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242 Cards in this Set

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  • Back
Synthesis of ACh?
Synthesized in nerve terminals by the cytoplasmic enzyme CHOLINE ACETYLTRANSFERASE, which catalyzes transfer of an acetate group from acetyl CoA to choline
Degradation of ACh?
Rapidly hydrolyzed and inactivated by tissue ACETYLCHOLINESTERASE (AChase),

Also by non-specific pseudocholinesterase (inactivates more slowly than AChase)
Where do we find ACh as a neurotransmitter?
CNS (N and M)

autonomic ganglia (N1)

adrenal medulla (N1-receptor stimulation releases Epi from adrenal medulla),

NM junction (N2)

sweat glands (M)
Alzheimer’s disease and ACh? How is ACh implicated in treatment?
ALZ involves a deficit of ACh in CNS

TX: w/ carbamate AChase inhibitors like DONEPAZIL (DOC)
ACh agonists?



“Can’t Be Metabolized” – more slowly metabolized and thus longer duration of action than ACh
Methacholine therapeutic use?
Dx of asthma, causes:
GI cramping

Tiny dose given
Choline esters…?
Nicotinic/muscarinic effects = ACh and CARBACHOL

Muscarinic effects = METHACHOLINE and BETHANECHOL
Bethanechol therapeutic use?
-is it tertiary or quaternary?
Urinary retention, bowel stasis, postop paralytic ileus

Quartenary – doesn’t cross BBB
Choline esters given i.v. will cause…?
Decreasd BP via NO released from vascular endothelial cells (muscarinic receptors)

↓BP can be blocked by atropine
Therapeutic use of pilocarpine?
Causes miosis and cycloplegia via contraction of ciliary muscle
-- effect decreases IOP via increased outflow of aqueous humor
-- treatment for open angle glaucoma

If treating acute narrow angle glaucoma, given w/ physostigmine (indirectly acting muscarinic agonist)
Pilocarpine S/Es?


A tertiary amine
-- not hydrolyzed by plasma AChase
-- metabolized by liver
-- induces cytochrome CYP450, so increases drug metabolism (actually, benzypyrene in cigarettes)
Nicotine effects?
1. ↑ sympathetic activity with ↑ HR and BP, cutaneous vasoconstriction (cold hands/fingers)

2. increased respiration and GI motility

3. large doses - muscle fasciculations, followed by depolarization blockade

4. CNS - convulsions with overdose (OD)
AChase Inhibitors?

Name the carbamates
Physostigmine (tertiary)

Neostigmine (quaternary)

Edrophonium (quaternary)
Physostigmine therapeutic use?
Eye drops cause miosis
-- lower IOP in glaucoma
Edrophonium therapeutic use?
1. Diagnosis of myasthenia gravis (MG)
-- differentiate between “myasthenic” and “cholinergic” crisis in patients
-- reduces brkdwn of ACh in NMJ; eyelids open
-- tx MG w/ neostigmine

2. Used w/ atropine in reversal of neuromuscular blockade (NmB) caused by non-depolarizing drugs (d-tc, pancuronium)
What are the organophosphates?


Isofluophate (DFP)
-- agriculture
-- home
-- biochem lab chem. (commonly used in protein chemistry)

These are IRREVERSIBLE inhibitors of ACHases that form covalent bonds w/ AChase active site
Signs and symptoms of OP poisoning?
NO change in BP (N1)
Skeletal muscle fasciculations (N2)
OP poisoning treatment?
1. Pralidoxime (2-PAM)
-- regenerates phosphorylated ACHase
-- must be admin quickly after OP poisoning b/c not able to break bond once it has aged

2, Atropine
-- muscarinic antagonist that can be used to treat cholinomimetic symptoms or OP toxicity, but b/c of its transient effects, is NOT curative

**Carboxylesterases in humans degrade organophosphates and prevent our death
Plant poisoning?
Increased ACh stimulation
-- treat w/ atropine

Decreased ACh stimulation
-- mydriasis, bronchodil, tachy, no sweating, no peeing
-- treat w/ physostigmine
What is the effect of a muscarinic receptor blockade?
-- no saliva, sweat, urine

-- confusion, delirium

-- increased core temp

-- mydriasis and cycloplegia (lack of accommodation)
What are the muscarinic antagonists?
-- scopolamine
-- atropine
-- cyclopentolate
-- benztropine

-- N-methylatropine
-- propantheline
-- ipratropium
-- glycopyrrolate
Scopolamine use?
Used orally or topically as a remedy for motion sickness
Atropine use?
Atropine causes muscarinic receptor blockade.

Used for bradycardia, heart block, and to reverse cholinergic poisoning
Cyclopentolate use?
Topical eyedrops for ciliary paralysis
-- mydriasis
-- allows fundoscopic exam
-- inhibits accommodation (↓ near vision)
Benztropine use?
Penetrates CNS well (tertiary), so used for Parkinson’s disease
-- ↓ cholinergic signaling
-- helps restore dopaminergic/cholinergic balance in the brain
Propantheline use?
Decreased ACh-stimulated secretion and motility in the GI tract
-- help w/ GI spasticity
Ipratropium use?
Prevent bronchoconstriction from air pollution/cold air by inhibiting ACh mediated constriction of bronchial airways
Glycopyrrolate use?
Used to suppress bronchiolar secretions during surgery via inhibiting ACh-mediated secretion
Approaches toward treatment of Glaucoma?
1. Decrease formation of aqueous humor
-- B-blocker
-- Carbonic anhydrase inhibitor
-- alpha2 receptor agonist

2. Increase outflow of aqueous humor
-- alpha1 receptor agonists
-- pilocarpine, isofluophate
-- PGF2 analogs (uveoscleral flow)
B-blockers that decrease formation of aqueous humor?
BETAXOLOL – better choice b/c relatively selective for B1-adrenoceptors, thus little effect on bronchial smooth muscle


Both by unknown MOA
Carbonic anhydrase inhibitor for glaucoma?

