Sketchy Pharma Flashcards
-Autoimmune Drugs -CV/renal drugs -Smooth muscle drugs
What part of the kidney does mannitol act as?
Mannitol = osmotic diuretic
-works at proximal convoluted tubule and descending loop of Henle (both of which are freely permeable to water) to draw water out into the lumen and increase free water removal
Use to draw free water out of the CNS (transiently teat ICP) and eye (decrease intraocular pressure transiently)
General use for cholinomimetics
Cholinomimetics = parasympathomimetics
Stimulate parasympathetic tone: increase gastric motility (use to treat non-obstructive ileus), increase lacrimation and salivation (tx Sjogrens), decrease intraocular pressure (use pilocarpine in glaucoma)
What lab value must be monitored in 75 yo F on Bosentan for pulmonary HTN
Bosentan = endothelin antagonist that can cause fatal hepatotoxicty
Monitor monthly LFTs
Main beta2 adrenergic effect
Beta2 activates Gs that activates PKA to relax smooth muscle
Relaxes smooth muscles in bronchial tree => bronchodilation
Relaxes smooth muscle in venuoles (vasodilation) => decreased SVR = drop in diastolic pressure
On fat cells activate lipolysis and FA release, promotes gluconeogenesis and insulin release
Describe the effect on BP of
(a) Phenylephrine
(b) Norepi
(c) Dobutamine
(d) Isoproterenol
(e) Epinephrine
BP changes
(a) Phenylephrine (pure alpha1) increases both systolic and diastolic => increases MAP w/o change in pulse pressure
(b) Norepi: alpha1 vasoconstriction => increase in MAP, little beta1
(c) Dobutamine (mostly beta1) is an inoptrope => increases systolic BP, increases MAP but w/ an increase in pulse pressure
(d) Isoproterenol (both beta1 and beta2) decreased MAP b/c of beta2 (decrease SVR) and widened pulse pressure b/c of beta1 (systolic stays relatively unchanged)
- so systolic RTS and diastolic drops, so MAP drops
(e) Epi: dose dependent change in BP
- low dose epi, beta effects predominate: widened pulse pressure (beta1 increases systolic, beta2 drops diastolic)
- high dose, alpha predominates: vasoconstriction, increased SVR, increase BP
Side effects of ACEi
a) Electrolyte abnormality
(b) Clinically troubling side effect (what bothers the pts
(c) Interaction w/ NSAIDs
ACEi side effects
(a) Hyperkalemia
- ACEi decrease aldo release, aldo generally holds onto Na causing K+ dumping, so w/o aldo we hold onto K+
(b) Persistent dry cough
- avoid this by switching to ARB if it is that troubling to pt
(c) NSAIDs decrease PGE production (PGEs vasoconstrict efferent arteriole) => both NSAIDs and ACEi dilate efferent arteriole (decrease GFR) => using them together can precipitate AKI
- same reason NSAIDs decrease loop diuretic efficacy (inhibit PGE and PGE decrease Na+ reabsorption and increases GFR)
Main indications for the following
(a) oxybutynin
(b) benztropine
Both are antimuscarinics
(a) Oxybutynin works to relax smooth muscle in the ureters and bladder wall to treat overactive bladder
(b) Benztropine is a central M1 antagonist used to treat EPS (symptoms of antipsychotics) and to improve tremor and rigidity in Parkinsons
Which diuretics work at the
(a) PCT
(b) Ascending loop of henle
(c) DCT
(d) CD
Diuretics
(a) Proximal convoluted tubule = acetazolamide, mannitol
(b) Ascending loop of henle = loop diuretics (furosemide)
(c) DCT = thiazides (HCTZ, chlorthalidone)
(d) Collecting duct = K+ sparing diuretics: amiloride, spironolactone
Are thiazides or loop diuretics used for edematous vs. mild HTN?
Thiazides work at DCT (where about 10% of Na is reabsorbed), so much less potent then loop diuretics that work at ascending loop of henle (completely ruins medullary gradient)
=> use loop diuretics for edematous states to get rid of large amounts of excess fluid, while using thiazides for mild HTN
Explain the mechanism of reflexive bradycardia w/ certain sympathomimetics
Sympathetomimetics w/ alpha1 effects (phenylephrine, NE, epi at high doses) cause reflexive bradycardia b/c baroreceptors sense elevated BP and reflexively activate beta tone
Explain the pH disturbance caused by acetazolamide
Acetazolamide = carbonic anhydrase inhibitor, decreases bicarb reabsorption at the proximal convoluted tubule of the nephron
-in exchange you get Cl- in to balance ions
=> results in hyperchloremic non-anion gap metabolic acidosis
Explain how diphenhydramine can be helpful in treating side effects of Risperidone
Diphenhydramine (H1 receptor blocker) is lipophilic => has CNS activity and can help re-establish the dopmaine-cholinergic balance in the brain, therefore helping w/ acute dystonia or other extrapyramidal side effects of antipsychotics
2 side effects specific for Verapamil over other CCBs
CCBs frequent side effects: light-headedness, headache
Verapamil specifically- constipation (literally in 25% of pts) and gingival hypertrophy (ew)
Features of acetylcholinestrase inhibitor overdose
ACh-ase OD = parasympathomimetic OD = symptoms of too much parasympathetic innervation = DUMBBELS
-also caused by organophosphate poisoning
diarrhea urination miosis (pupils constricted) bradycardia bronchospasm lacrimation salivation
Mechanism of nitrates for angina
Be specific- what molecules mediate??
Nitrates: broken down by vascular smooth muscle to release NO. NO then activates guanyl cyclase to increase cGMP. cGMP (key modulator) stimulates dephosphorylation of myosin light chain which stops it from binding to actin => smooth muscle dilation
Venous smooth muscle dilation = decreased preload = decreased LVEDV and myocardial O2 demand
Indications for CCB
(a) First line for stable angina
(b) 2 vasospasm d/o
(c) Neuro ppx
(d) HA
(e) Which for antiarrhtyhmic
Calcium channel blockres
(a) Stable angina use vasodilators (dihydropyridines) to dilate coronary arteries and decrease afterload
(b) Treat prinzmetal angina and Raynaud’s phenomenon
(c) Ppx of vasospasm after subarachnoid hemorrhage (MC 2/2 rupture of berry aneurysm)
(d) Migraine ppx
(e) Non-dihydropyridine (cardiac selective) as anti-arrhythmic
3 contraindications for ACEi
- Hereditary angioedema (C1 estrase deficiency)
- Pregnancy- ACEi is teratogenic
- B/l renal artery stenosis- makes sense here b/c these pts need angiotensin II on board to maintain their GFR
Why do pts on extended release oral nitrates need a daily break?
