BP. Can activate A1 and cuase vasoconstriction, but short-lived. Will see decreased BP and HR in long term.
Why does clonidine increase blood sugar?
Increases blood glucose bc decreased insulin release. Also causes sedation.
Why should clonidine be given with diuretics?
Decreased ADH secretion.
Causes sodium retention, so should be given with diuretics.
What’re two other unique uses of clonidine?
Analgesic activity for surgery. Anesthetic with clonidine to decrease use of opioids post op. Causes sedation.
Helps with opioid withdrawal, esp in neonate abscence syndrome.
Clonidine ADR
Withdrawal reaction
Orthostatic Hypotension
Impotence
Bradycardia
Guanfacine (Tenex)
Less potent than clonidine, selective for A2 receptors. Less sedation. Could have withdrawal.
Kids with ADD can be on a stimulant in the morning and use this to calm down at night.
What do direct acting vasodilators do?
Direct vasodilators work on arteries to cause dilation and decrease TPR. Last line agents for HTN, bc they have reflex sympathetic activation.
Increase CO, fluid retention, renin, and tachycardia. Can lead to tachyphylaxis.
Tachyphylaxis
Process in which you are tolerant to a drug so you have to keep increasing the dose to see effects. Heroine abusers need more heroine to get high.
In tachyphylaxis, you keep increasing your dose but you see no increased effect. Can increase anti-HTN and have no effect.
What are the direct acting vasodilator meds?
Hydralazine
Minoxidil (Rogaine)
Nitroprusside
Diazoxide
When bigger affects on arteries, you see more tachycardia, sodium, and water retention. What direct acting vasodilators is this seen in?
Minoxidil and Diazoxide
For chronic HTN, what direct acting vasodilator would you use?
Hydralazine with diuretic or beta blocker.
Hydralazine is good for acute bouts of HTN via IV. Minoxidil as well.
For patients having a hypertensive crisis, what direct acting vasodilator would you use?
Nitroprusside
Diazoxide
Fenoldopam
Cause vasodilation to decrease HTN immediately.
Hydralazine MOA
Increases cGMP to increase nitrous oxide pathway. Causes good vasodilation.
Blocks effects of calcium, works through nitrous oxide to increase cGMP, which causes vasodilation in smooth muscle.
How is hydralazine metabolized? How does this affect the drug levels?
Undergoes hepatic metabolism called acetylation. Can be fast or slow.
Slow acetylators have increased drugs in the body, bc not metabolizing fast.
Fast acetylators have levels go down more quickly.
Who is more likely to have treatment failure for treatment of HTN with hydralazine?
Fast acetylators, because levels go down quickly.
Hydralazine ADR?
Lupus like rash can develop in those who are slow acetylators. – Happens with high doses, long term use, women, caucasians, and slow acetylators.
Isoniazide ADR
In slow acetylators, cause Lupus like rash.
When is hydralazine contraindicated?
Coronary artery disease, elderly, and ischemia.
What is something you should tell a patient when prescribing hydralazine?
Stools may turn black.
Minoxidil MOA
Activates ATP modulated potassium channels, which lets potassium out to hyperpolarize and prevent smooth muscle from contracting.
Minoxidil ADR and use?
Can cause arrythmia, myocardial ischemia, and hair growth (hypertrichosis).
Marketed topically for hair growth now due to systemic effects. If applied in large quantities, can see cardiovascular effects. Don’t let kids get into it.
Nitroprusside
Good agent IV for hypertensive crises. Has 1 nitrous oxide particle to vasodilate and has 5 cyanide molecules.
Body makes some cyanide, so its not abnormal. Body can metabolize, but if you have a patient with poor renal function or high dose it can cause toxicity.
Nitroprusside ADR
Trembling, vomitting, convulsions, acidosis
Can combat by giving with sodium thiosulfate, which donates sulfur molecules to liver to process cyanide better.
Patients with renal toxicity can build up thiocyanate and develop toxicity. Not a good drug for those with poor renal function.
Fenoldopam
Dopamine agonist to stimulate cAMP. Good for renal natriuretic and diuretic properties to manage short-term blood pressure.
Fenoldopam ADR
dysrhythmias
How do we treat HTN?
JNC 8 Guidelines - Goal BP is less than 140/90.
If you have a black patient with or without diabetes, how does JNC 8 guideline say to treat?
Thiazide diuretic or CCB
DHP - amlodipine
More salt sensitive patients - respond better to TD and CCB.
If you have a NON- black patient with or without diabetes, how does JNC 8 guideline say to treat?
Start thiazide diuretics, CCBs, ACEI or ARB dependent on other disease states.
If you have a chronic kidney disease patient with or without diabetes, how does JNC 8 guideline say to treat?
ARB or ACEI, because they’re nephroprotective.
If goal BP isn’t achieved in one month, what does JNC 8 say to do?
Increase dose of drug or add a drug from another class.
Don’t use ARB and ACEI at same time. Need two different types of classes of drugs.
Ischemic Heart Disease
Imbalance between myocardial oxygen supply and demand. Demand out strips supply and have signs of ischemia in cardiac tissue.
Coronary Heart Disease
Atherosclerotic narrowing of one or more arteries. Can lead to unstable angina or acute MI.
Angina Pectoris
Clinical manifestations of MI > chest pain.
Pathophysiology of Ischemic Heart Disease
Supply: Arterial hemoglobin conc of oxygen and coronary flow and distribution. Cardiac extraction of O2.
Oxygen requirement: wall tension, heart rate, and contractility affect.
What affects oxygen demand of the heart in IHD?
Heart rate, contractility, and wall tension affect oxygen demand of heart.
Wall tension is function of preload and afterload.
Preload
Initial stretching of myocardiocytes prior to contraction. Can be related to ventricular and diastolic volume.
Afterload
Pressure heart must pump against, related to systemic vascular resistance.
As you have atherosclerosis, big plaques form and can cause major blockage of arteries.
Angina
Latent manifestation of ischemia that can occur with any degree of stenosis. Usually due to vasospasms.
Can see when 50% of left main is occluded or 75% of other major coronary arteries being blocked.
Can see in stenosis.
Stenosis
Defined as 90% blockage of artery with virtually no flow.
Prinzmetal Angina
A vasospastic or variant angina that occurs in younger patients. Usually due to an issue with autonomic control where SNS clamps on coronary arteries.
Can be so severe you see ST segment elevation (rare) and occurs at night or early morning hours.
Non-modifiable risk factors (Angina)
Family history of premature CV event.
Age over 45 for males and 55 for females.
Modifiable risk factors (Angina)
Sedentary life, diabetes, tobacco consumption, overweight, HTN, dyslipidemia.
Treating angina
Increase quantity of life by preventing acute coronary syndrome and increase quality of life by relieving symptoms.
Treatment Strategies of Angina
Decreasing the myocardial demand by decreasing heart rate, contractility, and wall tension to decrease preload and afterload.
Increase the myocardial oxygen supply to improve coronary blood flow and stabilize plaques to prevent acute coronary syndrome.
Treatment Plan of Angina
Reestablish flow through vessels by revascularization, via percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) to keep the vessel open and prevent re-stenosis.
Pharmacotherapy - Antianginals like beta blockers, calcium channel blockers, nitrates.
Vasculoprotective meds like antiplatelets, statins, ACEI.
