Pharm 2 Flashcards
ACC/AHA 2017 Guidelines
Normal BP <120
Goal for all patients <130/80
Stage 1 HTN: 130-139/80-89
Stage 2 HTN: > 140/90
When to start treatment:
IF CVD/ASCVD 10 year risk: >130/80
IF NO CVD/risk: >140/90
Consider 2 agents if >20/10 over goal
HTN agent s/p MI for all ages and races
B-blocker + ACE-I
(Aldosterone antagonist if HF present)
HTN agent for recurrent stroke prevention (all ages/races)
Thiazide + ACE-I
HTN agent in HF for all ages/races
B-blocker + ACE-I
Diuretics for fluid retention
Aldosterone antagonists
Hydralazine
1st line HTN
Thiazide
CCB
ACEI
ARB
(2nd line = combo of above choices)
Thiazides
Diuretic
Inhibit active exchange of Na and Cl (in equal amounts) in distal convoluted tubules
Indication:
-HTN (HCTZ, Chlorthiazide)
-Edema (Metolazone)
Interactions: digoxin, lithium, electrolyte based drugs, caution in sulfa allergy
*Not useful in anuric renal failure
ADE:
-Decrease K, Na, Cl, PO4, Mag
-Increase glucose, Ca, uric acid, lipids
-Photosensitivity
Loops
Diuretic *greatest diuretic effect of all classes
Inhibit exchange of Na/K/Cl on thick segment of ascending Loop of Henle
Indication:
-Better in HF than HTN
-HTN, edema, ascites, renal disease
*More useful than thiazides in pt w/ chronic renal insufficiency (GFR <30)
ADE:
-Decrease K, Na, Mag, Phos, Ca
-Increase glucose, uric acid, lipids
-Rash
-Photosensitivity
-Ototoxicity
Interactions
-Lithium
-Digoxin
-Ototoxic drugs
-K sparing diuretics
K-sparing
Diuretic *Modest diuretic effect, usually used in combo w/ others
Inhibit reabsorption of Na in distal convoluted tubule and collecting ducts (blocks aldosterone)
Main function=antagonize aldosterone
ACEI
Blocks conversion of angiotensin-1 to
angiotensin-2, halting vasoconstriction.
Also inhibits degradation of bradykinin
Renoprotective agent in cases where renal afferent arteriolar pressure is increased: lowers both afferent/efferent pressure. NOT helpful in already low afferent pressures
Indications: HTN/HF/post MI
HD effects
-vasodilation
-reduced preload and afterload
-increased CO
-increased Na/water excretion
ADE: rash, ACE cough, 1st dose hypotension, hyperK, angioedema, neutropenia, teratogenicity, renal insufficiency
Interactions: K supplements, diuretics, ASA
Contraindications: renal artery stenosis, pregnancy, Hx angioedema
ARB
block angiotensin II receptors on cell membranes
Indications: HTN, CHF
Interactions: K sparing diuretics/supplements, NSAIDS
ADE: Teratogenicity, cough, angioedema,
Contraindications: Renal artery stenosis
CCB
Blocks inward movement of calcium into muscle by binding to calcium channels in the heart and SM of the coronary and peripheral vasculature
DHP: dilatory properties
non-DHP: conduction disorders
Indications: HTN, angina, dysrhythmias, HF
non-DHP CCBS
Verapamil, Diltiazem
Decreases HR and contractility, slows cardiac conduction, dilates SM of coronary and peripheral arteriolar vasculature
ADES: Constipation (verapamil), dizziness, HA, nausea, LE edema
Interactions: Digoxin, beta blockers
Caution: heart block, decomp HF
DHP CCBs
Nifedipine, nicardipine, amlodipine
Effects on smooth muscle causes vasodilation, little effect on conduction
Indication: HTN, prinzmetal’s angina, HF
ADE: peripheral edema, HA, gingival hyperplasia
Interactions: Beta blockers
B-blockes
Competitively inhibit beta adrenergic receptors
Selective (B1): atenolol, metoprolol
vs
Nonselective (B1 and B2): propranolol, timolol
Decrease CO, sympathetic outlfow from CNS, inhibit renin release
Indication: HTN, HF, MI, angina
Caution: COPD, asthma, decompensated HF, DM, PVD, block