Pts can develop nitrate tolerance, where vascular smooth muscle beds decrease metabolism to NO (active molecule to increase cGMP and venodilate)
W/ reduced metabolism, pt gets side effects of headaches and flushing, so give daily break from the medication to prevent tolerance build up
Describe the features of atropine overdose
Think of atropine (antimuscarinic) overdose as the opposite of dumbbels
“dry as a bat” (decreased lacrimation and salivation)
“hot as a hare” (can’t lose heat by sweat)
Tachy (can’t slow down HR)
“blind as a bad” b/c antimuscarinics cause mydriasis and cycloplegia (inability to accomodate lens to nearby objects)
“mad as a hatter”
Explain the mechanism by which ACEi help in tx of chronic HF
- ACEi decrease SVR (by causing vasodilation) => decrease afterload
- ACEi cause natruiresis => decreased preload
Mechanism by which nitroprusside is helpful in hypertensive emergency
Nitroprusside is broken down in NO, then NO increases intracellular cGMP which relaxes vascular smooth muscle => vasodilates
Decreases peripheral vascular resistance/afterload
ACEi’s effect on
(a) SVR
(b) GFR
(c) Diuresis
ACEi inhibit conversion of ATI to ATII
(a) SVR decreases b/c blocked vasoconstrictor (ATII vasoconstricts), so decreased afterload
(b) GRF decreased
- ACEi causes vasodilation all around, including vasodilation of efferent arteriole
(c) ACEi cause a natural diuresis
Use of the following antimuscarinic agents
(a) Atropine
(b) Scopolamine
(c) Ipratropium
Muscarinic antagonists = drugs that block muscarinic (parasympathetic) tone
(a) Atropine- reverse lethal bradyarrhtyhmias or AV block
(b) Scopolamine (patch) for motion sickness
(c) Ipratropium/tiotropium: inhaled muscarinic antagonists for bronchodilation and decreased airway secretion in COPD
Best initial HTN agent if pt has concomitant
(a) HF
(b) Diabetes
(c) African American
(d) Edlerly
(e) Previous MI
Try to hit two birds w/ one stone
(a,b,e) If pt has concomitant HF, diabetes, or h/o MI: start w/ ACEi b/c can reduce mortality
(c,d) African Americans and elderly do specifically well w/ CCBs
Why aged cheese and wine can be dangerous to ppl on certain antidepressants
(a) Tx
Aged cheese and red wines contain tyramine which is metabolized by MAO-A (degrades Epi and NE). MAO can be blocked by MAO-inhibitors (class of antidepressants) => tyramine not broken down and goes on to cause hypertensive crisis
(a) Treat this hypertensive crisis w/ phentolamine (nonselective alpha blocker)
Differentiate the two classes of CCB
CCB (all of which block L-type voltage gated calcium channels) divided into
- Dihydropyridine: more selective for smooth muscle in arteries => used as vasodilators
- Nifedipine, Amlodipine, Nicardipine - Non-dihydropyridines: more cardio-selective => best for decreasing HR and contractility => reducing CO and myocardial O2 demand
- Verapamil = most cardiac selective
- Diltiazem = cardiac mostly w/ some vasodilatory effect
Explain beta-blocker use in acute vs. chronic HF
Avoid beta-blockers in acute HF (b/c you need the compensatory tachycardia and inotropy)
But then beta-blockers reduce overall mortality s/p MI and in chronic HF
-potentially 2/2 reduced myocardial oxygen demand, anti-arrhythmic effects, or inhibition of catecholamine-induced remodeling
Which psych drug does thiazide diuretics alter excretion of?
Thiazides decrease the renal excretion of Lithium => be careful of lithium overdose/toxicity in pt on both Li and thiazide diuretics
Name the drug
(a) Alpha-2 agonist for hypertensive urgency
(b) Nonselective alpha-antagonist for cocaine induced HTN
(c) Alpha antagonist for PTSD
(a) Clonidine = alpha2 agonist that reduces BP quickly => use in HTN urgency
(b) Phentolamine = alpha1 and alph2 antagonist given for cocaine induced HTN
(c) Proazosin = alpha-1 selective antagonist that can help w/ the nightmares and sleep disturbance in PTSD
Why are ACEi especially good for pts w/ HTN and diabetes?
ACEi slow the progression of diabetic nephropathy => really good for pts w/ HTN and DM
-also ACEi can be started in a pt w/ borderling high pressures who have albuminuria: albumin (protein) in urine sign of impending nephropathy => want ACEi on board
How do thiazides help in tx of diabetes insipidus?