What drugs will decrease HR, contractility, and systolic wall tension?
CCB, nitrates, and beta blockers
What drugs will increase coronary blood flow?
CCB, nitrates, aspirin, clopidogrel
Anti-PLT: aspirin and clopidogrel
Antianginal medications
Work to improve exercise capacity and reduce exercise induced ST segment changes. Decrease frequency of symptoms.
Beta blockers, CCB: DH and, nonDHP, and nitrates.
Grades of Angina
Depends on degree of symptoms on exertion.
Beta Blockers affect on Angina Treatment
On demand, decrease HR, contractility, and wall tension.
No effect on oxygen supply, because cause no coronary artery vasodilation.
Beta Blockers place in therapy for Angina?
First line in absence of contraindications.
Useful for patients with limited exercise capacity from angina, preexisitng heart failure, and post MI to prevent mortality.
Which beta blockers are best for angina treatment?
May use beta 1 selective or non-selective agent. B1 selective is better for asthmatics.
B1 selective: metoprolol, atenolol
Nonselective: propranolol, nadalol
Third gen: carvedilol, labetalol
Contraindications of Beta Blockers?
HR under 60bpm
Systolic BP < 100mmHg
AV block
Acute decompensated heart failure
Precautions with beta blcokers?
reactive airway disease, systolic heart failure, diabetes, and peripheral vascular disease.
ADR of beta blockers?
Hypotension, bradycardia, hyperglycemia, dyslipidemia, fatique, sexual dysfunction, worsened claudication
Which Beta Blocker causes nightmares?
Propranolol
What type of Calcium Channel Blockers has best effect at dropping HR and contractilityy?
non-DHP - Verapimil and Dilitiazen
Demand: Decrease HR, contractility, and tension. Might have slight increase in HR but will decrease wall tension to affect preload and afterload.
Supply: Might see mild dilation increase of stenosis and relief of vasospasm for those with vasospastic angina.
Non-DHP calcium channel blockers, place in therapy?
Non-DHP are good initial therapy for reduction of symptoms when pt can’t be put on beta blocker or symptoms aren’t fully controlled.
NDHP go by themselves; DHP are prescribed with BB.
What population is non-DHP CCB used in?
Used for those contraindicated to beta blockers, treats vasospastic angina, asthma, uncontrolled diabetes and LV dysfunction.
In LV dysfunction, why do you want to avoid non-DHP?
Don’t want to further depress function.
Calcium Channel Blockers are contraindicated when?
BP less than 100 systolic, HR less than 60bpm, acute heart failure, ejection fraction and AV block.
Precaution when using beta blockers and CYP 3A4 interactions.
Which CCB have CYP3A4 interactions?
Non-DHP verapimil and dilitazem
Inhibit CYP3A4 and are metabolized by it.
CCB ADR
Hypotension. DHP can cause headhace, flushing, and peripheral edema.
START OF CARDIOLOGY 4 CARDS
START OF CARDIOLOGY 4 CARDS
Nitrates MOA
Nitrates donate nitric oxide to stimulate production of cyclic GMP. – Guanosine triphosphate to cyclic guanosine monophosphate. – Help increase activity of protein kinase G to decrease cytostolic calciucm. By decreasing calcium released in cell, smooth muscles will relax and vasodilate. Lowering BP!
cGMP is normally broken down by PDE5 to decrease amount of cGMP there. Important drug interaction with erectile dysfunction meds, which work to inhibit PDE5. Might see synergistic effect which elads to increase cGMP and leads to synergistic vasodilation and decreases in BP.
Short acting nitrates
Used for relieving acute symptoms of MI and aren’t meant to be for long term control of symptoms.
Sublingual tablets and sprays. Absorbed by mucosa in mouth, not the GI tract. Used at onset of angina and every 5 mins. If no relief after first dose, call EMS and continue to use every 5 mins.
Patient Education of Short Acting Nitrates
Sitting or standing enhances effect.
Store in original packaging in a cool and dry place, because nitroglycerin is easily broken down. Need an amber vile to stop light from destroying it.
Replace tablets three to six months after opening to make sure they’re in tact.
Must spray under the tongue.
Long acting nitrates
Used to help control symtpoms from occuring in long term control. Used as back up agents while CCB or BB can’t be used or aren’t well tolerated.
If CCB or BB haven’t been working, you can add a long acting nitrate. Shouldn’t be a single therapy unless all others are contraindicated.
Long Acting Nitrate names?
Isosorbide mononitrate (Imdur) - lasts 12 hours, dosed daily.
Isosorbide dinitrate - duration three to six hours, dosed three times daily.
Patient education for long acting nitrates?
Comes in ointment and transdermal patch.
Ointment is applied with a wax backed card that prevents it from being transmitted to healthcare provider.
Transdermal patch - 12 hours on, 12 hours off. Same with ointment; want to avoid tachyphylaxis!
Long acting nitrates ADR
Headache, flushing, hypotension, reflex tachycardia.
Heart responds by increasing cardiac output which causes tachycardia.
Tachyphylaxis of nitrates
If you have a nitrate on 24hrs a day, body won’t be able to maintain hypotensive or vasodilatory effect. Even if dose is increased. You will not see an increase in its efficacy or activity, which is why you need a nitrate free period.
Nitrate free period is when patients have lowest symptom frequency. Nitrate free period is usually overnight.
Contraindications to nitrates?
Aortic valve stenosis, obstructive cardiomyopathy, and concurrent use of erectile dysfunction medications. BAD.
Viagra, Cialis, Levitra – When used with nitrates, concurrent use can lead to HTN, MI, or stroke.
Angina
Comoribidty: HTN
Whats the first line?
What do you avoid?
1st line - beta blocker; non-DHP is a good alternative.
Angina
Comorbidty: Prior MI
Whats the first line?
What do you avoid?
1st line is BB.
Avoid calcium channel blockers.
Angina
Comorbidty: LV dysfunction
Whats the first line?
What do you avoid?
First line treatment is Beta Blockers or Amlodipine.
Avoid other CCBs.
Angina
Comorbidty: Bradycardia and AV block
Whats the first line?
What do you avoid?
First line treatment is DHP CCB.
Alternatives include long acting nitrates.
Avoid NDHPs and BB.
Angina
Comorbidty: Diabetes
Whats the first line?
What do you avoid?
Frst line in Non-dhp or can use a long acting nitrate or cardioselective BB.
Avoid nonselective BB because it causes hyperglycemia.
Angina
Comorbidty: Asthma
What’s the first line?
What do you avoid?
Treat with non-DHP and cardioselective BB.
Avoid nonselective BB in asthmatics.
When are ACEI used in angina patients?
ACEI - good for patients with CAD, diabetes, or left ventricular systolic function.
Prevents remodeling and progression of diease. Protective effects decrease mortality in long run.
If patients can’t control angina symptoms with one therapy, like BB or non-DHP CCB, what can you do?
Optimize dose and raise or add an additional long acting nitrate on a BB. Combination therapy.
Third agent shoudn’t be needed. Do a further work up via angiography.
Anti-Platelet Medications and Uses?
Aspirin
Clopidogrel
Prevent blockages of arteries when theres’ atherosclerotic plaques. PLT can often get stuck here and cause a clot.This can prevent it from occurring.
Aspirin
Decreases recurrence of acute coronary syndrome.