Alpha2 receptor agonists for glaucoma?


Both used post-surgically, and not generally as outpt
Alpha1 receptor agonists for glaucoma?


Both stimulate the radial muscle of the iris to cause mydriasis and increase outflow
Pilocarpine and isofluophate for glaucoma?
Organophosphate Cholinesterase Inhibitors

Lower IOP by ↑ amt of ACh avb to contract meridional fibers of the ciliary muscle
PGF2 analogs for glaucoma?
ONLY ones to increase UVEOSCLERAL outflow


Will have ADDITIVE effect w/ any other drug
What are the ganglionic blocking drugs?
Trimethaphan – used to produce controlled hypotension during head and neck surgery

What do the ganglionic blocking drugs do?
Block Sympth NS and Parasympth NS

Block increase in plasma Epi induced by hypoglycemia
What is the effect of a ganglionic (N1-cholinergic receptor) blockade?
Blocks ALL of the nervous system

-- arteriodilation lowers TPR
-- venodilation decreases preload
-- decreased cardiac dp/dt
-- ↓TPR and CO = hypotension
-- decreased sweating
-- impotence (no ejaculation)

-- tachycardia (intrinsic HR is 70-100)
-- mydriasis and cycloplegia
-- ↓ salivation and lacrimation
-- ↓ GI secretion, motility, tone
-- ↓ gastric acid secretion
-- ↓ release of panc enzymes and bile
-- constipation and urinary retention
-- impotence (no erection)
Depolarizing, non-competitive neuromuscular blocking drugs?
Succinylcholine, decamethonium

Phase 1 = MEP depol
Phase 2 = repolarized but still refractory

Causes fasciculations prior to flaccid paralysis
Succinylcholine use?
NM blockade, Electroshock therapy
Non-depolarizing, competitive neuromuscular blocking drugs?
d-tubocurarine (curare)
pancuronium (the –curiums and –curoniums)

MEP never depolarized

No fasciculations prior to flaccid paralysis
-curium and –curonium use?
NM blockade
Changes in changes in NM blockade drug sensitivity?
Changes in drug sensitivity with diseases

1. myasthenia gravis (MG) the N2-receptor density is decreased
-- succinylcholine ↓ effect
-- curare ↑ effect

2. in burns and denervation injury, the N2-receptor density is increased
-- succinylcholine ↑ effect
-- curare ↓ effect
NE and Epi synthesis?
Tyrosine --> L- Dopa --> Dopa --> NorEpi --> Epi

Tyr to Dopa via tyrosine hydroxylase
-- rate-limiting step in NE/Epi synthesis
-- inhibited by METYROSINE

L- Dopa to Dopa via dopa decarboxylase

Dopa to NorEpi via dopamine β-hydroxylase
-- inhib by METYROSINE

NorEpi to Epi via phenylethanolamine-N-methyltransferase

METYROSINE also inhibits NE release from nerves
Presynaptic receptors affecting NE release?
See image pg 209 Module 1

INCREASED overflow of NE
1. Ang II stimulation
2. β2 stimulation
3. α2 block (prejxnal)
4. cocaine
5. TCAs

DECREASED overflow of NE
1. muscarinic (ACh) stimulation (prejxnal)
2. α2 stimulation (clonidine)
3. PGEs
α1-adrenoceptors are found at…?
POSTjxnal sites on effector organs, tissues and glands innervated by sympathetic nerves

(IP3 and DAG)

These adrenoceptors are usually excitatory, except in the GI tract.
α2 adrenoceptors are found at…?
1. POSTjxnal sites on effector organs, tissues, and glands innervated by the sympathetic nerves (↑ intracellular inhib of adenyl cyclase --> ↓[cAMP])

2. PREjxnal sites on sympathetic neurons (autoreceptors for increased K conductance)

3. PREjxnal sites on parasympathetic neurons of
-- SA node
-- sphincter muscle of iris
-- GI tract

These adrenoceptors are usually excitatory, except in the GI tract.
β1-adrenoceptors are found at…?
POSTjxnal sites of
-- cardiac muscle and cardiac conduction tissue
-- adipocytes
-- JG cells of the renal afferent arteriole

β receptors are generally inhibitory, except for effects on lipolysis, heart, and renin secretion
β2-adrenoceptors are found at…?
1. POSTjxnal sites of the
-- arterioles & venules
-- bronchioles
-- uterus
-- GI tract
-- liver

2. PREjxnal sites on sympathetic neurons (heteroceptors)

Mediate vasodilation and intestinal and bronchial smooth muscle relaxation
D1-receptors are found at…?
vascular smooth muscle of the renal afferent arterioles where they cause vasodilation (adenyl cyclase)
D2-receptors found at…?
synapses in the CNS
-- corpus striatum
-- hypothalamus
-- CTZ
-- limbic system

(inhibition of adenyl cyclase; increase K conductance)
General: Increase in parasympathetic activity has the following effects...
1. HR ↑
2. BP ↓ slightly
3. GI secretions and movements are increased
4. Gall bladder is contracted
5. Glucose is stored in the liver
6. Retina is protected from excessive light
7. Urinary bladder and rectum are emptied

Via Cholinergic (ACh) activity at muscarinic receptors
General: Increase in sympathetic activity has the following effects…
1. HR and dp/dt
2. BP
3. Blood flow to liver and skeletal muscles
4. Blood glucose concentration via glycogenolysis and gluconeogenesis
5. Glucagon release as insulin release inhibited