Thiazides (inhibit NaCl cotransporter at DCT) cause hypovolumeia induced increase in Na and Cl reabsorption in more proximal segments of the nephron
-this helps relieve some of the polyuria seen in nephrogenic DI b/c kidney is less dependent on collecting duct (ADH dependent) reabsorption of solutes/water
How does local phenylephrine act as
(a) Decongestant
(b) Pupillary dilator
(a) Local vasoconstriction in the nasal mucosa (lots of alpha1 receptors there) reduces edema of nasal mucosa
(b) Activates alpha-1 at pupillary dilator muscle => causes mydriasis
Main alpha2 adrenergic effect
Alpha2 = sympatholytic
(thru G1, decreases cAMP)
Decreases nt release (presynaptic inhibition) => decreased BP
Inhibits insulin release and lipolysis
Decreases aqueous humor production (esp. Brimonidine) so can be used for chronic open angle glaucoma tx
Why NSAIDs may reduce efficacy of furosemide
Furosemide inhibits NKCC at ascending loop of henle
PGE enhances furosemide’s effects by increasing GFR (by dilating afferent arteriole) and further reducing Na+ reabsorption
So NSAIDs (inhibit PGE production can interfere w/ loop diuretic efficacy
When combined w/ nitrates, which drug combo has a mortality benefit for diastolic HF pts
Hydralazine (potent arterial dilator) + nitrates (potent venous dilator) has a mortality benefit for diastolic HF
Hydralazine decreases afterload while nitrates decrease preload
Explain how digoxin acts as a inotrope
Digoxin = cardiac glycoside from the fox glove plant, NaK ATPase inhibitor
NaK ATPase inhibited => Na+ not transported out of the cell so intracellular Na increases which stimulates/reverses Na/Ca exchanger
-Na needs to get out of the cell somehow so it exchanges w/ Ca => increased intracellular and SR Ca which increases contractility
Explain use of tamsulosin in older men
Tamsulosin = selective alpha1 blocker- blocks smooth muscle contraction of urethra relieving the urinary retention seen in BPH
Which specific diuretic should be used in the tx of Liddle syndrome
Liddle syndrome = congenital overactivity of ENaC Na+ reabsorption channel in the collecting tubule
Use Amiloride, K+ sparing diuretic that directly inhibits ENaC channels
Which receptors are activated by the following sympathomimetics
(a) Phenylephrine
(b) Norepi
(c) Dobutamine
(d) Isoproterenol
(e) Epinephrine
(a) Phenylephrine = relatively pure alpha1 agonist (all about dat smooth muscle activation/contraction)
(b) NE: Primarily alpha (both alpah1/alpha2), bit of beta1
(c) Dobutamine = mostly beta1 (so increased CO) w/ a little beta2 (decrease in diastolic)
(d) Isoproterenol: both beta1 (HR and contractility) and beta2 (vasodilation- reduced diastolic 2/2 reduced SVR)
(e) Epi: potent beta and alpha, dose dependent
- low dose: beta predominates
- high dose: alpha predominates
Which of the 5 senses may be impaired by furosemide?
Hearing- furosemide can have a dose-dependent ototoxic effect
Misoprostol
(a) Main side effect
(b) Use as ppx
(c) OBGYN use
Misoprostol = PGE1 agonist
(a) Diarrhea b/c of increased gastric activity
(b) Use as ppx for NSAID-induced gastric ulcers b/c PGE1 increases mucin-production by GI tract
(c) Used to stimulate uterine contractions to hasten labor or terminate pregnancy
Digoxin
(a) Predictor of mortality in acute toxicity
(b) GI involvement
(c) Pathognomonic visual feature
Digoxin
(a) Degree of hyperkalemia = predictor of mortality
- recall if Na/K ATPase is inhibited, K+ can’t get into cells => hyperkalemia
(b) N/V/abdominal pain
(c) Color vision changes, xanthopsia = objects appear yellow
Main types of shock treated by
(a) Phenylephrine
(b) Norepi
(c) Dobutamine
(d) Epinephrine
(a,b) Phenylephrine and NE used in hypovolemic, distributive shock (b/c increase SVR/venous return) and septic shock
(c) Dobutamine = inotrope for acute decompensated heart failure or cardiogenic shock
(d) Epi in anaphylactic shock
Main effects of angiotensin II
(a) on GFR
(b) on Na reabsorption
(c) on aldo release
Angiotensin II = potent pressor (vasoconstrictor)
(a) Increases GFR via constriction of efferent arteriole
(b) Works at PCT to increase NaHCO3 reabsorption
(c) Increases aldo release from adrenal cortex
Suffix of
(a) ACEi
(b) ARBs
(c) Benefit of ARBs over ACEi
(a) ‘pril’ = Lisinopril, analapril = ACEi
(b) ‘sartan’ = Losaratn = ARB
(c) Same activity, use ACEi first then use ARB in ppl who can’t tolerate ACEi
- ex: ppl who get persistent dry cough from ACEi
Main indication for digoxin immune FAB
Digoxin immune FAB (antibody) for sympatomatic (aka arrhythmias) digoxin toxicity
-so pt on digoxin has arrhythmia => give Digoxin immune FAB
Danger when first starting ACEi
(a) Why start HF pts on low dose then increase gradually
When first starting ACEi look out for hypotension and syncope
(a) Esp in pts w/ existing HF (already have super high renin) b/c this sudden removal of the pressor effects of ATII can cause dangerous hypotension and syncope
Potential electrolyte abnormalities induced by furosemide
Furosemide inhibits NKCC in the thick ascending loop of henle
- can cause hypokalemia (b/c not reabsorbing K+)
- also can cause hypomagnesemia, b/c inhibiting NKCC reduces the lumen positive pressure that causes excretion of Mg, so furosemide stimulates secretion of Mg
Major thing to avoid when treating cocaine overdose
Mostly symptomatic/supportive therapy
But DONT give beta-blockers, b/c unopposed alpha activity will vasoconstrict and lead to end organ damage
Instead can give phentolamine (alpha antagonist) to reduce BP
Mechanism of cocaine that causes
(a) HTN/tachycardia
(b) agitation/seizures
(c) Nasal septum perforation
Cocaine = inhibits NET and DAT (NE and DA transporters responsible for reuptake of nts by the presynaptic neuron)
(a) Peripheral NET inhibition => increased NE peripherally = increased BP and HR (mainly alpha1)
(b) Central DAT inhibition => arousal, seizures, midriasis (dilated pupils), agitation
(c) Locally increases NE release in the nose = potent vasoconstrictor (alpha1) => ischemia locally
Name some unwanted side effects of diphenhydramine
Diphenhydramine = H1 receptor blocker, lipophilic so crosses BBB
- has some 5-HT receptor antagonist effects => stimulates appetite = weight gain
- antagonizes muscarinic receptors => can cause same pic as atropine overdose: pupillary dilation, urinary retention, dry mouth, constipation, delitium
- also inhibits alpha1 receptors => dizziness and hypotension
Explain why dobutamine is used as a pharmacologic agent for cardiac stress test
Dobutamine = beta1 agonist = Gs receptor to increase intracellular cAMP in cardiac myocytes
-so increases HR and contractility (overall CO) which also increases myocardiac O2 demand => can reveal areas most sensitive to ischemia = use as pharmacologic stress test
Lab abnormalities seen on thiazide diuretics
(a) BMP changes
(b) Lipid panel
Thiazide induced lab abnormalities
(a) Hypokalemia (b/c more Na to the collecting duct, so more K+ pushed out while reabsorbing Na), hyperglycemia (thiazides impede insulin release and tissue glucose uptake)
- hyponatremia
(b) Hyperlipidemia: increase LDL and TG
Indication for a selective NE transport inhibitor
NET inhibitor = Atomoxetine (straterra) = stimulant used to tx ADHD
-NET reuptakes NE at the presynaptic neuron => inhibition increases NE available in the synapse
2 indications of pilocarpine
Pilocarpine = parasympathomimetic
Tx dry mouth and glaucoma
-increases salivary secretions (M3 receptors on glands) and contracts ciliary muscle to increase aqueous humor outflow to high intra-ocular pressure
Go to 3 drug combo for treating primary hypertension
Primary HTN tx: thiazide diuretic (HCTZ) + ACEi (Lisinopril, ARB if dry cough) + CCB (long acting dihydropyridine to vasodilate)
Explain why some women may like spironolactone, and why some males may hate it
Spironolactone (K+ sparing diuretic) inhibits aldo receptor, but also has some cross reactivity, it’s an anti-androgen (both blocks testosterone synthesis and directly antagonizes androgen receptor)
=> spironolactone is used in tx for women w/ PCOS to decrease hirsuitism and symptoms of hyperandrogenism
=> spironolactone can cause low-T => gynecomastia, impotence, decrease in libido in men :-(
Which CCB is safest during pregnancy?