ADE: hypotension, bradycardia, CNS effects, impotence, hyperlipidema, hypoglycemia masking
Nonselective beta blockers
Inhibit B1 and B2 adrenergic receptors
Propranolol, timolol, nadolol, penbutolol
Can cause bronchoconstriction (special caution in asthma/COPD)
Selective beta blockers
Inhibit B1
Atenolol, metoprolo, acebutolol, betaxolol, esmolol
Preferred w/ PVD, DM, and reactive airway disease
Alpha/beta adrenergic blockers
Carvedilol, labetalol
Inhibit alpha 1, beta 1, beta 2
No effect on lipid and CHO metabolism
ADE: orthostatic hypotension, dizziness
Alpha-1 Adrenergic blockers
Prazosin, terazosin
Relaxation of arterial and venous smooth muscle, decreased PVR
Minimal changes in CO, renal blood flow, GFR
Indication: HTN, BPH
ADE: palpitations, postural hypotension, syncope
Alpha 2 agonist
Clonidine, methyldopa
Indication: HTN, pain management
ADE: rebound HTN, drowsiness, dizziness, constipation
*Methyldopa-useful in HTN in pregnancy
ADE: SLE, sedation, orthostatic hypotension, hemolytic anemia, increased LFTs
Hydralazine
Arterial vasodilator: decreases PVR
but
increases CO and causes reflex tachycardia
Indications: HTN, HTN crisis
ADE: HA, nausea, angina, lupus like syndrome
Digoxin
Cardiac glycoside
+inotropic action, – neurohormonal activation, sensitizes cardiac baroreceptors
Indication: improve symptoms and quality of life in HF, no affect on mortality
Caution: electrolyte disorders, renal insufficiency, thyroid disorders, hypermetabolic state
ADE=digitalis intoxication (N/V, dizziness, visual disturbances), hyperkalemia, conduction abnormalities
VERY NARROW TI
Goal drug level: 08
Keep K+ 4.0, Mg 2.0
Drugs that increase levels: amiodarone, CCB, diuretics, macrolides
Drugs that decrease levels: St. John’s wort, antacids, reglan
Statin benefiting groups
- ASCVD
- LDL >190
- LDL 70-190, age 40-75 w/ DM and no ASCVD
- Estimated 10 year risk >7.5 for individuals 40-75 w/ LDL 70-190 and no DM
Statins
Inhibit HMG-CoA-Reductase (important step in cholesterol synthesis)
Rosuvastatin, atorvastatin, Simvastatin, Pravastatin
Issues: liver abnormalities, myalgia/myopathy which can elevate CPK and lead to rhabdo, many drug/food interactions (metabolized by CYP3A4)
Fibrates
Promotes fat removal from plasma via enzyme
activation (LPL, Reduces hepatic secretion of LDL
Primarily triglyceride lowering agent
ADE: GI, flu-like, rash, photosensitivity, myopathy, pancreatitis, gallbladder disease
Interactions: statin, warfarin
Bile acid sequestrants (resins)
Cholestyramine
Reduces LDL; may increase HDL
Prevents bile acids from being absorbed and
returned to liver, leading to fecal elimination
Side effect profile discourages use
Nicotinic acid (niacin)
Available OTC, Rx
Lowers VLDL, which ↓ production of LDL
May also increase HDL
ADE: flushing, tingling, itching, Hepatic toxicities reported
interactions: statins
Beta 2 agonists
Bronchodilators
SABA: albuterol/levalbuterol (rescue, onset ~15 min)
LABA: formeterol/salmeterol (maintenance), used in conjunction w corticosteroids
ADE: tachycardia, tremor, hyperglycemia, hypokalemia
Indications: sympathomimetics, MAOI
More effective to use corticosteroid + Beta 2 agonist than higher doses of corticosteroids alone
Can see tolerance develop over time
Methylxanthines (Theophylline)
MOA: SM relaxation from PDE inhibition, preventing breakdown of cAMP
ADE: convulsions, arrhythmias, CNS stimulation, N/V
insomina, aggravation of reflux/ulcers
VERY NARROW TI (5-15)
Decreased metabolism: erythromycin, cimetidine, liver failure, heart failure, elderly