Clopidogrel
Anti PLT agent - put patients on a drug like this if they can’t take aspirin.
Treatment strategy for patient with anginal symptoms - SUMMARY
Unless contraindicated, patient should be on aspirin.
If they’ve had a prior MI, should be on beta blocker.
If they have any DM or LV dysfunction, should be on an ACEI. “Renal protective effects”.
Look at lipid lowering therapy when appropriate. See who benefits from statins.
Sublingual nitroglycerine is used for acute relief.
Recurrent symptoms you can use prophylactic therapy with BB, CCB, or long acting nitrates.
Wha treats vasospastic angina?
Amlodipine
Avoid beta blockers, because they lead to worsened symptoms.
Hemostasis
Blood should remain fluid within vessels.
Should be able to clot quickly when there’s an injury.
If thrombi occur, must be able to reestablish fluidity.
Vascular injury physiology
Vascular injury leads to vasospasm, done through mediators like TXA2 through arachodonic acid pathway.
Limits blood flow to area and forms a platelet plug activated by collagent and mediators.
Forms a fibrin clot from tissue factors.
When done, fibrinolysis occurs, where clot is broken down by plasmin and vessels are normal.
Glycocalyx layer
Smooth part of endothelial surface has a mucopolysaccaride layer to prevent clotting cascade.
What is present on surface of cells to bind thrombin and activate protein C?
Thrombomodulin; binds thrombin and activates protein C, which inactivates clotting factors five and eight.
Protein C
Natural anticoagulant that inactivates factor five and eight.
Antithrombin III
Circulates in blood to bind to thrombin and inactivate it.
Heparin
Body produces this. Binds to Antithrombin III and kicks it into over drive to increase activity 1000 fold to deactivate factors 12, 11, 10, and 9.
Prostacyclin
inhibits PLT activation
Thromboxane
stimulates PLT activation
Plasmin
Digests fibrin, inactivates factors 5, 8, and 12.
Platelet activation process
Collagen is exposed through injury; see Von Willebrand factor bind to collagen and release TXA2 and ADP.
When interact with PLT, it causes conformational change exposing new receptors GPIIb/IIIa.
Fibrinogen binds to receptors to form platelet plug.
Thrombin, factor 2, interacts with receptors to sitmulate PLT activation. ADP activates receptors to further activate PLT
What inhibit PLT activation?
At rest, things that include inhibition of PLT activation are prostacyclin secreted by endothelium. to stop clotting.
Collagen isn’t exposed.
Low levels of thrombin.
PLT don’t express the receptors on surface, so they can’t bind to each other.
Aspirin MOA
Irreversible inhibitor of all COX enzymes.
Acetylates COX1 and COX 2, which is irreversible for the life of the PLT. Also, prevent formation of thromboxine, which is a PLT activator. Inhibit COX1 prevents PLT from activation.
160mg/day has COX maximally inhibited.
How long does aspirin take effect on PLT?
Irreversible, 7-10 days.
Why aren’t NSAIDs used for cardiovascular protection?
Ibuprofen - 24hr Naproxen - 48 hrs Diclofenac - 48hrs Indomethacin - 48hrs Piroxicam - 72 hrs
Reversible; so have shorter duration of action for PLT inhibition than aspirin.
NSAIDs and Aspirin
Side Effects
Inhibiting COX1, see increase in Dyspepsia, GERD, PUD, and bleeding in GI. Bruisng might be more common.
Dipyridamole (Persantine)
Has vasodilation properties; combines with aspirin to form Aggrenox to prevent transient ischemic attacks and stroke, bc vasodilation and anti PLT activity.
How do ADP Receptor Blockers work?
P2Y1 and P2Y12 receptors?
When ADP reacts with P2Y1 receptor, it induces a conformational change leading to PLT aggregation.
When ADP reacts with P2Y12 receptors, it inhibits cAMP induced inhibition and leads to more PLT activation.
For PLT activation, you need to activate BOTH receptors.
Receptor blockers inhibit fibringoen and receptors. ALso interfer wtih the binding of von willebrand factor.
ADP Receptor Blockers names
Ticlopidine
Clopidogrel
Ticagrelor
Prasugrel
ADP Receptor Blocker MOA
Inhibit PTY12 receptor.
How long does it take to see effects of ADP receptor blockers?
Most have a delay in effects 2-3 days. Maximal effect at 8-11 days.
Loading dose is used to get to steady state quicker. Can be synergisticlally used with ASA.
When are ADP receptor blockers used?
Prevent stroke, MI, PAD, and post-angioplasty.
Given orally and good for long term use.
Ticlopidine
ADP receptor blocker; use is limited to those who can’t tolerate aspirin.
Its a prodrug thats hepatically activated.
Ticlopidine MOA
Binds disulfide bridge of P2Y12 receptor to inhibit PLT activation.
Ticlopidine ADR
Thrombotic thrombocytopenic purpura - AI reaction to drug; can cause death if not reated early.
Hemorrhage
Use is limited to those who can’t tolerate aspirin.
Clopidogrel
Prodrug; binds sulfur on P2Y12 receptor, synergistic with aspirin.
Hepatic activation; loading dose used.
Clopidogrel ADR
Hemorrhage; less risk of TTP. Better than Ticlopidine
Prasugrel ADR
ADP receptor blocker; similar to clopidogrel.
ADR include HTN, worsening hyperlipidemia, and bleeding risk.
Ticagrelor (Brilinta)
ADR?
Has a longer duration of action for ADP receptor blocker. Recommended over clopidogrel because it has more PLT inhibition.
ADR increased uric acid, bleeding, and dyspnea.
Abciximab (ReoPro)
Monoclonal antibody; protein that was formed against a specific target. Targetted against glycoprotein IIb/IIIa receptor.
Further blocks binding of PLT.Immediate onset and works 18-24hr after infusion is stopped.
Used intraoperatively or with acute coronary syndrome.
Abciximab ADR
Bleeding, thrombocytopenia
Repeated administration use you’re worried about patient developing antibodies against the treatment.
Eptifibatide (Integrillin)
ADR
Peptide inhibits fibrinogen from binding to IIb/IIIa receptors.
Continuous infusion for 96 hours and given with ASA and heparin to prevent stensosis.
ADR bleeding, thrombocytopenia.
Tirofiban (Aggrastat)
ADR
Non-peptide inhibitor. Renallly eliminated.
ADR include bleeding, bradycardia, and dizziness.
Name the glycoprotein IIb/IIIa blockers
Abciximab
Eptifibatide
Tirofiban
aPTT
Monitors intrinsic pathway.
PT
Monitors extrinsic pathway.
Factor 7
Factor 10
Both paths meet to factor 10, where prothrombin is activated to thrombin to form fibrin and make a stable clot.
Natural inhibitors of PLTs
Antithrombin III
Protein C and S
What’s Heparin?
Glycosaminoglycan; naturally occuring product found in mast cells in the body. Chains of varying lengths are formed. They attach to core protein.
Unfractionated Heparin MOA
Regular Heparin; helps antithrombin III cause breakdown of factors 2, 10, 9, 11, and 12.
Forms scaffold for binding antithrombin III to bind to factor more easily.
1000 fold increase when heparin is around.
Where is unfractionated heparin from?
How is it administered?
Heparin is extracted from porcine intestinal mucosa or bovine lung.
Given IV or subQ. Immediae onset of action.