CCB during pregnancy = Nifedipine (dihydropyridine vasodilator)
Main side effects of nitrate therapy
Nitrate side effects: pounding headache, cutaneous flushing, tolerance (decreased metabolism to NO over time causing dizziness/HA- explains the need for daily breaks)
Differentiate Spironolactone and amiloride
Both are K+ sparing diuretics that work at the collecting duct
Spironolactone inhibits the aldo receptor, while amiloride inhibits ENaC (one of the main transporters aldo stimulates)
-but spironolactone is nonspecific => can block androgen receptors and block testosterone synthesis
Amiloride is more specific, doesn’t have any effects on androgens
Other indications for beta-blockers in addition to HF
- migraine ppx
- essential tremor (propranolol)
- treating symptoms of thyroid storm
- antiarrythmic (class II)
Differentiate the mechanism of these two drugs in tx of acute HF:
Milrinone and Nesiritide
Milrinone = PDE inhibitor to decrease cAMP breakdown: increased cAMP increases cardiac contractility (intrope)
Nesiritide = synthetic BNP which increases cGMP in smooth muscle cells => arterial and venous dilation => decreased preload and afterload, also causes natriuresis
Name some drugs used during hypertensive emergency
Drugs for hypertensive emergency: vasodilators!!! (decrease afterload)
- beta blockers (esmolol, metoprolol)
- labetalol (both beta and alpha blocker): beta blocker decreases HR/contractility, alpha blockade causes vasodilation
Other vasodilators
- IV CCBs (Nicardipine)
- Hydralazine
- Nitroprusside
- Fenoldopam (D1 receptor antagonist to vasodilate renal arterial bed)
Alpha-methyl Dopa for use in HTN
(a) Side effect
Alpha-methyldopa = L-Dopa analogue (precursor to dopamine)
-dopamine activates alpha2 receptors centrally to decrease BP
Key here is that it’s safe for use during pregnancy
-so alpha-methyldopa as alpha2 agonist to tx HTN in pregnancy
Recall: labetolol = other anti-hypertensive useful in pregnancy
(a) Key side effect: Lupus like syndrome
Name 2 RF for digoxin toxicity
RF for digoxin toxicity
- Hypokalemia- low serum K increases digoxin binding to NaK ATPase
- Renal insufficiency b/c then increased half life of digoxin
- can be caused by drugs such as antiarrhythmics
Dangerous side effect of nitroprusside
Nitroprusside can cause cyanide toxicity
-manifests as seizures, altered mental status
Side effects of
(a) Beta1 blockade
(b) Beta2 blockade
(c) General beta-blockade in men
(a) b1 blockade => bradycardia and exacerbation of AV block
- so contraindicated in pt w/ existing heart block
(b) b2 blockade => can exacerbate COPD and asthma 2/2 bronchoconstriction
- so chose cardioselective (b1 selective) blockers to tx HF in pt w/ h/o ashtma
(c) Beta blockers can cause impotence in men
Differentiate mechanism of cocaine and amphetamines
Cocaine inhibits NET and DAT to decrease catecholamine reuptake at synapse
Amphetamines increase catecholamine release by presynaptic neuron so more is available in the synapse
Contraindications of cholinomimetics
Cholingeric tone works at both nicotinic and muscarinic receptors
-activation of muscarinic receptors (esp M3) => bradycardia, bronchospasm/bronchoconstriction, and increase rest/digest
Contraindications: asthma, peptic ulcer disease, COPD
What is a contraction alkalosis?
(a) 2 ways by which thiazides and loop diuretics cause this
Contraction alkalosis = increase in pH due to volume loss
(a) Thiazides and loop diuretics:
increase fluid loss
increase aldo => increase H+ excretion
increase ATII => increase HCO3- reabsorption
Signs of beta-blocker toxicity
(a) Reversal
Bradycardia, AV block, dyspnea
(overdose on beta blockade)
(a) Reversal agent = glucagon packets
- glucagon works directly on heart (not via adrenergic system, so not impacted by beta-blockade) to increase HR
Use of pyridostigmine vs. edrophonium in tx for MG
Both are peripherally acting acetylcholinestrase inhibitors (increase ACh at nmj)
First line tx for MG is pyridostigmine
Edrophonium has super short half life (like only helps symptoms for 5 mins) so not used for tx, but good to use for distinguishing underdosed tx of MG from cholinergic crisis
If give edrophonium and symptoms improve- increase dose of pyridostigmine
If give edrophonium and symptoms don’t improve = cholinergic crisis and stop pyridostigmine
Name 3 classes of vasodilatory agents used in the tx of pulmonary HTN
Tx of pulmonary HTN
- PGE1 agonists: Epoprostenol
- PDE5 inhibitors: Sildenafil (hence the old lady on Viagra)
- Endothelin antagonist: Bosentan
Why are beta-blockers sometimes combined w/ nitrate therapy?