Increased metabolism: smokers, oral contraceptives, phenytoin
Not recommended for exacerbations
Anticholinergics (muscarinics)
MOA: prevents increase of cGMP and antagonizes
action of Ach, resulting in bronchial SM relaxation
SAMA=ipratropium
LAMA=tiotropium
Corticosteroids
oral: prednisone, methylprednisolone. Short term, gain control of inadeuately controlled persistent asthma (3-10 days)
inhaled: beclomethasone, flunisolide. Long term for prevention
MOA: antiinflammatory, reduces airway hyperresponsiveness. inhibits cytokine production, inflamm cell migration and
activation
1st line Tx starting at step 2 but not for acute attacks
ADE: candidiasis, cough, dysophonia, HA, reversible glucose increases, fluid retention, peptic ulcer
*adrenal axis suppression @ high doses
Growth issues in long term use? If concern replace w/ mast cell stabilizers
Mast cell stabilizers (Cromolyn sodium)
MOA: anti-inflammatory; stabilizes mast cell
membranes, inhibiting activation and release of
mediators from eosinophils and epithelial cells
Indication: most useful in younger, allergic asthmatics with mild persistent asthma, also useful in exercise induced asthma
May take some time to see effects. Weak drug compared to corticosteroids
ADE: (Rare) cough, congestion
No risk growth suppression
Leukotriene modifiers (montelukast)
MOA: Block leukotriene receptors on inflammatory cells and SM (montelukast),
Stop synth of leukotrienes via lipoxygenase inhibition
Well tolerated, minimal ADE, less effective than corticosteroids
Enzyme inhibition of CYP450: decrease metabolism of warfarin and theophylline
Watch LFTs
Monoclonal Antibody (IgE binder) Omalizumab
MOA: Forms complexes with IgE and prevents binding to
receptors limiting inflammatory mediator release
Indication: >12 y/o moderate-severe asthma and failed traditional agents
Opioid actions
CNS: analgesia, sedation, euphoria, resp/cough suppression, N/V, pupil constriction
GI: delayed gastric emptying, increased intrabiliary pressure, constipation
Other: histamine release from mast cells, immune suppression, hypotension/bradycardia, osteoporosis, hyperalgesia
Morphine
MOA: Activation of m, k, and d opioid receptors, activation of Gi –> K+ channels hyperpolarize and depress neuron function
Metabolism: Primarily in gut wall and hepatocyte, conversion to M6G (active) and M3G (neurotoxic). ~10% excreted unchanged (renal)
ADE: resp depression, sedation, N/V, mental clouding, urinary retention, constipation, pruritis, hypotension
Contraindications: (relative) liver/heart failure, resp failure, asthma, hypotension
Codeine
Weak opioid, analgesic properties related to conversion to morphine by CYP2D6 (watch polymorphisms)
Hydromorphone
Low levels of active metabolites, so preferred in renal failure
ADE: CP
Oxymorphone
Low propensity to release histamine
Meperidine
Phenylpiperidine opioid w/ relatively short half life
Less constipating than morphine
ADE: CNS excitation (tremors, muscle twitches, seizures)
Not for Tx of chronic pain d/t metabolite toxicity, not to be taken w/ MAOI, not for pt w tachycardia
Fentanyl
Highly lipophilic, highly potent opioid that can be given transdermal/transmucosal
Very short half life, no active metabolites (preferred in renal insufficiency)
TD fentanyl is less constipating than morphine
Not for opioid naive pt, not for acute, intermittent, mild pain
Methadone
Long acting u, k, d opioid agonist and NMDA antagonist
Half life: 20-35 hours (4-10 days to reach Css). Metabolism highly variable btwn individuals (portion of drug that is free vs. protein bound and metabolic activity towards CYPS)