1. Renal and cutaneous blood flow
2. Splanchnic blood flow
3. Visceral activity

Also, bronchioles are dilated
Know the site of action of drugs on a sympathetic nerve jxn = uptake1, MAO-A & MAO-B, storage granule
-- located in outer mbrn of mitochondria
-- removes the amine group of the side-chain to metabolize 5-HT and NE
-- found mostly in liver, GI tract, and placenta

-- located in outer mbrn of mitochondria
-- found mostly in blood platelets

-- found on presynaptic neuron
-- blocked by TCAs and SSRIs

PREsynaptic α2 receptor
-- feedback inhibition which can modulate NE or 5-HT release
-- Mirtazapine blockade amplifies release for any given frequency of neuronal stim
CV effects of Norepi?
SYMPATHETIC response to Norepi

-- ↑ dp/dt

-- ↑ dp/dt

-- ↑ HR

-- ↑ conduction velocity
-- ↓ AP duration, refractory period

-- ↑ automaticity, conduction velocity
-- ↓ conduction time, refractory period, AP duration
Drug Z is given i.v. and ↑BP, and ↓HR.

After treatment w/ atropine, Drug Z will then cause ↑BP, and ↑HR

What is Drug Z?

Initially, it increases BP, and the HR decreases due to baroreceptor reflex.

When given atropine, this blocks muscarinic receptors, so NO vagal response is available. The body isn’t able to mount a baroreceptor reflex, so the NE increases BOTH BP and HR
CV effects of Epi?
↑HR, dp/dt, CO, SBP, and PP

↓DBP with physiological doses

(Think fight or flight)
CV effects of Dopa?
↑dp/dt (β1)

↑DBP (α1)
Epi general effects?
increased skeletal muscle BF

decreased skin, renal and GI BF

↑ HR, dp/dt, CO, SBP and PP, decreased DBP with physiological doses
Dopa general effects?
increased RBF/mesenteric BF (block by haloperidol)

increased dP/dT (beta1), increased DBP (alpha1)
How do we control dp/dt post MI?
Use Dopa instead of NE or Epi to maintain dp/dt post MI b/c Dopa ↑RBF, whereas NE and Epi ↓RBF
Epi + halothane = ?
Epi + α-blocker = ?
Use α-blocker (Epi + phentolamine) so that you only get β effects
-- ↑HR, dp/dt, CO, SBP, and PP
-- ↓ DBP w/ physiological doses
Epi + β-blocker = ?
will get you only α effects
-- ↑BP
Why do we add Epi to local anesthetics?
Prevents systemic absorption because it causes skin vasoconstriction to keep the local local

Also, you won’t bleed as much and it enhances platelet aggregation
alpha1-agonist = mydriasis without cycloplegia
-- will still have light response

useful for fundoscopic exam (actually, we use tropicamide)
(beta2-agonist) decreases uterine contraction in premature labor

can also use NSAIDs b/c they block PGs which cause uterine contraction
Bronchodilate and ↑HR?
isoproterenol (non-selective beta1 & beta2-agonist)
Bronchodilation with less  HR?
albuterol, terbutaline (selective beta2-agonists)
pre- and post-synaptic alpha2-adrenoceptor agonist
-- activate prejxnal receptors in the vasomotor center of the medulla to reduce sympathetic tone
-- ↓BP, w/ decrease in TPR, and minimal long-term effects on cardiac output and HR
List examples of indirect adrenergic agonists.
1. tyramine-containing foods
2. methylphenidate
3. ephedrine

No effect after pre-tx w/ RESERPINE (destroys NE storage granules)
-- Only directly acting agonists increase dp/dt and HR in isolated heart from animals treated w/ reserpine
Tyramine-containing foods?
Contraindicated in pts taking phenelzine or tranylcypromine which non-selectively inhibit MAO-A and MAO-B

increase in BP caused by tyramine blocked by reserpine
guanethidine (sympathetic blocking agent)
3 P’s

S/E's = depression, insomnia, decreased appetite
and linear growth rate
Amphetamine toxicity?
nervous, excited, agitated, ↑ HR/BP, toxic psychosis = paranoid schizophrenia, formication w excoriations, convulsions w OD
-- difficult to distinguish from effects of cocaine

Treat psychosis w CHLORPROMAZINE
Direct beta1 and beta2,

Indirect alpha
-- no alpha after reserpine
What are the 3 P’s?
Phenoxybenzamine (PBZ)

Alpha blockers
Phentolamine, PBZ, Prazosin, and HR?
Phentolamine, PBZ
-- increases HR via baroreflex

-- no effect on HR
Ergotamine, dihydroergotamine?
partial alpha agonists

Used for tx of migraine
What is the major S/E of alpha blockers?
orthostatic hypotension
blocks alpha1A-receptors in GU tract in patients w BPH to enhance voiding
Epinephrine and alpha blockers?
Epinephrine-reversal by alpha-blockers such as phentolamine, phenoxybenzamine and prazosin

The vasopressor effect of a large (supraphysiological dose) of EPI is reversed to a vasodepressor effect by an alpha-blocker (only β effects)
How do we control BP during surgery for pheochromocytoma?
Pretreat w/ alpha and beta-blockers to prevent any changes in BP caused by the release of EPI from the pheo during surgery
What if we infuse a physiological dose of EPI?
Lowers DBP and increases SBP.
-- vasodilates some vascular beds via beta2-receptor stimulation and
-- constricts other vascular beds via alpha2-receptor stimulation.

NET effect is arteriolar vasodilation with a fall in TPR and thus DBP.

SBP increases because EPI increases cardiac output via increased venous return, and cardiac contractility and decreased afterload (DBP).
Effect of SBP and DBP with:
1. Epi
2. Epi and alpha block
3. Epi and beta block
Epi alone:
-- Lowers DBP and increases SBP.