Benefits of unfractionated heparin
Doesn’t cross placenta or BBB; also isn’t found in breast milk.
Heparin is preferred in pregnant woman.
Heparin dosing
Half life may be increased if patient has liver cirrhosis or renal failure.
How do you monitor toxicity and efficacy of heparin?
aPTT (activated partial thromboplastin time).
Patients aptt/normal aptt = Looking for therapeutic ratio of 1.5-2.5.
Indications to use Heparin?
Venous thrombosis, PE, MI, coronary angioplasty.
Main toxicity with heparin?
Major bleeding, but can be reversed with protamine to prevent heparin from interacting with antithrombin III.
Heparin induced thrombocytopenia (HIT) - Rare, 5-10 days after heparin infusion, antibodies are made to heparin and PLT factor 4. Works to activate PLT, which cause clots throughout the body and you won’t have any circulating PLTs left.
If your patient on heparin is having a major bleeding event, how can you fix it?
Protamine will bind heparin to stop its effects.
What is HIT?
Heparin induced thrombocytopenia (HIT) - Rare, 5-10 days after heparin infusion, antibodies are made to heparin and PLT factor 4. Works to activate PLT, which cause clots throughout the body and you won’t have any circulating PLTs.
Low Molecular Weight Heparin
Same drug, but has a shorter molecule. 5K daltons.
Use unfractionated heparin, but can enzymatically cleave the long monosaccaride chains to have a LWMH.
Names of LMWH
Enoxaparin (Lovenox) - used most frequently.
Dalteparin
Tinzaparin
Lovenox and LMWH MOA
Works on antithrombin III, but don’t affect IIa. Have greater effort against Factor XA.
Shorter chain is able to interact with antithrombin III and Factor XA. Factor 2A doesn’t fit to bind. That’s why it has low activity against it.
LMWH adminstration and dosing
SubQ as a fixed dose or weight adjusted dose.
To prevent DVT, standard dose of 40mg. To treat a clot, will be a higher, weight-adjusted dose. 60mg of Enoxaparin daily.
What do you monitor on LMWH?
Monitor Anti-factor XA Assay. Only need to monitor for renal failure or extreme weights.
Doesn’t affect aPTT because you’re not acting on IIa.
LMWH ADR
Less bleeding than heparin.
May cause HIT. Don’t give to patient with history of it.
Fondaparinux (Arixtra) MOA
Pentasaccaride that works on XA. Not IIa.
Fondaparinux Monitor? Administration? Elimination?
Could monitor Antifactor 10A assay.
Given Subcutaneously once a day.
Renally eliminated - make dose adjustments for renal patients.
Fondaparinux Benefits?
Lowest incidence of HIT, because its the shortest molecule to react with those antibodies.
Good for patients with history of HIT.
Fondaparinux uses? What reverses it?
Used for prevention of PE and treatment of active clots.
Protamine has no effect to reverse Fondaparinux effects.
Direct Thrombin Inhibitor Meds
Lepirudin
Bivalirudin
Argatroban
What are Direct Thrombin Inhibitors based off of?
Based off Hirudin, which is in salivary glands of leeches that inhibit thrombin (2A) itself.
Direct Thrombin Inhibitor MOA
Inhibit factor IIa itself. Can be monitored with aPTT.
If you needed a renal failure patient on a direct thrombin inhibitor, which one would you prescribe? Why?
Argatroban, hepatically excreted
If you have patients with hepatic failure, what direct thrombin inhibitors could you prescribe?
Lepirudin and Bivalirudin, because they’re both renally excreted.
When are direct thrombin inhibitors used?
Used in patients going into coronary angioplastly or patients with HIT to anticoagulate them until you can get them on a new therapy.
Warfarin
Mainstay for oral anticoagulation.
Racemic mixture, S-enantiomer is more potent.
Warfarin MOA
Vitamin K antagonist; that works to prevent recycling of Vitamin K, which inhibits active Vitamin K to liver to produce new clotting factors.
Factors II, VII, IX, X, protein C, and S will be inhibited to prevent formation of clotting factors. Less clotting factors in the blood means it’ll take longer to form clots in blood.
Results of Warfarin
Decrease in vitamin K dependent cofactors by 10-40%.
Does not work on existing clotting factors.
Why does Warfarin have a delayed onset?
Can’t act on existing clotting factors.
Don’t get therapeutic effect until 3 to 5 days after starting, because the body’s current factors need to be depleted first to get the warfarin effect.
What’s one of the first clotting factors Warfarin wipes out?
Protein C is the first one.
When you initially begin warfarin, you have a procoagulant effect bc you’re losing the protein C and its natural anti-clotting factors.
Why does warfarin first induce a hypercoaguable state for first 24-48 hours?
Because protein C is removed from the blood which loses an anticlotting protein.
How do you manage hypercoaguable state of warfarin?
Bridge with heparin until INR reaches appropriate level.
Take hearpin off and leave them on the warfarin.
Warfarin absorption and metabolism?
Given orally with 100% absorption.
Long half life. Metabolized in liver.
S warfarin - CYP2C9 (something inhibits it, you get increased effects).
How long does it take or warfarin to get to steady state?
3-5 days to get to steady state.
Warfarin is highly protein bound. What does this mean?
If another drug binds to albumen tighter, it causes warfarin levels to increase in the blood. Can lead to increased effects.
Why is it unsafe to use warfarin in pregnancy?
Crosses the placenta.
Possibly okay to use in breast feeding though.
What will decrease effectiveness of Warfarin?
As you increase intake of vitamin K, you decrease warfarin efficacy!
Don’t eat green leafy vegetables. Need to dose a person’s diet. Can’t change it or medication will be less effective.
What will increase effectiveness of Warfarin?
CYP2C9 inhibition
Protein binding interaction that beats warfarin.
Vitamin K increase, but then drop you see increase in warfarin.
Disrupt flora of gut; can have increase activity bc it could remove vitamin k. Antibiotics could do this.
How do you monitor Warfarin?
PT and INR
What does PT measure?
PT measures factors II, VII, and X.
INR
Inernational normalized ratio to calculate sensitivity index for good INR value.
Healthy = 1
Warfarin = Target 2 - 3
Valve replacement = 2.5 to 3.5
Warfarin sensivity
Have poor activity of CYP2C9, which cause high levels of warfarin. Happens in caucasians.
Warfarin toxicity signs
Bleeding - won’t happen if INR is in range. Reversal of bleeding is Vitamin K.
Can cause skin necrosis from protein C and S deficiency.
Causes birth defects in pregnancy.
What reverses bleeding of warfarin?
Fresh frozen plasma with Vitamin K to reverse warfarin.
Alternatives to warfarin
Bothersome to use Warfarin, because it was diet dependent and you had to monitor INR often. WIth so many drug interactions, it becomes problematic.
Alternatives were used so you could monitor less when on it.
Dabigatran
Rivaroxaban
Apixaban
Dabigatran (Pradaxa)
Oral direct thrombin inhibitor; works to prevent fibrinogen to fibrin and prevents activation of factors V, VIII, XI, and XIII.
Used for DVT, PE, and Afib.
No routine monitoring.
Downfall of Dabigatran?
No antidote to stop bleeding.
A monoclonal antibody can reverse it, but its expensive and not a lot of places carry it.
Rivaroxaban (Xarelto)
Oral product; inhibits factor XA. Used for DVT, PE, and Afib.