No active metabolites
Primarily metabolized by CYP3A4, induces CYP3A4
QTc prolongation
Less prone to developing tolerance, best opioid for tx neuropathic pain
Tolerance
Progressive loss of effect with sustained administration of an opioid receptor agonist
Progressive decrease in drug efficacy
Increased dosing decreases pain
May develop adverse effects with increased dosing
Opioid induced hyperalgesia
Paradoxical increase in sensitivity to painful stimuli
Increased dosing increases pain
Same pain or different pain
Increased sensitivity to pain
Pain transmission
Nociceptor stimulation in injured tissue causes release of bradykinin, 5HT, K+, histamine, prostaglandins, Substance P that further sensitize/activate other nociceptors (decreasing pain threshold)
Nociceptor activation produces action potentials that are transmitted to the spinal cord along myelinated A-delta fibers (sharp, fast) and unmyelinated C-fibers (slow, dull, burning)
Pain signals transmitted via spinal cord to thalamus and project to cortical regions where pain is received
Modulation of pain through: endogenous opioids (endorphins), descending pain pathway (5HT, NE @ dorsal horn)
Cyclooxygenase inhibitors
Effects: antiinflammatory, analgesic, antipyretic
Most are highly protein bound
ADE: bleeding, gastric ulceration, renal impairment
COX 1 inhibition:
Gastric ulceration/bleeding/renal impairmnt
MI/CVA protection
COX 2 inhibition:
Decrease pain/fever/inflammation
MI/CVA risk
Acetaminophen
COX-inhibitor w/ no anti-inflammatory action
Indication: mild-moderate nociceptive pain (lacks efficacy in neuropathic/functional pain)
Very little protein bound (unlike other NSAIDS)
Metabolism: extensive liver metabolism through conjugation w/ glucoronic acid, small portion CYP mediated
Acetaminophen metabolism
Liver: extensive through conjugation with glucuronic acid (60%), sulfuric acid (35%), and cysteine (3%). A small proportion undergoes CYP-mediated N-hydroxylation (CYP2E1).
Major metabolism pathway–> nontoxic metabolites
Minor pathway (mediated by CYP450) –>Toxic metabolite (NAPQI) —> glutathione –> nontoxic metabolite
P450 induced by alcohol
Glutathione inhibited by alcohol AND tylenol OD
Aspirin
Irreversible COX1 and COX2 inhibitor
Indication: inflammatory disorders mild-moderate pain, menorrhagia
Vd: highly protein bound
Metabolism: Plasma esterase to yield salicylate which is 90% eliminated through hepatic metabolism
Half life of ASA very short, but salicylate 2-3 hr (and up to 30 hr if hepatic mechanisms become saturated)
tNSAIDS
Reversible inhibitors of COX 1 and COX 2
Risk of MI/CVA d/t TXA2/PGI1 imbalance
Inhibit TXA2 (COX1) vasoconstrictor/promote plt agg
Inhibit PGI2 (COX2) vasodilator/inhibit plt agg
Nonselective COX inhibitors have bias towards COX2 inhibition
COXIBS
Selective COX 2 inhibitors
Just as effective as traditional NSAIDs in suppressing inflammation and pain
Somewhat lower risk for GI side effects
Can impair renal function and cause hypertension and edema
Increased risk of MI and stroke
PGE2
In GI mucosa
Protective @ stomach lining (increase mucous production, bicarb, mucosal blood flow)
Inhibiting=peptic ulcers and GI bleeding
Carbamazepine
Indications: epilepsy (1st line for partial and tonic clonic), trigeminal neuralgia, bipolar mania
Action @ voltage gated Na channels (stabilize in inactive state)
Advantages: less sedating than other AEDs, mood stabilizing effects, no cognitive deficits
High (75-90% protein bound)
Metabolized by CYP3A4, induces CYP1A2, 2CP, 3A4.