Epi and alpha block
-- can only stim vascular β2 receptors to cause vasodilation
-- large fall in TPR and DBP

Epi and beta block
-- can only stimulate vascular α receptors to cause vasoconstriction
-- large rise in TPR and DBP
Atenolol & metoprolol
Beta blockers that block β1
Propanolol & timolol
Beta blockers that block β1 and β2
Beta blocker used for…?
-- decreased O2 requirement via ↓dp/dt and HR
-- but LV-EDV increases

Causes ↓ HR, AV conduction, dp/dt

Blocks increase in HR caused by hemorrhage, minoxidil, hydralazine, diazoxide, nitroprusside, NTG
Beta blockers vs. NTG and oxygen demand
beta-blocker (BB) decrease oxygen demand by decreasing HR, dp/dt and afterload (DBP)

NTG decreases oxygen demand by decreasing venous return and LV-EDV
Beta blocker S/Es?


AV block

delayed recovery of [glucose] in pts w/ Type 1 DM after s.c. injection of too much insulin
Decreased IOP w/ cycloplegia
-- does not affect visual accommodation OR papillary size

(do not use propranolol b/c it causes local anesthesia of cornea)
What causes Beta-blocker withdrawal syndrome?
patient tx w beta-blocker for angina…

d/c drug --> increased cardiac -receptor stimulation --> increased O2 demand --> angina and MI (tachycardia, palpitations, tremor, chest pain)

Receptors will downregulate w/in a few days
How do we treat the symptoms of hyperthyroidism?
Tx with Propranolol to ↓ tachycardia and tremor and prevent the peripheral conversion of T4 to T3,

Propanolol is the only beta-blocker to have the effect on T4 and T3
1.↓ NE release via depletion of neuronal NE stores, poisons NE storage vesicles

2. no effect of TAP drugs (tyramine, amphetamine, phenylpropanolamine) after pretreatment w reserpine;

3. no alpha effects of ephedrine after reserpine
1. decreased nerve-stimulated NE release
2. competitive inhibitor of NE uptake1
3. anti-HT effect blocked by TCA’s b/c TCA’s block entry of guanethidine into neuron
1. blocks uptake1 of NE, Epi, DA, 5-HT in CNS

2. blocks uptake1 in peripheral sympathetic neurons - potentiates effects of NE and Epi, but not isoproterenol (ISO)

3. Euphoria via release of DA in nucleus accumbens

4. local anesthetic effect via blockade of Na+ channels in sensory neurons (and causes hemostasis w/o Epi addition like other locals)
Cocaine toxicity?
dilated pupils, euphoria, hallucinations, excitation, halo vision, itchy skin, ↑ BP/HR, convulsions
-- difficult to distinguish from amphetamine
Cocaine w/d syndrome?
sleepiness, depression, anhedonia
MAO inhibitors?

SELEGILINE – selectively inhibits MAO-B to prevent breakdown of DA in CNS
-- can be used to treat Parkinson’s
-- NO adverse food rxns
MAO “cheese rxn”?
Inhibition of MAO-A in gut wall allows dietary tyramine to enter the circulation

Tyramine releases NE to cause HT and tachycardia
Clonidine and α-methyldopa?
Antihypertensive drugs

↓ SNS activity via stimulation of alpha2-receptors in CNS
-- ↓ plasma NE
-- ↓ plasma renin activity (PRA) --> usually proportional to sympth tone and Na/H2O balance
-- ↓ HR

Clonidine has off-label use by psych

α-methyldopa goes into the brain, then becomes α-NE
S/E’s of clonidine & α-methyldopa?
sedation, dry mouth, edema

alpha-MD = hepatitis, “flu” syndrome, (+) Coomb’s test
What is clonidine w/d syndrome?
sweating, ↑ HR, abrupt return of BP to HT value, abdominal pain, tremor, headache, apprehension

(differs from beta-blocker withdrawal syndrome = ↑ HR with palpitations but no tremor, sweating, abdominal pain or ↑ BP)
Drugs that DECREASE plasma NE?
-- clonidine
-- alpha-MD

-- guanethidine


ganglionic blockers
Drugs that INCREASE plasma NE?
alpha blockers, hydralazine, minoxidil, diazoxide, nifedipine, HCTZ, sodium nitroprusside

VASODILATORS – baroreflex ↑ in sympth tone, thus ↑ plasma NE
Name the arterial vasodilators.



Dilate resistance vessels
-- ↓ TPR & BP
-- ↑ HR, dp/dt, CO, PRA, and plasma NE
S/E hydralazine?
SHIP drug!
1. edema

2. SLE-like syndrome
-- arthralgia
-- fever
-- arthritis
-- malar rash
-- (+) ANA
S/E minoxidil?
1. hirsutism; effect additive w/ finasteride

2. edema
S/E diazoxide?
1. Inhib of insulin release
-- hyperglycemia

2. edema
Which drugs do we use in a hypertensive emergency?
1. diazoxide
-- arterial vasodilator

2. sodium nitroprusside (SNP)
-- nitrate vasodilator
-- dilates arteries & veins

3. labetalol
-- beta blocker to ↓HR
Sodium Nitroprusside?
1. dilates arteries and veins via release of nitric oxide (NO) from SNP molecule

2. balanced vasodilation
Sodium Nitroprusside in normotensive pt?
decreases TPR and venous return
-- NO change in CO
Sodium Nitroprusside in CHF pt?
decreases preload and afterload
-- leads to INCREASE in CO
Thiocyanate toxicity?
Toxicity of Sodium Nitroprusside

1. anorexia, nausea, delirium, hallucinations and psychosis
2. usually occurs after several days of therapy and assoc w/ decreased renal fxn

-- mental disorientation and metabolic acidosis in assoc. w/ increased dose requirement
How do we treat thiocyanate toxicity?
(pic on pg 232 of cardio syllabus)

DC the sodium nitroprusside

Give furosimide to improve renal fxn (gets rid of the thiocyanate)