Nitrates venodilate, which can cause venous pooling and hypotension. This hypotension can stimulate reflex sympathetic activity (tachycardia) which increases mO2 demand (ummm the opposite of what we want)
So give concomitant beta-blocker to block this reflex sympathetic activity
Mechanism of action of the 4 sympathetic nervous system receptors
G proteins that function as transducers: QISS
alpha1: Gq (same as M1 and M3): activate IP3-DAG pathway to increased intracellular calcium
alpha2: Gi (inhibitory) decreases cAMP
beta1: Gs- increases cAMP to increase intracellular Ca
beta2: Gs- increases cAMP that activates PKA and relaxes smooth muscle
Describe the involvement of ENaC and alpha intercalated cells at the collecting duct
Collecting duct:
- ENaC channels on luminal surface for Na+ reabsorption
- alpha intercalated cells contain H+ATPase for H+ secretion
ENaC reabsorbs Na+, creating a negative luminal pressure that draws out K+ and H+
Name 2 states in which ACEi tx provides mortality benefit
- chronic heart failure
- after MI
Mechanism thought to be b/c of reduction of ATII mediated cardiac remodeling
Main beta1 adrenergic effect
Beta1 activates Gs => increased intracellular cAMP and Ca2+
2 locations
- cardiac myocytes/nodal cells to increase HR and contractility => overall increase cardiac output
- on JGA cells to increase renin release- hold onto volume and maintain BP
Which receptors are activated by dopamine at different doses
‘DBA’ order of activation
D1 (Gs activating PKA) at low dose (smooth muscle relaxation)
B1 (Gs increases cAMP) at medium dose (cardiac activation)
A1 (Gq for IP3-DAG) at high dose (pressor effects)
Define hypertensive emergency
Hypertensive emergency = systolic over 180, diastolic over 120, with evidence of end-organ damage
E/o end organ damage: blurry vision, altered mental status etc
Differentiate nicotinic and muscarinic receptors
(a) Location
(b) Mechanism of action
Receptors activated by ACh to stimulate parasympathetic innervation
Nicotinic receptors
(a) 3 places: ganglia, nmj of skeletal muscle, in the adrenal gland
(b) Ion channel activation
Muscarinic receptors (a) At the effector organs M1: nerves and CNS M2: cardiac- atria, AV and SA node M3: glands, smooth muscle organs (b) Work via G-protein coupled receptors -M1 and M3 work by activating IP3-DAG cascade to increase intracellular calcium -M2 works by decreasing cAMP
Main side effect of alpha blockers
Orthostatic hypotension w/ reflexive tachycardia
-b/c alpha1 tone is what causes the vasoconstriction that maintains BP when we stand
Mechanism of furosemide
Furosemide = inhibits NKCC transporter at the thick ascending loop of Henle
- thick ascending loop is impermeable to water (so only solutes are reabsorbed, this is used to dilute the interstitium)
- so inhibit Na+ reabsorption here
Less Na+ reabsorption => diuresis, also ruins the medullary concentration gradient needed by collecting duct to concentrate urine
Digoxin- describe the cardiac changes to look out for and involvement in arrhythmias
Digoxin (cardiac glycoside, NaK ATPase inhibitor) directly stimulates vagal innervation => can induce bradycardia and AV nodal block
-vagal stimulation makes Digoxin a second line agent for atria arrhythmias
Then Digoxin increases intracellular Ca and AV block => can cause almost any arrhythmia
-so ironic that it’s used both for treating certain arrhythmia, and it causes arrhythmias
Briefly describe the amino acid precursor used in catecholamine synthesis
(a) Inhibitor
Tyrosine (AA precursor) transported to nerve terminal –> L-dopa –> DA –> NE
(a) Met-tyrosine can be used to prevent conversion of tyrosine to L-dopa
Differentiate these beta-blockers: metoprolol, carvedilol, labetolol
Metoprolol is cardiac (b1) selective
Carvedilol is nonselective beta-blocker w/ some alpha1 blocking
Labetolol is also (like Cavedilol) a nonselective beta-blocker w/ some alpha1 blocking that is safe for use in pregnancy
Fenoldopam
(a) Mechanism of action
(b) Key feature
(a) Fenoldopam = specific D1 receptor antagonist. Increases intracellular cGMP which vasodilates arterial beds
- vasodilates specifically: arterial, coronary, and renal arteries
(b) Key is that it dilates renal arterial bed => increases renal perfusion while decreasing BP (very unique feature)
- causes natruiersis
Contraindications to nitrate therapy
(a) 2 cardiac conditions
(b) Simultaneous medication
Nitrate contraindications
(a) Right-sided MI and HOCM, both preload dependent d/o
(b) PDE5 inhibitors such as Sildenafil 2/2 dangerous drop in BP
Clonidine
(a) Mechanism
(b) Indications
(a) Clonidine = alpha2 agonist
(b) Alpha1 = Gi, inhibitory, sympatholytic
- reduce HTN in hypertensive urgency
- ADHD refractory to stimulants
- First line for Tourette’s
Expected BMP change after starting pt on ACEi
Expect a bump in creatinine
-b/c ACEi decrease GFR (by dilating efferent arteriole) => expected bump in creatinine when first start on ACEi
Main alpha1 adrenergic effect
Alpha1 = sympathomimetic
(thru G1, activating IP3-DAG increasing intracellular Ca) causes smooth muscle contraction
Vasoconstriction of arterioles => increased BP
Vasoconstrictions of veins => increased venous return
Constriction of urethra and prostate => urinary retention
Constriction of ?? => pupillary dilation (but basically sympathomimetic so widen up eyes to see the bear)
With epi on board: what effects would you see if the following were given
(a) alpha-blocker
(b) beta-blocker
Epi is dose dependent, low dose beta predominates and high dose alpha predominates
Both increase BP, w/ low dose dropping diastolic and widening pulse pressure
(a) Alpha blocker given: diastolic pressure drops (beta2), HR rises (beta1), pulse pressure widens
(b) Beta blocker given: Pulse pressure narrows (beta2 no longer dropping diastolic), MAP increases b/c of vasoconstriction causing increased SVR
Digoxin
(a) 2 indications
(b) Mechanism of both indications
Digoxin
(a) Tx of refractory (to ACEi and diuretic) chronic heart failure, also antiarrhythmic
(b) Inhibits Na/K ATPase
- works at antiarrhythmic by direct vagal stimulation
Differentiate HCTZ and chlorthalidone
Both are thiazide diuretics (inhibit NaCl cotransporter at DCT) but chlorthalidone has longer half life = longer duration of action
Name two anti-epileptics used for migraine ppx
Topiramate (Topamax) and Valproic Acid (Valproate)
Big distinguishing factor of low dose dopamine when used as pressor
Low dose dopamine activates D1 receptor (Gs => PKA => smooth muscle relaxation) which increases GFR and renal blood flow
While phenylephrine and other alpha1 agonists will decrease renal blood flow
Relative contraindications to Verapamil and Diltiazem