Initially high half life, decreases w/ multiple doses because it induces its own metabolism
*also decreases concentration of other CYP mediated AEDs
ADE: acute intox, resp depression, ataxia, drowsiness, blurred vision
BBW for severe hemolytic anemia and derm rxns (HLH allele)
Preg category D
Phenytoin
Indication: partial and tonic clonic seizures, during and after NSGY
MOA: Stabilizes inactive state of volt-gated Na channels
High variability in oral bioavailability (20-90%)
High protein binding, low Vd
*drug interactions mainly related to protein binding
Metabolism via CYP2C9, induces other CYP enzymes
Zero order kinetics: elimination rate increases with higher concentrations (saturable)
ADE: ataxia, diplopia, drowsiness/sedation, gingival hyperplasia, anemia, lymphadenopathy, osteoporosis
Preg category D
Gabapentin
Indication: partial seizures, postherpetic neuralgia **no efficacy for tonic-clonic seizures
MOA: likely inhibits Ca channel activity
Insignificant protein binding, excreted unchanged in urine/no hepatic enzymes (fewer drug interactions)
ADE: somnolence, dizziness, ataxia, fatigue, HA, tremor (generally well tolerated)
Pregnancy category C–safer than other AEDs
Pregabalin (Lyrica)
Reduces glutamate, NE, and Substance P levels (analgesic properties, neuropathic pain management)
*abuse liability
Phenobarbital
Indication: Epilepsy, sedation
MOA: barbiturate, action @ GABA receptors
Drug of choice for infant/neonatal seizures
ADE: resp depression, sedation, physical dependence, hyperactivity, cognitive impairment
Levetiracetam (Keppra)
Indication: partial, tonic-clonic seizures
Can exacerbate neuropsych disorders and aggression
Valproate
Indication: generalized seizures (beyond just tonic clonic), BPD, migraine prophylaxis
MOA: Na channel inactivation, reduction in T type Ca currents, increase GABA signaling
90% protein bound
Metabolism via CYP2C9, inhibits 2C9 and UGT
ADE: A/N/V, sedation, ataxia, tremor, rash, alopecia, weight gain
Rare risk of fulminant hepatitis which may be fatal
BBW for hepatic toxicity and teratogenicity
Preg Category D *worst AED
Interactions: inhibits metabolism of CYP2C9 substrates (phenytoin, phenobarbital, ethosuximide)
Lamotrigine
Indication: Partial, tonic clonic seizures, BPD
MOA: Na channel inactivation
Insignificant protein binding
Extensive hepatic metabolism, induces UGT
Half life reduced by phenytoin, carbamazepine, phenobarbital. Increased by valproate
Toxicity: weight gain, ataxia, nervousness, dizziness, blurred vision
Risk of SJS and DIC (more common in peds)
Ethosuximide
Indication: absence seizures
MOA: Decreases low threshold Ca currents in thalamic neurons
Insignificant protein binding
75% hepatic metabolism via CYP3A4, no enzyme induction
ADE: N/V/A, drowsiness/lethargy/dizziness, urticaria, SLE, eosiniphilia
Preg category D
SSRI
Citalopram, escitalopram, fluoxetine, paroxetine, sertraline
MOA: highly specific in inhibiting SERT, efficacy attributed to subsequent actions of elevated 5-HT at postsynaptic 5-HT1A receptors
ADE: nausea (5-HT3), agitation, insomnia, sexual dysfunction (5-HT2), serotonin syndrome= tremor, hyperthermia, CV collapse
Inhibit CYP enzymes (esp Paroxetine and fluoxetine inhibit 2D6 and should not be used w TCAs)
Highly protein bound
Fluoxetine and sertraline have active metabolites with long half lives. Need washout period before starting TCA
Mostly category C in pregnancy (Paroxetine category D)
Serotonin syndrome
Risk when SSRIs/SNRIs used in combo w/ TCAs or OD of TCA
Tremor, hyperthermia, CV collapse
SNRI
Venlafaxine, Desvenlafaxine, Duloxetine
MOA: Inhibit SERT and NET
ADE: Similar to SSRIs + b-adrenergic effects (HTN, tachy, CNS activation)
Low risk OD but must not use with MAOIs
No CYP metabolism (elimination by conjugation) so no high profile drug interactions
Lower protein binding (exception = duloxetine is highly protein bound)
Overall shorter T1/2 than SSRIs
Also for anxiety disorders and pain
TCAs
Amitryptiline, imipramine
MOA: Inhibit both 5-HT and NE reuptake, major metabolites also have activity (antagonism at muscarinic Ach, H1, alpha-adrenergic receptors)