Tx with thiosulfate
Cyanide toxicity?
(pic on pg 232 of cardio syllabus)

occurs when thiosulfate becomes depleted

-- muscle weakness, spasm, disorientation
How do we treat cyanide toxicity?
Treat w/ nitrite or thiosulfate
What are the Ca channel blockers?
Nifedipine – primarily affects vessels

Diltiazem – primarily affects heart

Verapamil – primarily affects heart
Ca channel blocker action?
1) block Ca++ channels at SA/AV nodes, cardiac myocytes, arterial VSM

2) decrease in BP: nifedipine>diltiazem>verapamil

3) decrease AV conduction via increase in ERP: verapamil>diltiazem

4) nifedipine - slight increase in HR with increase or n.c. in AV conduction

5) angina - decrease oxygen demand (decrease dp/dt, HR and afterload) w increased oxygen delivery via dilation of coronary arteries and arterioles
Therapeutic uses of Ca channel blockers?

exertional and vasospastic angina

AV nodal re-entry tachycardia (V+D)
Which drugs DECREASE dp/dt/
Ca blockers
What are the effects of Ang II?
1. ↑ BP (via increased water reabsorp)

2. increases SNS activity via CNS

3. presynaptic enhancement release of NE

4. blocks NE uptake1 -- ↑dp/dt

5. causes release of ADH

6. release of aldosterone

7. decreases mesenteric BF

RAAS reinforces the sympathetic NS; each enhances the other’s release
Which drugs decrease mesenteric blood flow to treat GI bleeding?
NE and Ang III (get escape)

ADH and octreotide (no escape)
-- retain Na to ↑ Aldo and ↑H20
-- octreotide is a somatostatin agonist
What are the ACE inhibitors?


Prevent conversion of Ang I to Ang II
What are the effects of ACE inhibitors?
1. decrease TPR and BP with no change in HR and CO

2. block formation of Ang II, block enzymatic destruction of bradykinin (BK)

3. ACEI’s potentiate the decrease in BP caused by i.v. bradykinin

4. ACEI's increase the plasma concentration of BK
ACEi side effects?
1. fetal toxicity (category X)

2. K+ retention

3. cough
-- cough caused by BK & PG and is blocked by aspirin (ACEI’s block metabolism of bradykinin)
Ang II receptor antagonist - no cough
Therapeutic use of ACE inhibitors?
1. MOA in tx of CHF
-- increase CO by decreasing preload and afterload
-- reverses cardiac remodeling caused by angiotensin II (ang II)

2. HT patient with DM
-- tx w ACEI to ↓ BP and ↓ proteinuria (protects kidneys)
What are the diuretic drugs?

Furosemide, ethacrynic acid


Amiloride and Triamterene


Acetazolamide MOA?
1. Inhibits carbonic anhydrase in PT and DT to prevent reabsorption of bicarbonate

2. Inhibits formation of aqueous humor and CSF, some effect to ↓ gastric acid secretion

3. Increased excretion of Na+, K+, bicarbonate - urinary pH increases to 8-8.5
Therapeutic use of acetazolamide?
1. used to increase urinary pH to enhance renal clearance of acids, e.g., salicylates,

2. used to tx glaucoma and altitude sickness

3. tx of acidosis, via renal loss of bicarbonate

4. stimulates respiration
Acetazolamide S/Es?
hyperchloremic metabolic acidosis
Respiration: stimulants vs. inhibitors?
-- acetazolamide
-- nicotine
-- Epi
-- theophylline, caffeine

-- EtOH
-- opiates – morphine
-- benzo’s – diazepam
-- barbiturates
How do you make urine alkaline?
CaI or Na bicarbonate

Increases renal clearance of acidic drugs

Ex: OD w/ aspirin
How do you make urine acidic?
ammonium chloride

Increases renal clearance of basic drugs

Ex: OD w/ amphetamine
What are the loop diuretic drugs?

Ethacrynic acid
MOA of loop diuretics?
Inhibit Na,K,2Cl symporter in ascending L of H

Also blocks Na transport in macula densa of DT
Effect of loop diuretics?
1. Increased urinary excretion of Na, K, Ca, Mg, Cl, and water

2. Increased delivery of Na to LDT/CD causes K loss

3. Blocks Na+ transporter in macula densa cells of DT --> no sodium sensed --> ↑ PRA and Ang II --> secondary hyperaldosteronism --> exacerbates K loss

4. Cl loss caused hypokalemic, hypochloremic metabolic alkalosis

5. Urine isotonic in presence and absence of ADH

6. PG-dependent increase in RBF and GFR

7. Increases hematocrit via decreased plasma volume
Therapeutic use of loop diuretics?
acute pulmonary edema


peripheral edema


bilateral hearing loss via toxicity to CN VIII; potentiated by aminoglycosides (e.g., gentamicin)
Loop diuretics S/E’s?
1. hypokalemia w alkalosis

2. hypomagnesemia

3. hyperglycemia

4. dilutional hyponatremia
-- cannot make a dilute urine in order to excrete free water

5. hyperuricemia (bad for gout)

6. Li toxicity caused by their enhanced reabsorption in PT

7. enhances digoxin toxicity via hypokalemia
-- less K+ to compete w digoxin for Na+-K+ ATPase binding sites
Acts in the distal tubule and ↓ GFR in all pts

Blocks NaCl symporter in principal cells of DT
HCTZ effect?
1. ↑ excretion Na, K, Mg, Cl and water

2. ↓ excretion of Ca++ in hypercalcinuria
-- used to decrease formation of kidney stones

3. ↓ free water clearance
-- urine always hypertonic; causes dilutional hyponatremia

4. Increased delivery of Na to LDT/CD causes K loss

5. blocks Na transporter in macula densa cells of DT --> no sodium sensed --> ↑ PRA and Ang II --> secondary hyperaldosteronism --> exacerbates K loss
HCTZ therapeutic use?