No routine monitoring is needed. Renally excreted but DO NOT NEED A DOSE ADJUSTMENT.
If patient is bleeding on Rivaroxaban, how do you reverse it?
Reversed with prothrombin complex concentration; this is just plasma and clotting factors.
Apixaban (Eliquis)
Oral Factor XA inhibitor. Used for DVT, Afib, PE. No monitoring needed.
If patient is bleeding on Apixaban, how do you reverse it?
Can be reversed with prothrombin complex concentrate.
What is Apixaban metabolized by?
What could happen with inducer/inhibition?
CYP3A4
If you have CYP3A4 inhibition board, you might have increased levels which lead to bleeding. If you have an inducer, you might see decreased effects and more clots.
Acute Coronary Syndrome
STEMI - completely occlusion of coronary vessel.
NSTEMI - Non STEMI and unstable angina (angina at rest).
Thrombus formation
In acute coronary syndorme, thrombus is formed in the coronary vessels. Coronary vessel with plaque, which occludes the vessels. When enclosed in fibrous cap, it doesn’t trigger a clot.
To begin thrombus formation, you need an endothelial injury to occur either spontaneously (where plaque ruptures) or a procedural injury (during a stent placement). Once you have exposed collagen, you have PLT activation, adhesion, and aggregation occuring. PLT bind by Willebrand pathway.
PLT are activated and expose IIa/IIIb receptors. Clot cascade starts. Fibrin strands form and it creates an occlusive thrombus, with very little flow.
What do you take during procedures to inhibit thrombus formation?
PLT inhibitors and direct thrombin inhibitors are used to prevent thrombus formation..
What is thrombin?
Key link between tissue injury, coagulation, and platelet response. Key mediator for pathways to activate formation of fibrin and more PLT activation. Crtical mediator.
Initiation of Thrombus Formation
Injured tissue has tissue factor to activate factor 7, which is important in extrinsick pathway, which afctivates factor X and factor 2.
Thrombin is important to kick off extrinsic pathway as well. Amplification of factor 2 is done and more PLT activation as well.
As you propagate, more PLT are activated and more thrombin is formed to lead to clot stabilization.
Main goals of therapy for acute coronary syndrome
Reestablish blood flow, relieve chest pain, prevent MI, and prevent development of HF after acute coronary syndrome.
What medications are used in treatment of acute coronary syndrome?
Aspirin at first sign of hest pain - chew and swallow to aid in release of drug to be absorbed faster.
Nitrates - short acting, sublingual nitroglycerin, which can treat symptomatic part of chest pain.
Beta blockers - good for those with unstable angina or angina at rest to risk progression to MI.
When is it contraindicated to use aspirin?
Allergy, recent GI bleed, or recent intercranial hemorrhage.
Nitrate use with Acute Coronary Syndrome
Start with a sublingual therapy until in hospital where you switch to IV infusion if patient is still symptomatic.
Used to treat chest pain only.
Nitrates ADR
Hypotension, headache, reflex tachycardia, which increases oxygen demand on heart and worsens the ischemia…. Be careful who you give it to.
Why is it bad to give nitrates to hypotensive patients or patients on phosphodiesertase inhibitor?
Hypotension or PDE inhibitors can cause a bigger drop in BP.
Beta blockers in treatment of Acute Coronary Syndrome
Start in IV followed by PO.
If a patient has an MI and bradycardia or hypotenstive, what do you want to avoid using right away?
Don’t start them on a beta blocker right away. Later it can reduce after effects.
Caution BB if they have bradycardia, hypotension, heart block or severe reactive airway disease.
When is it appropriate to use morphine in acute coronary syndome?
Opioid analgesic to manage chest pain, when unresponsive to nitrates. Used in STEMI.
Morphine ADR
Can cause hypotension, due to release of histamine, and allergy.
Acronym of treatment for chest pain???
MONA
Morphine, Oxygen, Nitrates, Aspirin. Nitrates and morphine only treat pain; no mortality benefits.
Fibrinolytics
Work to directly activate or inactivate conversion of plasminogen to plasmin.
Plasminogen is inactive, but when converted to plasmin by tissue plasminogen activator (tPA) it lyses fibrin, cleaves fibrinogen, and inhibits factors II, V, and VII.
This helps clear clot more quickly.
Streptokinase
Fibrinolytic; that forms a stable 1:1 complex with plasminogen and exposes catalytic site, which helps to convert active plasminogen to plasmin.
CLOT BUSTER - Endogenous tissue activator can also bind to plasminogen bound to fibrin to convert to plasmin and lyse the clot.
Importance of Streptokinase and Urokinase?
RED FLAG for their use?
Fibrinolytics; activate circulating and fibrin-bound plasminogen.
Lack specificity so could cause bleeds in other parts of body.
Not used in the US as much anymore.
tPA or Tenecteplase benefits?
Only work on fibrin bound to plasminogen, which is more specific to clots and less risk for bleeding.
Fibrinolytics ADR
Bleeding; give a patient tPA but causes intercranial hemorrhage. Prefer to send patients to cath lab so you’re less likely to cause systemic bleeds. Without access to cath lab, these will be administered.
Allergic reactions can happen because they’re protein based. Leads to fever, chills, and rash with streptokinase and urokinase.
Ventricular arrythmias
When is it contraindicated to give fibrinolytics???
EXAM QUESTION, KNOW ALL 9 OF THEM.
9 CI of FIBRINOLYTICS
- Surgery within ten days including organ biopsy, puncture of vessels, trauma or cardiac resuscitation.
- Serious GI bleed within last three months.
- Hypertension where diastolic is greater than 110! HIGH!
- Active bleeding or hemorrhagic disorder.
- Previous cerebrovascular accident or active intercranial process.
- Aortic dissection
- Acute pericardititis
- STK prior exposure or alelrgic reaction
- Pregnancy.
Why aren’t fibrinollytics used in US?
Aren’t used in US.
Streptokinase and urokinase are older and have a greater risk for allergic reactions. Can be used in Europe though.
Urokinase
Developed from human fetal kidney tissue, hence “urokinase”. Not antigenic because its human tisssue.
Streptokinase
More antigenic, because its a foreign protein.
If a patient has an occluded catheter that is clotted off, what can you administer?
Put a fibrinolytic like tPA in the line to break it down.
Tissue Plasminogen Activator
Altepase (Activase)
Most commonly used fibrinolytic; made by recombinant DNA technology from Chinese hamster ovary cells. WTF.
They activate fibrin bound plasminogen. Used for occluded catheter, ischemic strokes, and MI.
Tenecteplase
Fibrolytic.
Seen used for myocardial infarction.
Indications for use of fibrinolytics?
“Time is tissue” - The sooner you get drugs working, the higher the benefit.
Indications include those less than 75 years of age if you get within 12 hours of onset, you can get some benefit. If after that time, they won’t really work.
Relatively few patients use these. Most patients go to cath lab because systemic risk of bleeds from fibrinolytic is too high.
What other agents used for non-STEMI?
Glycoprotein IIb/IIIa inhibitors; can be used before percutaneous coronary intervention (PCI)
Before pt has a stent placed, what should they be put on for clot prophylaxis?
P2Y12 receptor antagonist; as a clot prophylaxis with stent placement.
Patient with STEMI should be put on ___ while they wait to go to cath lab?