Non-dihydropyridines decrease HR and contractility- decrease nodal activity => don’t give to pts w/ any heart block or conduction abnormalities
-don’t use w/ beta blockers which also decrease/block AV nodal conduction
Differentiate mechanism of 1st and 2nd generation anti-histamines
(a) G-protein coupled
(b) Indications
Anti-histamines block H1 receptors (not talking H2 receptor blockers used for stomach acid reduction)
First generation anti-histamine = diphenhydramine, meclazine
(a) Gq coupled protein
(b) First line for acute allergy/hives (type I hypersensitivity), also can tx EPS symptoms from antipsychotics, can be used for insomnia (b/c cause drowsiness), tx motion sickness (b/c lipophilic and cross BBB)
Second generation = loratidine, fexofenadine, cetrizine
(a) Again inhibit H1 (Gq protein coupled)
(b) Tx allergic symptoms w/o the drowsiness and other CNS side effects (anti-muscarinic) b/c these are less liphophilic => don’t cross BBB
Organophosphate poisoning
(a) Features
(b) 2 drugs for tx
Organophosphate binds (eventually bind becomes covalent and irreversible) to acetylcholinestrase, so organophosphate poisoning presents as
(a) Overdose of paraysmpthateic innervation = DUMBBELS: diarrhea, urination, miosis, bradycardia, bronchospasm, lacrimation, salivation
(b) Tx
- atropine to reverse the central muscarinic toxicity
- pralidoxime to block both muscarinic and nicotininic receptors, reverse the paralysis
Mechanism of thiazide duiretics
Thiazides inhibit the NaCl cotransporter at the distal convoluted tubule
So decrease NaCl reabsorption at DCT
Which diuretic may be beneficial in tx pt w/ HTN and osteoporosis?
Thiazide diuretics
-enhance calcium reabsorption => useful to help bone mineralization and potentially even prevenet fractures
NOT loop diuretics, furosemide actually increases Ca2+ excretion
Tx of atropine overdose
Atropine (competitive muscarinic inhibitor) tx w/ physostigmine
Only pyridostigmine (and not other ACh-ase inhibitors) b/c pyridostigmine can cross BBB => CNS penetration (while pyridostigmine, neostigmine both can’t penetrate CNS)
Use of methacholine challenge test
Methacholine = cholinomimetic that contracts smooth muscles of the bronchial tree => exacerbates asthma/COPD
Main indication for azetazolamide
Decrease CSF production in pseudotumor cerebri (idiopathic intracranial hypertension)
Aldosterone
(a) Location of receptor
(b) Action
Aldo
(a) Intracellular receptor (b/c aldo is a steroid hormone)- inside ENaC containing cells and alpha intercalated cells
(b) Aldo increases Na+ reabsorption (thru ENaC transporter) which increases negative transluminal pressure, increasing K+ excretion and activity of H+ATPase to secrete H+
Mechanism of side effects seen in elderly who take diphenhydramine
Diphenhydramine (first generation histamine-1 receptor blocker) also has anti-muscarinic effects => can cause delirium and cognitive impairment, especially in the elderly
Describe adrenergic effect on aqueous humor production and how this is targeted to treat glaucoma
- beta2 activation increases aqueous humor production => use beta-blocking agents in glaucoma
- alpha2 activation (specifically Brimonidine) decreases aqueous humor production => alpha2 agonist to tx glaucoma
Explain etiologies of emesis when the irritant is in the
(a) GI tract
(b) Vestibular system
(c) Area postrema
Emesis from irritant in the
(a) GI tract = enteritis, gastritis, post-op (2/2 intra-op manipulation of vagal nerve)
- tx w/ Onadestron (5-HT3 inhibitor)
(b) Vestibular system from motion sickness
- tx w/ meclazine (H1 receptor blocker) or scopolamine (M1 receptor antagonist)
(c) Area postrema = just outside BBB in the 4th ventricle, chemotherapy-induced nausea
- Tx w/ Metoclopramide
Name the 3 inputs to the nucleus solitarius
Nucleus solitarius = central nucleus that mediates vomiting reflex
3 inputs
- directly from GI tract from vagal afferents (CN X)
- vestibular system from CN VIII
- area postrema right outside the BBB in the 4th ventricle
Mechanism by which GI irritation causes vomiting
GI irritation increases 5-HT (serotonin) release, activating the 5-HT3 receptors on vagal afferents that travel directly back to the nucleus solitarius
Differentiate mechanism of anti-emetics
(a) Onadestron
(b) Meclazine
(c) Scopolamine
(d) Metoclopromide
(e) Aprepitant
(a) Onadestron (Zofran) inhibits 5-HT3 receptors on GI tract vagal afferents
(b) Meclazine = H1 receptor blocker to block nausea from vestibular system (motion sickness)
(c) Scopolamine = M1 antagonist (anti-muscarinic) to block nausea from vestibular system (motion sickness)
(d) Metoclopromide (Reglan) inhibits D2 receptors in the area postrema to block central vom-inducing substances (like chemo in the CSF)
(e) Aprepitant = NK1 receptor antagonist (neurokinin receptors on the area postrema) to treat chemotherapy induced vomiting w/o the side effects of reglan
2 risks of of onadestron therapy
Onadestron (5-HT3 receptor antagonist) used as anti-emetic, risks:
- serotonin syndrome: esp if used concomitantly w/ SSRI
- prolonged QT (recall anti-ABCDEs for drug-induced prolonged QT)
Name some side effects of Metoclopramide
Metoclopramide = D2 receptor blocker
- can cause EPS b/c of dopamine blockade
- can cause hyperprolactinemia (gynecomastia, galactorrhea, decreased libido, oligomenorrhea) due to loss of prolactin inhibition by dopamine
- risk of NMS at high dose
- prolonged QT
2 indications of metoclopramide
Metoclopramide = D2 receptor blocker
- Used as anti-emetic b/c blocks D2 receptors on area postrema
- Used as pro-kinetic of upper GI tract (tx delayed gastric emptying post-op or in diabetics) b/c blocks D2 receptors in GI tract
Benefit of aprepitant over metoclopramide
Area postrema (vomiting center) has both D2 receptors and NK1 (neurokinin receptors)
Metoclopramide antagonizes D2 receptors to act as anti-emetic, but this comes w/ a hole host of side effects
- EPS, tardive dyskinesia
- hyperprolactinemia
- risk of NMS
- QT prolongation
- depression, drowsiness (esp in elderly)
While Aprepitant (NK1 receptor antagonist) doesn’t have any of these side effects…
Insulin receptor
(a) Pathway signaling molecule
(b) Effect of ligand binding
Insulin receptor
(a) Intracellular tyrosine kinase
(b) Insulin binding to its receptor activates tyrosine kinase that causes:
1. increase of GLUT4 translocation onto plasma membrane
2. stimulates anabolic processess (lipolysis, glucogenlysis)
How does insulin change serum K+
Insulin stimulates NaK ATPase => draws K+ into cells (in exchange for Na out)
So insulin can be used to tx hyperkalemia, also means when giving insulin in DKA you should co-administer K+ to prevent hypokalemia
Which insulin form can be given intravenously?