kidney stones

-- distal loss of Na and water enhances the reabsorption of filtrate in the PT
-- less volume sent distally
-- urine vol ↓ by 50%
1. hypokalemia w alkalosis

2. hypomagnesemia, hyperglycemia, hyponatremia;

3. uniformly decreases GFR

4. hyperuricemia (bad for gout)

5. Li+ toxicity caused by their enhanced reabsorption in PT

6. enhances digoxin toxicity via hypokalemia
-- less K+ to compete w ith digoxin for Na-K ATPase binding sites

7. diuretic effect contracts the blood volume & therefore potentiates the fall in BP caused by anti-HT drugs
-- especially sympatholytic drugs (e.g., clonidine and alpha-blockers like prazosin)
What are the K sparing diuretics?



spironolactone (aldo receptor antagonist)
K sparing diuretics contraindication?
All are contraindicated in renal insufficiency b/c they can cause fatal hyperkalemia
Amiloride and triamterene MOA?
1. block Na channels in principal cells of LDT/CD

2. increased Na excretion with decreased K excretion

3. make urine alkaline by inhibiting H ion secretion from intercalated cells of DT
Spironolactone MOA?
1. Aldo antagonist

2. Partial agonist at androgen/progesterone receptors

3. Blocks aldosterone receptors in the principal cells of the LDT and CD
Spironolactone therapeutic use?
1. NO effect in adrenalectomized patient

2. Secondary hyperaldosteronism
-- associated w/ cirrhosis

3. nephrotic syndrome;

4. reverses cardiac remodeling caused by aldosterone in patients with HF
Spironolactone S/E’s?

gynecomastia (males)

menstrual irregularities


deepened voice (females)
CLINICAL: Patient tx with OCP containing estrogen + norethindrone develops hirsutism. Why? Tx?
Hirsutism results from androgenic effects of the progestin norethindrone which is a derivative of 19-nortestosterone;

Tx: Spironolactone
CLINICAL: Postmenopausal female develops hirsutism - how to tx?
CLINICAL: Patient with an adrenal tumor has ↑ BP and plasma [HCO3], ↓ plasma [K] and PRA; plasma [Na] is normal  dx? and tx?
Conn’s syndrome – aldo secreting adrenal tumor
-- zona glomerulosa causes Na retention
-- ADH causes water retention
-- but plasma Na will be NORMAL

Tx w/ spironolactone
Review: What stimulates Aldo?

2. Ang II
Hypokalemia from furosemide and HCTZ can be prevented by…?
K+-sparing diuretic drugs

ACE inhibitors – blocks Ang action

B-blockers – inhib renin release of Ang

To a certain extent, by p.o. K+ supplements
When trying to determine which diuretic drug was used, you must consider the following…?
1. First look at urine flow rate

2. Then look at the changes in electrolyte excretion

3. Finally, you can also consider pH
The effects of diuretics on urinary flow…?
1. 8-10ml/min
-- furosemide OR
-- mannitol

2. 2-3ml/min
-- acetazolamide
-- thiazide
-- K-sparing agent (TASk)
The effects of diuretics on quantitative changes in electrolyte excretion?
1. FUROSEMIDE is distinguished from MANNITOL by the fact that FUROSEMIDE causes greatest increase in electrolyte excretion

2. ACETAZOLAMIDE causes massive increase in bicarb excretion

3. K-sparing agent decreases K excretion

4. Drug that remains is thiazide
What are the cardiac glycosides?

Cardiac glycoside kinetics?
-- Half-life= 1-1.5 d
-- renal Cl
-- decreased GFR decreases Cl and increase half-life

-- Half-life = 7 d
-- hepatic Cl
-- ↓ Cl and ↑ half-life in patient w cirrhosis and CHF

1. ↓ GI absorption w cholestyramine (ion exch resin) or antacids
-- ↓ plasma [dig] and ↓ cardiac effect

2. older patients
-- ↓ Vd, so ↓ loading dose
-- ↓ GFR, so ↓ maintenance dose
-- older patients can have decreased GFR with normal serum [Cr] (b/c Cr byproduct of skel m.; if ↓skel m., then ↓ Cr, so [Cr] doesn’t change

3. QUINIDINE ↑ plasma digoxin by displacing digoxin from skeletal muscle and ↓ renal Cl

-- binds to skel muscle
-- Vd determines loading dose
-- Cl determines maintenance dose
Cardiac glycoside MOA?

1. Inhibition of Na-K ATPase
-- increases dp/dt, but decreases resting membrane potential (Vm)
-- lack of pumping Na out causes automaticity in fast fibers
-- low K: potentiates inhibition of ATPase: causes automaticity and ↓ERP in ventricles (K and dig compete for same binding site on ATPase)
-- low Mg: same a Ca overload inside cells - causes automaticity
-- high Ca: Ca overload inside cells causes automaticity

2. Acts in CNS to ↑ vagal tone
-- ↓ HR, atrial contraction and AV conduction
Therapeutic use of cardiac glycosides?

Used to control (decrease) ventricular rate in patients w atrial flutter or fibrillation
-- ↑ vagal tone decreases AV conduction, so fewer atrial signals pass the AV node

Good for heart failure and no adverse effect on dp/dt
Glycoside S/E’s?

AV block


n/v (CTZ)

CNS-abnormal color vision, halo vision, esp. in elderly
What are the antidysrhythmic drugs?