Put on heparin in conjunction with Fibrolytics or antiPLT meds.
Stent placement of metal can lead to PLT activation. How do you prevent it?
ADP receptor antagonists to prevent recurrence of stenosis and PLT aggregation.
How are teratments different for NSTEMI and STEMI?
Early treatment is similar - MONA.
Fibrinolytics are NOT recommended in STEMI because the bleeding risk is too high.
GlycoproteinIIb/IIIa receptor angtaonists, used more commonly, like Abciximab.
Enoxaparin preferred over heparin.
Chronic Heart Failure
Ischemic heart disease and MI is a large cause of CHF. ~ Most cases.
Patients with HTN and cardiomyotpathies, from alcohol or drugs.
Adoxyrubicin and Adonyrubicin
Chemo drug that causes cardio myopathies.
Systolic dysfunction
Due to decreased contractility of ventricles from loss of muscle mass, hypertrophy, or dilated cardio myopathy.
Manifested by reduced ejection fraction.
Diastolic dysfunction
Impaired relaxation. Seen with LVH - thicker and stiffer ventricles can’t relax as well or fill as efficiently. Caused by ischemic tissue as well, because theres impaired removal of calcium in cytosol which causes more contraction.
Decreased ventricular filling leads to decreased CO.
What happens when heart detects it isn’t pumping enough blood in CHF?
Increase preload - blood returning back to heart. Done by sodium and water retention.
Vasoconstriction occurs. SNS activation leads to tachycardia and increased contractility. Leads to LVH which worsens CHF.
Right sided HF
Peripheral edema, jugular venous dystension, hepatomegaly, bloating, constipation, ascites
Left sided HF
dyspnea on exertion, orthopnea, tachpnea, cough, pulmonary edema, hemoptysis
What is Decompensation?
How is it caused?
CHF symptoms are exacerbated at rest. Can have decreased exercise tolerance or worse symptoms at rest.
Frequently, due to lack of compliance with salt and water diet or not staying on medications apropriately. Caused by arrhythmia, uncontrolled HTN, or fluid overload.
Nonpharmacologic Recommendations for CHF patients?
Limit fluid and sodium restriction to decrease symptoms. Physical activity can improve functional status and work off extra fluid.
What is the mainstay treatment for CHF patients?
Diuretics are good to get rid of fluid, but don’t provide any mortality benefits in the long term.
Thiazide diuretics aren’t potent enough, so Looooop Diuretics are the go to drug for HF therapy!
Why do you monitor a patient’s weight on diuretics?
Monitor the patients weight so you can detect fluid overload, which is a one pound increase in weight over several days.
Diuretics do not decrease progression of mortality in CHF patients. Why are they used?
Symptomatic relief; not a mandatory therapy. Decreease sodium and water retention and get rid of extra fluid.
If patient doesn’t have fluid overload or weight gain, they don’t need a diuretic.
What’s the go to drug for CHF patients to reduce mortality and slow progression of disease?
ACEI - decrease preload and afterload, decrease SNS activation, and prevent remodeling of left ventricle.
Slows progression of disease to decrease mortality.
If CHF patient can’t tolerate ACEI, what should you prescribe?
ARB is backup
Benefits of ACEI in HF
Hemodynamic improvement, improved exercise tolerance, slower progression of disease, less hospital admissions, and prolonged survival.
Problems with ACEI in HF
Can acutely impair renal function (start at a low dose and titrate up), elevated potassium levels, cough, angioedema.
What Beta Blockers have been shown to have mortality benefits in CHF treatment?
Carvedilol
Metorpolol succinate XL (long form)
Bisoprolol
How do you successfully use Beta Blockers in CHF patients?
Start at a low dose and in hospital, so you can monitor their perfusion. Titrate the dose up throughout six to eight weeks.
Carvedilol
Metorpolol succinate XL (long form)
Bisoprolol
Benefits of Beta Blockers in CHF?
Improved exercise tolerance. Normally, impairs it, but by slowing heart, ventricles have more time to fill for improved exercise.
Increase in ejection fraction and slower disease progression. Decreases hospitalization, need for transplant, and mortality.
What’s the first line therapy for Class II-IV heart failure?
Class 2 to $ - BB are a first line therapy, esp if they’re post-MI.
Also need something like ACEI to inhibit angiotensin 2.
Digoxin MOA
Steroid based molecule used for heart failure.
Works by inhibiting Na-K-ATPase. Digoxin inhibits this pump to have more sodium in the cell, which increases activity of exit pump which brings sodium out and ends with more calcium in the cell! – Leads to stronger contractions, which is why it benefits heart failure. However, more activity is from neurohormonal effects.
Using digoxin at lower concentrations, can see decrease in SNS and increase in PNS activity, resensitize baroreflex, and decrease RAAS system.
Digoxin effects on heart
Leads to decrease HR, better conduction from AV node, and better pumping actions
Target levels of Digoxin
0.5-1ng/mL.
Higher levels lead to worsened outcomes in heat failure patients.
What is digoxin used for in HF patients - symptomatic relief or increase in mortality benefits?
Provides symptomatic relief, improved exercise tolerance, but no survival benefit.
Digoxin place in therapy with CHF?
Doesn’t slow disease progression. Just used with ACEI and BB to control symptoms.
Where is digoxin really preffered in patients?
Atrial fibrillation ot prevent clotting.
What are signs of Digoxin Toxicity?
Need therapeutic drug monitoring.
Anorexia, nausea, visual disturbance. If patient has photophobia or halo around lights, big indicator of toxicity. Yellow vision = xanthopsia.
What are central symptoms of digoxin toxicity?
Can see delirium, fatique, and abnormal dreams.
What are some cardiac effects of digoxin toxicity?
Digoxin induced depolarization, – PVC, bradycardia.
Nodal slowing, esp in overdose.
Digoxin is CI in patients with:
Patients with advanced AV block, severe bradycardia, PVCs or ventricular arrythmia.
Hyperkalemia and WPW.
If you have a patient with digoxin toxicity, how do you reverse effects of toxicity?
Digoxin Immune Fab, which is an antibody that will target digoxin. It binds to digoxin to relieve body of the toxicity.
Works quickly.
What are indications to use aldosterone antagonists in CHF?
Helps reduce mortality in grade 3 or 4 HF. Mechanism has neurohormonal inhibition and slows remodeling of LV.
Spirnolactone
Do not give if patient Cr < 2.5 or K>5. May cause gynecomastia.
Eplenerone used to avoid gynecomastia.
What do inotropic agents do?
In decompensation, they help to increase squeeze on heart or increase intotropy.
Mirinone
Inamrinone
Milrinone and Inamrinone MOA
Introptropic agents; work on PDE3 - work on heart instead of elsewhere.
They increase contractility and have some vasodilation to have heart beat harder and lead to decrease in afterload. Will decrease CO.
How are inotropic agents adminsitered?
Approved for short term IV use in decompensated heart failure.
Helps patient during decompensation and low ejection fraction to get throug the hump and recover.
Dobutamine
Intropic agent; IV infusion for acute exacerbation. Selective beta 1 agonist to increase heart rate and cardiac output.
Dopamine
Inotropic agent via IV infusion. Helps increase output from heart and activates dopamine, A, and B receptors.