(a) Clinical significance
Only regular insulin (intermediate acting) can be given IV
(a) Rapid acting, IV- this is the form given during DKA
Give the names of
(a) Rapid acting insulin preparations
(b) Intermediate acting
(c) Long acting
Names of the drugs
(a) Rapid acting preparations: Glulisine, Aspart, Lispro
(‘girls and lads’)
(b) Regular insulin, NPH
‘rest now’
(c) Detamir, Glargine
‘don’t go’
Give the names of the drugs
(a) Sulfonylureas
(b) Meglitinide
(a) Sulfonyulreas = sulfa drugs that bind to ATP-dependent K+ channel to close it, depolarizing beta-islet cell membrane and causing insulin release
Names = Glipizide, Glyburide
(C) Meglitinide = non-sulfa drugs (so can be used in ppl w/ sulfa allergies) w/ the same mechanism as sulfonylureas
Names = Repaglinide, Nateglinide ‘glinide’
What type of drugs are the following:
(a) Glipizide
(b) Repaglinide
(c) Exanatide
(a) Glipizide = sulfonyurea = secretagogue, binds ATP-dependent K+ channel to depolarize beta-cell and cause insulin release
(b) Repaglinide = Meglitinide = secretagogue w/ same mechansim as sulfonyulrea but is a non-sulfa drug (can be used in ppl w/ sulfa allergy)
(c) Exanatide = GLP-1 (glucagon-like peptide 1, usually secreted by intestinal L-cell in response to food load) agonist: increases insulin release, decreases glucagon release, delays gastric empting
What kind of drugs are the following:
(a) Glyburide
(b) Sitagliptin
(a) Glyburide = sulfonyurea = binds ATP-dependent K+ channel to depolarize beta islet cell and cause insulin release
(b) Sitagliptin = DPP-4 inhibitor, DPP-4 breaks down GLP-1 (glucagon-like peptide 1). So inhibiting DPP4 allows more GLP1 to be around.
GLP-1 increases insulin release, decreases glucagon release, and delays gastric emptying
Insulin secretagogue drugs
(a) Name the two classes
(b) Weight change in pts
(c) Side effect
Insulin secretagogues
(a) Sulfonyulrea and Meglitinides
(b) Can cause weight increase b/c these drugs stimulate insulin release and insulin is an anabolic hormone
- stimulates nutrient storage
(c) High risk of hypoglycemia since stimulate insulin release regardless of food intake
Side effects of Sitagliptin
Sitagliptin = DPP4 inhibitor (inhibits breakdown of GLP-1), more GLP-1 around to increase insulin release, decrease glucagon release, delay gastric emptying
Side effect = increased risk of URI and nasopharyngitis
Benefit of GLP-1 agonists over sulfonyulrea
GLP-1 agonists do not carry a risk of hypoglycemia b/c activity is glucose dependent, so effects diminish as glucose levels approach normal
Sulfonylureas have high risk of insulin since stimulate insulin release regardless of oral intake
Contraindication to metformin use
Renal failure- kidneys excrete metformin essentially unchanged, if not excreted then increased risk of lactic acidosis
Metformin already poses risk of lactic acidosis, then further increased if kidneys not metabolizing
3 activities of metformin
Metformin
- decreases gluconeogenesis in the liver
- increases peripheral uptake of glucose
- increases peripheral sensitivity to insulin
Metformin side effect
(a) MC
(b) Most dangerous
Side effects of metformin (inhibits gluconeogenesis and improves insulin sensitivity)
(a) MC = GI upset: N/V/D
(b) Most dangerous = lactic acidosis
- increased risk in renal insufficiency (less renal fxn to excrete metformin) or tissue hypoxia (higher load of lactate produced)
Mechanism of piolitazone
Pioglitazone = PPARgamma ligand, PPARgamma is an intracellular nuclear receptor that regulates transcription of certain genes
-specifically activation of PPARgamma ligand upregulates adipnectin which increases insulin sensitivity and fatty acid oxidation
Oral diabetes drug that
a) Can cause wt loss
(b) Can have delayed onset (takes days-weeks for full effect
Oral diabetic agents
(a) Cause wt loss: metformin
(b) Delayed onset = pioglitazone = PPARgamma agonist, PPARgamma is
Side effect of pioglitazone
Pioglitazone = PPARgamma ligand that activates adiponectin production to increase insulin sensitivity and increase fatty acid oxidation
-stimulates TG uptake => reduces serum TG but can also lead to weight gain
Main side effect = fluid retention and peripheral edema => contraindicated in heart failure
Mechanism of dapaglifloxin
Dapaglifloxin and canaglifloxin are SGLUT2 inhibitors- => decrease glucose reabsorption at the proximal convoluted tubule
2 side effects of dapaglifloxin/canaglifloxin
- Increased risk of UTI and vaginal candidiasis
2. Dehydration (glucose acts as osmotic solute to suck water out into urine)
Mechanism of alendronate
Alendronate = bisphosphonate
- inhibits binding of osteoclasts to bone => inhibits bone breakdown
- also inhibits osteoclast differentiation and recruitment
Name another indication for alendronate aside from osteoporosis tx
Alendronate = bisphosphonate = inhibits osteoclast binding to bone to decrease bone breakdown
- can be used to acute treat hypercalcemia (ex: hypercalcemia of malignancy), b/c reduces bone breakdown therefore reduction of Ca2+ put into serum
- can treat Paget’s disease = overactive osteoclasts that lead to disorganized bone growth
Alendronate side effects
(a) MC
(b) Most dangerous