Quinidine MOA?
blocks Na+ channels in fast fibers
Quinidine effects?
1) Na channel block ↓ phase 4 automaticity and phase O slope
-- ↓ conduction velocity so it widens the QRS

2) Delays ventricular repolarization via K channel block
-- ↑ APD, ERP and Q-T interval
-- gets rid of automaticity (PVCs)

3) SA node
-- no direct effect
-- anticholinergic effect causes tachycardia

4) AV node
-- atropine-like effect ↑ conduction (increases HR)
-- but direct effect ↓ conduction (P-R increases)
Quinidine therapeutic use?
Atrial and ventricular dysrhythmias

Give digoxin before quinidine to tx A flutter and A fib so digoxin prevents increase in AV conduction from atropine-like action of quinidine

ATROPINE -- ↑HR and takes away inhibition of AV conduction by vagus
Quinidine S/E’s?
hypotension (-blockade)

↓ dp/dt

diarrhea (limits use)

tinnitus w OD
CLINICAL: Pat w atrial fibrillation given quinidine to slow ventricular rate, but ventricular rate ↑ soon after quinidine. Why? What to do about it?
Immediate atropine-like effect of quinidine ↑ AV conduction

TX: Verapamil or Diltiazem to ↓ AV conduction and slow ventricular rate.
Procainamide S/E’s?
SLE and arthritis in slow acetylators
-- genetic defect
-- inactive form of acetylase enzyme
-- cannot clear drug by hepatic transformation
Disopyramide effects?
1. marked increase in dp/dt

2. marked antimuscarinic effects
-- dry mouth
-- constipation
-- contraindicated in BPH & glaucoma
Lidocaine MOA?
block of Na+ channels in fast fibers

given i.v. due to low F
Lidocaine effects?
1. ↓ phase 4 automaticity to prevent PVC’s

2. no effect at SA or AV nodes, BP or dP/dT

3. local anesthetic effect via Na+ channel block in sensory fibers

DOES NOT widen QRS (primarily affects ischemic tissue)
Lidocaine therapeutic effects?
1. ventricular arrhythmias

2. local anesthetic
Lidocaine S/E’s?
-- Tx w/ BZ
Amiodarone MOA?
1. Inhibition of K channels

2. Blocks Na channels

3. Non-competitive alpha and β blockade
Amiodarone effects?
-- ↑ APD, ERP interval in fast fibers
-- ↑ Q-T (but doesn’t precip torsade)

-- powerful suppression of phase 4 automaticity

-- hypotension & bradycardia
-- slows sinus rate and AV conduction (P-R increased)

Almost perfect antidysrhythmic except for S/Es
Amiodarone therapeutic use?
recurrent ventricular tachycardia/fibrillation
Amiodarone S/E’s?
1. pulmonary fibrosis

2. hypo- or hyperthyroidism

3. blue, purple or slate gray skin
-- purple man
-- 30% iodide by wt

4. corneal microdeposits
Verapamil MOA?
blocks L-type Calcium channels at SA and AV nodes and cardiac myocytes

Works primarily at the heart! (VD)
Verapamil effects?
SA node
-- ↓HR

AV node
-- ↓ conduction velocity
-- ↑ ERP
-- fewer atrial signals pass through the AV node to the ventricles
-- myocardium = ↓ dp/dt = ↓ CO
Verapamil therapeutic use?
AV nodal re-entry tachycardia
Verapamil S/E’s?
1. ↓ dp/dt

2. decreased CO in HF

3. AV block
CLINICAL: Patient with atrial fibrillation and no HF has palpitations and dizziness. Tx and MOA?

MOA: ↑ ERP of AV node slows ventricular rate --> improved AV filling --> ↑ CO
Antiplatelet drugs?

Abciximab, Eptifibatide, Tirofiban

Ticlopidine, Clopidogrel
Irreversibly inhibits COX-1 of platelets to prevent the synth of TXA2
Abciximab, Eptifibatide, Tirofiban?
1. antagonist of the platelet IIb/IIIa which uses fibrinogen to bind platelets together

2. given in OR and ER via i.v.
Ticlopidine, Clopidogrel?
antagonist of platelet purinergic (ADP) receptors
CLINICAL: A patient requires an antiplatelet drug after MI or stroke, but the patient has aspirin hypersensitivity. How to Tx?
Use ticlopidine or clopidogrel
Heparin MOA?
1. accelerates binding of antithrombin III (AT III) to activated clotting factors 2, 9-12

2. increases aPTT
Heparin kinetics?
1) a glucosaminoglycan, HMW = 5-30 K

2) not effective p.o.; works in vivo and in vitro

3) not metabolized by the liver: removed from circulation by reticuloendothelial system

4) ↑ lipoprotein lipase (hydrolyzes TG’s to glycerol + FFA) to ↓ postprandial lipemia
Heparin therapeutic use?
Treat MIs and DVTs
Heparin antagonist?
protamine sulfate
Heparin S/E’s?
antiplatelet effect additive w aspirin

Heparin resistance?
results from decreased [ATIII] in blood
LMW heparins?


LMW heparin MOA?
LMW = 2-6 K

LMW acts primarily on Xa, so little effect to increase the aPTT
LWM heparin reversal of anticoagulant effect?
Can only be PARTIALLY reversed by protamine sulfate
LMW heparin clearance?
Cleared by kidneys instead of RE system

Longer half-life than heparin
Warfarin, dicumarol MOA?
Inhibits post-translational vitamin K1-dependent gamma-carboxylation of glutamate residues on factors 2,7,9 & 10
-- via inhibition of enzyme vitamin K1 epoxide reductase

Only works in vivo, slow onset of action
-- (2-3 d, full effect at 5 d) increases PT (INR) (greatest effect on factor 7)
Therapeutic use of warfarin?
1. to treat DVT’s

2. prevent emboli in patients with prosthetic cardiac valves

3. prevent thrombotic stroke in patients with atrial fibrillation
Warfarin interactions?
1. Highly bound to plasma proteins
-- many drug-drug interactions