ADE:
muscarinic- dry mouth, blurred vision, constipation, urinary retention, delayed gastric emptying
H1: sedation
alpha-adrenergic: postural hypotension
Risk of overdose: ventricular arrhythmias, confusion, mania (narrow TI)
Interactions: CYP substrates, SSRI/SNRIs, potentiate alcohol/anesthetic agents, anti-HTNs
Most are long acting w/ active metabolites, highly protein bound
Monoamine receptor antagonists
Mirtazapine, trazadone
Fewer sexual side effects than SSRI/SNRIs
Very sedating
MAOIs
Inhibits MAO mediated degradation of monoamines (irreversible inhibition of MAO-A and MAO-B)
Risk of triggering HTN crisis if pt eats food rich in tyramine
ADE: CNS stimulation, orthostatic hypotension
Atypical antidepressant: Buproprion (Wellbutrin)
Stimulant
Also for smoking cessation, appetite suppression
Inhibits NE/DA reuptake
Lowers seizure threshold
Ketamine
NMDA receptor antagonist: increases glutamate levels in the brain and produces rapid antidepressant effect (10-15 min), normally for seizures/sedation/analgesia
At high doses, may cause sedation and out of body experiences
ADE: sedation, inattention, dissociation, abuse potential, SI
Brexanolone
Allopregnalone=neuroactive metabolite of progesterone, peaks during 3rd trimester and falls after delivery
(+allosteric modulator of GABA channels)
Cont. infusion over 60 hours approved for tx of postpartum depression
ADE: sedation–> LOC, HA, dizziness, dry mouth, hot flashes
Benzodiazepines
Anxiolytic-GABA receptor actions
alpha 1 subunit: sedation
alpha 2/3: anxiolysis
anticonvulsant, hypnosis, anterograde amnesia
Advantages: high TI, rapid onset of action, little induction of liver enzymes
ADE: rebound anxiety, withdrawal
Buspirone
MOA: blockade of 5-HT1A autoreceptors but stimulation of 5-HT1A postsynaptic receptors (partial agonist)
Anxiolytic w/ lower abuse potential than Benzos
Time to onset similar to SSRIss, slower and less effective than benzos
Parkinson’s symptoms
Tremor
Rigidity
Akinesia/bradykinesia
Postural instability/abnormal gait
Sleep disturbances
Other (N/V, pain, fatigue)
Autonomic (urinary, sweating, orthostasis)
Psych (depression, anxiety, cognition)
MAO-B Inhibitors
Rasagaline, seligiline
increase DA levels in the striatum
For mld cases or as adjunct during Levodopa off periods
Benefits rapidly decline
ADE: nausea, hallucinations, confusion, depression, insomnia, orthostatic hypotension, HTN
Centrally acting anticholinergics
Benzotropine
Partially block cholinergic receptors to help balance cholinergic & DA activity
Ind: mild disease
< 60 years old without cognitive impairment
Amantadine
Promotes release of DA from terminals in dorsal striatum. May increase DA @ receptors by releasing intact striatal DA stores, may block neuronal DA reuptake
Monotherapy for tremor or combo w/ Levodopa/Carbidopa to reduce Levodopa induced dyskinesia
Need dose adjustment for renal insufficiency
Decreases efficacy after few months (drug holiday can restore)
DA agonists (non-ergot)
1st line for Parkinsons. Direct activation of DA2 R in striatum. Less effective than levodopa, but less likely to cause dyskinesias
All can cause impulse control disorders d/t DA activation @ PFC
Pramipaxole: sleep attacks unique, renal excretion
Ropinirole: nausea more common, liver metabolism
Rotigotine: TD (extensive 1st pass metabolism), for early/mild Sx
Apomorphine: SQ. D2 and alpha 1/2 adrenergic receptors; increases NE. QT prolongation
Levodopa/Carbidopa
Most effective therapy for Parkinson’s but takes several months of tx before seeing full response
Dyskinesia=most troubling ADE
Off periods and weaning off occur
Levodopa–increases DA synth in striatum and helps restore proper balance btwn DA and AcH=h
Carbidopa–enhances effects of Levodopa by inhibition of decarboxylation in peripheral tissues
COMT inhibitors
Selective, reversible inhibitor of COMT –> decreased peripheral levodopa metabolism, prolonging T1/2 and duration of levodopa.
Increases duration of on phase, reduces weaning off phenomenon
ADE: dyskinesia, N/D, hallucinations, ortho hypo, urine discoloration