Side effects of bisphosphonates
(a) MC = upper GI side effects such as acid reflux, esophagitis, even esophageal ulcers
- explains why pts are told to take these meds w/ a lot of water and sit upright for 30 mins after taking
(b) Most dangerous = rare side effect of jaw osteonecrosis
Benefit of Raloxifen over estrogen therapy for osteoporossi
Raloxifen = SERM = selective estrogen receptor modulator, so only is an agonist of estrogen receptors at specific tissues
Activates estrogen receptors at bone to decrease bone mineral loss, while antagonizing estrogen receptors on breast and uterine tissue => doesn’t increase risk of breast/uterine malignancy like endogenous estrogen
How does PTH affect bone resorption
PTH stimulates osteobalsts to upregulate RANKL (RANK-ligand), RANKL binds to RANK on osteoclasts to activate bone breakdown
How does calcitonin affect bone resorption
Calcitonin inhibits osteoclasts => reduces bone break down to ‘tone down calcium’
So calcitonin can be used in the tx of Paget’s disease where overactive osteoclasts resorption causes disorganized bone structure
How does the monoclonal antibody Denosumab act compared to PTH
PTH stimulates RANKL expression on osteoblasts, which binds to RANK to activate osteoclasts to break down bone and release Ca2+ into serum
Denosumab = anti-RANKL monoclonal antibody that blocks the osteoblast’s ability to stimulate osteoclast bone breakdown => useful in tx of osteoporosis
Differentiate ADH’s two receptors
(a) G-coupled protein
(b) Location
ADH receptors
V1
(a) Gq coupled => activates PLC (phospholipase C) to increase intracellular Ca2+
(b) On vascular smooth muscle cells to cause vasoconstriction (hence vasoPRESSIN)
V2
(a) Gs coupled => activates adenylyl cyclase to increase cAMP
(b) On collecting duct basolateral membrane to stimulate translocation of aquaporin2 onto apical surface
Extrarenal V2 also located on vascular endothelium to stimulate release of both vWF and factor VIII
Name 3 drugs for the tx of nephrogenic DI
- Thiazide diuretics
- Amiloride (K+ sparing diuretic) specifically good for Li induced nephrogenic DI
- NSAIDs (ex: Indomethacin), reduces PGE production which antagonist ADH
Indication of desmopressin in addition to central diabetes insipidus
Desmopressin = ADH analog
V2 receptors are present extrarenally on vascular smooth muscle, stimulation increases release of both vWF and factor VIII
So desmopressin can be used in the treatment of von Willebrand deficiency and Hemophilia A (factor VIII deficiency)
Conivaptan use in tx of SIADH
Conivaptan (‘vaptans’) are ADH receptor antagonists
So use (along w/ free water restriction) in tx of SIADH to block ADH receptors on collecting tubules and prevent more water retention
Explain how ADH can be useful in the treatment of bleeding varices
ADH is called vasoPRESSIN after all!!! V2 receptors on vascular endothelial smooth muscle cells cause vasoconstrictino => constrict the mesenteric arterioles to reduce portal pressure and aid in tx of bleeding esophageal varices
Location of glucocorticoid receptor
(a) Mechanism of action
Glucocorticoid (steroids) are lipophilic so can enter the cell, glucocorticoid receptors are in the cytoplasm, then once bound to receptor the complex moves into the nucleus where it acts directly as a transcription regulator
(a) Receptor and ligand together bind to DNA to alter transcription
Explain how glucocorticoids
(a) Reduce leukotrienes
(b) Inhibit lymphocyte attraction
(c) Inhibit neutrophil attraction
Glucocorticoids
(a) Reduce both PGE and leukotriene synthesis b/c glucocorticoids inhibit phospholipase A2 (PLA2) that is the first step in removing arachidonic acid (precursor molecule for PGE and leukotrienes) from the plasma membrane
(b) Glucocorticoids inhibit NF-kappaB which stimulates IL-2 and TNF-alpha which are needed to recruit and activate both T and B lymphocytes
(c) NF-kappaB (inhibited by glucocoritoicds) is responsible for producing neutrophil adhesion molecules needed for neutrophils to leave blood stream and exit to cause inflammation.
CBC in pt on glucocorticoids: what will be elevated vs. reduced
Glucocorticoids
-inhibit NF-kappa B => decreased IL2/TNFalpha (activate T and B cells) and reduced neutrophil adhesion molecules => neutrophils can’t leave BV so get neutrophilia 2/2 marginalization of neutrophils
All other WBC cell lines (T-cells, B-cells, especially helper-T cells) are reduced
Explain metabolic (glucose and fat) changes due to glucocorticoids
Glucocorticoids (think like cortisol, stress hormone)
- stimulates gluconeogenesis
- stimulate proteiolysis and lipolysis to provide substrate for gluconeogenesis
- induces insulin resistance, which along w/ increased glucose production => hyperglycemia
Explain the following findings in glucocorticoid tx
(a) Moon face
(b) Striae
(c) Fracture
(d) Hypokalemia
(e) Reactivation of Tb
Glucocorticoid side effects
(a) Moon facies 2/2 increased lipolysis to provide substrate for stimulated gluconeogenesis
(b) Striae b/c fibroblasts are inhibited
(c) Fracture b/c glucocorticoids stimulate osteoblasts
(d) Hypokalemia 2/2 crossover w/ mineralocorticoid activity
(e) Reactivation of Tb 2/2 immune suppressoin