Describe Cardiac Muscle
Striated in nature. Tissues have automaticity. Electrical conduction is all or none phenomenon, because you need to reach an electrical threshold for myocytes to contract.
Intercalated disks allow muscle contraction to occur between cells.
Cardiac Conduction System
Starts with SA node, down to AV node, to bundle of his, where is goes to purkinje fibers to allow signal to transmit through ventricles.
SA node and AV node Automaticity
Leak channels that allow for slow influx of sodium to reach a threshold to kick off the action potential.
Atrial muscle has no automaticity so they wait for the signal to come in. SA node triggers atrial muscle.
Fast response cells of cardiac muscle
What happens in each phase of fast response cells?
Fast cells; have no automaticity.
Phase 0 - inward Na currents start; signaled by action potential.
Phase 1 - outward K+, inward Cl-. Lowers membrane potential.
Phase 2 - Plateau effect due to inward flux of Ca2+. Makes cell more positive.
Phase 3 - outward flow of K+ to reset cell for next contraction.
Phase 4 - Na/K ATPase works to maintain normal potential for cells.
Flow of electrolytes during ventricular action potential
Graph
Phase 0 has rapid spike in membrane potential, because Na influx.
Phase 1 has K out and Cl- going in to lower potential.
Phase 2 is plateauing, because of Calcium influx.
Phase 3 has potassium pushed out of cell to get back to the normal electronegativity.
Phase 4 goes back to membrane potential.
How does Torsades occur?
IK channel is important to prevent QT prolongation.
When it is blocked, QT prolongation will occur and it delays resetting of myocytes.
Absolute refractory period
No matter what signal comes along to trigger, muscle is in a state where it absolutely can’t contract again. Earlier on in deporlization.
Relative refractory period
If strong enough signal comes along, it can start up a reentrant rhythm.
Slow Response Cells - How are they different?
Explain the action potential of slow response cells.
SA and AV nodes; have automaticity to allow for cardiac conduction. Generate the intial action potential.
Phase 4 - Na/K ATPase to maintain electronegativity, but there’s a leaky influx of sodium.
Phase 0 - when you hit a threshold, calcium influx.
Phase 2 - Calcium stilll coming in, but K is going out.
Phase 3 - outward flux of potassium to reset cells.
Adrenergic effect on heart release catecholamines onto beta receptors of heart. This increases heart rate.
How does adrenergic affect change electrolytes?
Outward flux of potassium allowed it to be more electronegative….
SO If you decrease outflux, you’re cell is more positive and you can reach the threshold for action potential sooner.
Cholinergic affect on heart has acetylcholine activate muscarinic receptors. This decreases the heart rate.
How does cholinergic affect change electrolytes?
Cholinergic increase outward flux of potassium making cell more negative.
Lower resting potential makes the cell take a longer time to get the influx of sodium to hit for the action potential to be triggered.
Mechanism that causes arrhythmia to arise?
From abnormal impulse formation - automaticity from ectopic pacemaker or changing influx/depolarization.
Can also have abnormal impulse conduction.
How does ischemic tissue affect action potentials in the heart?
Ischemic areas of heart conduct through tissue slower.
Because ischemic tissue is slowed, reentrant rhythms can start, due to different in refractory period of healthy tissue to ischemic tissue.
Can cause heart blocks!
Before using antiarrythmics….
Fix underlying and precipitating causes first, like hypoxia, ischemia, and electrolytes.
Classifications of Antiarrythmics:
Na Channel Blockers
Work to decrease excitability. Less sodium influx has less automaticity from SA and AV node as well as fast response cells.
Classifications of Antiarrythmics:
Action potential prolongation
AP prolongation occurs when you prolong potassium channels. Prolonging refractory perid stops reentrant rhythms.
Classifications of Antiarrythmics:
Beta Receptor Blockade
Prolong AV refractorniness and conduction, you increase energy required for atrial fibrillation.
Classifications of Antiarrythmics:
Calcium channel blockers
Decrease slow response cells excitability.
Class 1A indication
Sodium Channel Blockers
SVT, VT, V fib prevention and PVC prevention
Class 1B indications
Sodium Channel Blockers
VT, V fib prevention, symptomatic ventricular beats
Class 1C indications
Sodium Channel Blockers
Life threatening VTACH, Fib, refractory SVT.
Class 2 indications
Beta Receptor Antagongists
SVT and Fib
Class 3 indications
Prolong repolarization by blocking K channels.
Refractory VT, A fib, futter, SVT
Class 4 indications
Calcium Channel Blockers
SVT
Class 2 and Class 4 uses?
Good for rapid conduction from SA and AV node to ventricle.
SVT, A flutter. Work on nodal tissue.
Class 1A, B, C and Class 3 uses?
Useful for ventricular tachycardia, A fib, V fib.
How do sodium channel blockers work?
Resting state of membrane prevents sodium from influxing to myocyte until you reach threshold. Sodium channels activate and then llow inward flux, which causes increase in AP.
Inactivated phase - come in and close off further flux of sodium. Hasn’t reached resting state, but blocks inward flux of sodium.
Each class works different on chanenls.
Class 1A
Blocks channels to have slow phase 0, slow conduction, and prolong action potential.
Prefer open channel to inactivated. When channel is open, they go in and inhibit.
Have a slow dissociation.
1A Quinidine
Class 1A antiarrythmic. D-isomer of Quinine.
Works by slowing conduction and prolonging refractory period to prevent reentrant rhythms, especially in ischemic tissue.
Slows Phase 0 and increases threshold for excitability. Takes stronger AP to trigger cell to have action potential.
Decrease automaticity in SA and AV node.
1A Indirect action of quinidine?
Not sure why this is important.
Has anticholinergic affects.
A blocker at higher doses; may see effects on BP due to that.
1A Clinical uses of quinidine?
Used to maintain rhythm in patients with atrial flutter or atrial fibrillation. Helps control ventricular tachycardia.
Can be used with anticoagulants for clots in atria during atrial fibrillation or flutter.
What does quinidine inhibit?
CYP2D6 enzyme, when inhibit you can see higher levels of codeine and morphine.
1A Quinidine Toxicity - SUPER TOXIC!
N/V/D very frequently! Quinidine makes you queezy.
Can induce its own arrythmia or Torsades… Torsades risk , because action potential is prolonged!!!!!!!!!!!!!!!!
May cause hypotension due to alpha block effect.
Thrombocytopenia is rare, but may be fatal. :(
Cinochism occurs! New word.
1A Quinidine causes cinochism. What is that?
Tinnitus, dizziness, and blurred vision.
1A Procainamide
Amide derivative of procaine; has a short duration of action.
Less anticholinergic activity and alpha blocking activity.
NAPA byproduct formed - has some class three activity to block potassium channels.
How are fast acetylators affected by procrainamide?
More NAPA byproduct is produced, because they metabolize procrainamide fast.
Can lead to arrythmias!!
1A Procainamide ADR
Hypotension, slowing of conduction, lupus like syndrome in slow acetylators!
Get that warm rash, because they metabolize or acetylate slow and drug levels are high.
IV version is tolerated better than quinidine. Oral form is not.
1A Disopyramide
What is it used for?
Like quinidine, but has more anticholinergic actions and negative inotropic affects - decreased contractility.
Used for ventricular tachycardia and supraventricular arrythmias like A fib or A flutter.