2. Displacement of warfarin from plasma proteins has two effects
-- ↑ PT and ↑ clearance of warfarin

3. metabolized by CYP450
CYP450 inhibitors?
grapefruit juice

Inhibition will INCREASE plasma warfarin and PT
CYP450 inducers?
chronic EtOH
benzopyrene (cigarette smoke)

Induction will DECREASE plasma warfarin and PT
Warfarin antidote?
Vit K1 (phytonadione)

Fresh frozen plasma

Factor IX concentrate (contains factors 2,7,9 & 10)
CLINICAL: Patient OD's with warfarin are attempts suicide with rat poison --> which clotting factors and lab tests affected?
↓ activity of factors 2,7,9 and 10

↑ aPTT and PT (usually doesn’t affect aPTT but will w/ OD)

no effect of factors 8 or 13 or bleeding time
CLINICAL: Which type of cardiac dysrhythmia requires tx with warfarin?
Atrial fibrillation
What are do thrombolytic drugs do? Name them.
all ultimately convert plasminogen to plasmin
-- plasmin destroys fibrin to lyse clots

Urokinase MOA?
Direct activation of plasminogen
When tPA and plasminogen bind to fibrin in close proximity, plasminogen is converted to plasmin by tPA
-- normal, intrinsic activation of plasmin
Streptokinase MOA?
changes conformation of plasminogen to expose an active protease site that hydrolyzes another plasminogen molecule to plasmin
S/E’s of fibrinolytics?
systemic destruction of clotting factors 5 & 8 causes bleeding, esp. in CNS (hemorrhagic stroke)
CLINICAL: Patient with MI treated with several drugs and develops intracranial bleeding. Which drug caused it?
Streptokinase (or choose other thrombolytic in list)
Inhibitors of fibrinolysis?
Aminocaproic acid

A lysine analog that binds to the lysine-binding sites on plasmin which blocks the binding of plasmin to fibrin
What are the antilipemic drugs?
Statins (lovastatin)
Gemfibrozil and Fenofibrate
MOA of statins?
Inhibition of hepatic HMG CoA reductase reduces an intracellular hepatic sterol pool which suppresses the promotor region of the genes which code for HMG CoA reductase and LDL receptors

Lack of sterol results in the increased synthesis of HMG CoA reductase and LDL receptors

Increased hepatic LDL receptors take up LDL cholesterol to lower Tc
Net effect of statins?
↓Tc, LDL, VLDL, and TG

slight ↑ in HDL
S/E’s of statins?
myositis/myopathy = muscle pain and weakness assoc with ↑ CPK
-- damage can progress to rhabdomyolysis which can cause renal shut-down
-- give mannitol + i.v. fluids to flush out the toxic myoglobin
Ezetimibe MOA?
the inhibition of cholesterol absorption from the GI tract decreases an intracellular hepatic sterol pool
-- leading to increased gene expression of hepatic LDL receptors
-- increased hepatic LDL receptors take up LDL cholesterol to lower Tc
Net effect of ezetimibe?
selective for LDL cholesterol
-- so only Tc and LDL decrease
Therapeutic use of ezetimibe?
used to tx patients who develop muscle weakness on a statin

So switch to EZE OR
↓ statin dose and add EZE to get beneficial LDL equal to the highest statin dose
Gemfibrozil and Fenofibrate MOA?
activates lipoprotein lipase (esp. in skeletal muscle) to increase hydrolysis of VLDL
Net effects of Gemfibrozil and Fenofibrate?
↓ Tc, LDL, VLDL and TG's

slight ↑ in HDL
Gemfibrozil and Fenofibrate therapeutic use?
-- common in DMII
S/E’s of Gemfibrozil and Fenofibrate?
myositis/myopathy = muscle pain and weakness assoc w/ ↑ CPK
-- muscle damage can progress to rhabdomyolysis
Niacin MOA?
Niacin therapeutic use?
↑ HDL cholesterol
Niacin S/E’s?
flushing and itching in face and upper body
What do antianginal drugs do?
all ↓ oxygen demand and/or ↑ oxygen supply

all ↑ endocardial blood flow
What are the beta blockers?



B-blocker MOA?
Negative chronotropic & inotropic effects decreases the rate-pressure product (HR x SBP)

Also decrease cardiac afterload (= decreased DBP)

↓HR, ↓dp/dt, ↓ afterload
Net effect of B-blockers?
Decreased cardiac oxygen demand
What are the nitrates?
-- glyceryl trinitrate
-- isosorbide mono- and dinitrate
MOA of nitrates?
NO donors which selectively venodilate
-- venodilation ↓ venous return to ↓ LV wall tension during diastole and systole (↓preload)
Net effect of nitrates?
decreased cardiac oxygen demand
Problem w/ nitrates?
Drug tolerance is a big problem
What are the calcium channel blockers?



MOA of verapamil and diltiazem?
1. negative chronotropic & inotropic effects decreases the rate-pressure product (HR x SBP)

2. also decreases cardiac afterload (= decreased DBP)

3. also dilates large epicardial vessels and small endocardial resistance vessels

4. Decreased oxygen demand and increased oxygen supply
MOA of amlodipine and felodipine?
1. Decreased cardiac afterload (DBP)

2. Increased blood flow through large epicardial vessels and small endocardial resistance vessels

3. Decreased oxygen demand and increased oxygen supply
Treatment of CHF?
1) decrease preload with diuretic drugs
-- ↓ blood volume

2) decrease both preload and afterload (balanced vasodilation) with an ACEI or ARB

3) enhance cardiac contractility (dp/dt) with digoxin

4) reverse cardiac remodeling caused by ang II with an ACE or ARB

5) reverse the cardiac remodeling caused by aldosterone with spironolactone

6) reverse the cardiac remodeling caused by the SNS with carvedilol

7) add digoxin to tx when ACEI + diuretic not working or when patient is in chronic atrial fibrillation