SIgns of Disopyramide toxicity
Hypotension, antimuscarinic effects…
Decreased contractility could worsen CHF. Torsades at risk.
If a patient has heart block, hypersensitivity, or glaucoma; what anti-arrythmic do you avoid?
Disopyramide
1A antiarrythmics PDQ
Procainamide, Disopyramide, Quinidine
1B sodium channel blockers
Shorten phase 3 and decrease ectopic foci automaticitiy.
They target inactive channels, but have higher affinity for ischemic tissue than normal tissue.
What is 1B Lidocaine?
Local anesthetic used to numb areas for sutures, etc.
1B Lidocaine used to treat?
Has extensive first pass metabolism, so should be given IV.
Can be given intravensouly to treat WPW, VTACH, premature beats, and Vfib.
Actions of 1B Lidocaine
Binds to open/inactive channels. More effective on sodium channels in iscemic tissues.
Good for patients iwth active MI and ventricular arrythmias.
1B Lidocaine Toxicity
CNS toxicity in patients with poor hepatic function!
Can see drowsiness, confusion, muscle twitches, nystagmus.
Seizures can occur - this might lower threshold so don’t give to patients with pmhx of seizures.
1B Mexiletine
Analog of lidocaine that has oral availability.It decreases automaticity and conduction in ventricles.
Used to treat congential long QT syndrome and prevent torsadaes. IMPORTANT.
1B Mexiletine ADR
N/V/tremor
Blood dyscrasias, changes in granulocytes and platelets.
Class 1B sodium channel blockers names:
Mexiletine
Lidocaine
Class 1C Sodium Channel Blockers
Slow phase 0 and conduction to prolong the refractory period. Affect normal heart tissue.
Focuses on open channels.
Ver slow dissociation.
1C Flecainide
Blocks sodium channels and has class 3 activity where it blocks potassium too..
Prolongs PR, QRS and QT.
Long half life; can be oral or IV. PRevents PVCs.
1C Flecainide - Clinical uses
Life threatening sustained ventricular arrythmias. Supraventricular arrythmias.
Can only be used in patients without structural damage to the haert.
1C Flecainide Toxicity
Blurred vision, tremor
Induce a VTACH, which can be resistant to other treatments since sodium channels are blocked.
Can cause bronchospasm, seizures, adn death for MI patients.
1C Propafenone
B blocking activity to work on SA and AV node; similar to flecainidie.
1C Propafenone toxicity
Can cause arrythmia; see bradycardia, bronchospasm from non-selective BB activity in drug.
Decreased contractility from BB can also worsen CHF.
Class 2 Beta Blockers
Work to slow conduction and decrease automaticity to prolong AV conduction and decrease phase 4 depolarization.
2 Propranolol
Non selective beta blocker to slow AV conduction and decrease speed and contracility of the heart.
Can supress PVCs and membrane stabilizing effect..
2 Propranolol - Clinical indications
Supraventricular arrythmias
Ventricular ectopic beats
MI
2 Propranolol Toxicity
Worsen heart failure, can see heart block, hypotension, hyperglycemia, bronchospasm, heart failure, and digitalis toxicity
2 Metoprolol
B1 seelective blcoker
less bronchospasms here
2 Esmolol
Given IV, short acting agent good for SVT to decrease sinus rate.
Class 3 Potassium Blockers
Prolong repolarization due to potassium efflux. Prolong phase 3, refractory period, and duration of action potential.
Used to treat A fib and A flutter.
3 Amiodarone
Very long half life of 40 days. Has a slow onset and slow elimination. May need a loading dose to get to steady state.
When is amiodarone used?
Recurrent ventricular tachycardia or fibrillation resistant to other drugs to maintain normal rate in atrial fibrillation.
Replace lidocaine in MI. Lidocaine used to be used, but amdiodarone is now go to for ventricular arrythmias during codes.
Actions of 3 amiodarone
Blocks potassium channels, inactivated sodium channels, calcium channels, and alpha and beta receptors to decrease automaticity and decrease automaticity to prolong refractory period.
3 Amiodorone Toxicity
SMURFS
Occur when dosed chronically; can see hypotension from alpha and beta affects.
Pneumonitis, pulmonary fibrosis - fatal.
Neurotoxicity, neuropathy, muscle weakness
BLUE GREY SKIN COLOR
photosensitivity
thyroid abnormalities
3 Amdiodarone drug interactions
Increases digoxin, warfarin, flecainide, phenytoin, and procrainamide levels.
3 Ibutitlide
Prolongs opening of sodium channel, which coutneracts opening of potassium channels.
Prolongs repolarization and action potential.
3 Ibutitlide uses
Used as a way to convert A fib or A flutter.
3 Ibutitlide ADR
Due to blocking of potassium channels, can see prolonged QT and heart block!
3 Dofetilide
Frequently prescribed; helps maintain normal rhythm in A fib and ventricular arrythmias. Used in VA hosp. a lot.
3 Dofetilide ADR
Torsades and marked QT prolongation - do EKGs before hand and any time you change your dose.
Eliminated by kidneys, so monitor the kidneys and electrolytes to prevent risks of torsades and other arrythmias.
What do you monitor for on Dofetilide?
EKG before you start and any time you change dose. Also monitor the kidney function and electrolytes to make sure you’re not putting patient at risk of torsades or another arrythmia.
3 Sotalol
Beta blocker that inhibits potassium channels; decreases phase 4 depoarlization.
3 Sotalol indications
A flutter, A fib, ventricular tachyarrythmia
3 Sotalol toxicity
Torsades due to potassium blocking affects
Bronchospasm
Class 4 Calcium Channel Blockers
Block L type calcium channels for slow av node conduction and decreased automaticity
4 Verapimil and Dilitiazem
Only non-DHP are here; work on vasculature, not the heart.
Blocks activated and inactivated channels. Targets most active tissue causing arrythmia.
Decreases AV conduction nad supresses SA node.
4 Verapimil and Dilitiazem uses
Control A fib and PSVT
4 Verapimil and Dilitiazem TOXICITY
Hypotension, edema
CYP3A4 inhibition
Don’t use in ventricular arrythmias, sick sinus syndrome, or depressed cardiac function.
Adenosine
Natural product body makes consistently that inhibits molecules in CNS to prevent seizures by activating adenosine receptors.
It inhibits hearts by blocking calcium channels. You hyperpolarize cell with potassium and prevent it from being triggered again. Can stop heart for two to three seconds.
Can give to heart to reset itself and get rid of arrythmia.
Adenosine clinical uses
WPW and paroxysmal supraventricular tachycardia
Adenosine ADR
Flushing, shortness of breath, burning in chest.
Adenosine Administration
Has a short half life, so needs to be administered apropriately.
Push drug fast via IV and flush with fluids afterwards to ensure it reaches heart ASAP
Digitalis
Works to slow AV conduction, inhibits calcium channels in AV node, and increases parasympatheic tone and decreases SNS.
Can induce heart block
Uses of digitalis
Slow ventricular rate
Induce heart block
DO NOT use with calcium channel blcokers or beta blockers, becuase you odn’t wanna decrease the activity of the nodal tissue too much.
Digitalis toxicity
N/V/D anorexia, CNS confusion, delirium, headache, seizures.
Magnesium Sulfate
Used to treat Torsades de Pointes via IV to get patient out of rhythm.
Can cause bradycardia, flushing, headache, and respiratory paralysis.
