Pharmacology Exam 3 Review Guide

Which lipoproteins contain apolipoprotein B100?

LDL-C (“bad cholesterol”) contains lipoprotein B100. Apo B100 is important because it binds the LDL receptor on hepatocytes, allowing LDL to be removed from the plasma. The slides also note in the liver-target figure that VLDL precursors involve APOB-100, and the Lp(a) is formed when apo(a) binds to APOB-100 on LDL.
LDL, VLDL, Lp(a)

Which anti-dyslipidemics act in the liver?

- Statins inhibit HMG-CoA reductase in the liver
- Bempedoic acid inhibits ATP-citrate lyase (ACLY) in the liver
- Bild acid sequestrants act in the gut, but their effect causes the liver to shunt more cholesterol into bile acid synthesis and increase LDL receptors.
- Niacin decreases Apo-A1 degradation in the liver and also decreases hepatic TAG synthesis
- PCSK9 inhibitors increase LDL receptor recycling on liver cells

What is the mechanism of action of statins?

Statins are HMG-CoA reductase inhibitors. They inhibit the rate-limiting step of cholesterol biosynthesis in the liver and mimic the natural substrate. Structurally, they bind the catalytic site of the enzyme, trap it in an unproductive state, and prevent enzymatic activity. Functionally, inhibiting HMG-CoA reductase lowers intracellular hepatic cholesterol, which activates SREBP and increases LDL receptor gene expression. That leads to more LDL receptors on the liver cell surface, greater uptake of LDL from plasma, lower LDL-C, and reduced secretion of TAG-rich VLDL.

What are the structural and functional differences between type 1 and type 2 statins?

- Type 1 statins are prodrug lactones with a central naphthyl ring structure and a butyryl group. They are more hydrophobic, so they have greater distribution than the acid forms. They require ring opening, and for lovastatin and simvastatin this involves CYP2A4, which creates more drug-drug interaction potential.
- Type 2 statins are already in the acid form. Their butyryl group is replaced by a fluorophenyl group. Because they have an open ring, they do not need CYP activation, so they generally have fewer DDIs.

Functionally, both inhibit HMG-CoA reductase, but type 2 strains have extra binding interactions, including polar interactions involving the fluorophenyl region, which contributes to high affinity.

How do statins and CYP3A4 interact?

- Some statins, especially lovastatin and simvastatin, use CYP3A4 in their activation/ring opening process, so they are vulnerable to CYP3A4-mediated drug interactions
- Atorvastatin is metabolized by CYP3A4, undergoing hydroxylation at the 2- and 4- positions on the phenyl ring, followed by glucuronidation. The slides also specifically state that atorvastatin is an inhibitor of CYP3A4, so it can affect the metabolism of other drugs.
- If another drug such as ketoconazole inhibits CYP3A4, statin blood levels can rise.
- Rosuvastatin has little CYP metabolism and is only minimally metabolized by CYP2C9, so it has fever CYP3A4-related inhibitions.

CYP3A4 increases DDI risk with certain statins, especially atorvastatin, lovastatin, and simvastatin.

Compare and contrast atorvastatin and rosuvastatin.

1.    Similarities:
Both are statins used for hypercholesterolemia, familial hypercholesterolemia, coronary atherosclerosis, and prophylaxis of coronary atherosclerosis. Both lower LDL-C by inhibiting HMG-CoA reductase and increasing LDL receptors. Both can be combined with agents such as ezetimibe, bempedoic acid, and cholestyramine. Both can cause serious adverse effects like myopathy/rhabdomyolysis and hepatotoxicity.
Differences:
- Atorvastatin is more lipophilic, so it penetrates non-hepatic tissues more and is associated with more tissue-related adverse effects. Its hepatic uptake is mainly by passive diffusion. It is metabolized by CYP3A4 to active metabolites, then glucuronidated, and excreted in bile/feces. It also has an indication for stroke in the slide set, and the slides list hemorrhagic cerebral infarction as an atorvastatin-only adverse effect.
- Rosuvastatin is more hydrophilic, so it is more hepatoselective and tends to have fewer non-hepatic adverse effects. Its liver uptake is via organic acid transporters. It undergoes little metabolism, with a minor amount converted to CYP2C9 to inactive metabolites; much is excreted in bile/feces. The slides list acute renal failure as a rosuvastatin-only adverse effect. Rosuvastatin would generally be preferred over CYP3A4-heavy statins in a patient with major CYP3A4 interaction concerns.

What is the metabolic break down process of gemifibrozil?

Gemfibrozil is metabolized first by glucuronidation (UGT), then it is oxidized by CYP2C8, which is important for drug-drug interactions.

How do the mechanisms of action differ between statins and bempedoic acid?

Both drugs reduct hepatic cholesterol synthesis and increase LDL receptors, but they inhibit different enzymes:
- Statins inhibit HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis. This lowers hepatic cholesterol, activates SREBP, increases LDL receptor expression increases LDL uptake, and lowers plasma LDL-C
- Bempedoic acid inhibits ATP-citrate lyase (ACLY), an earlier step in cholesterol biosynthesis, upstream of HMG-CoA reductase. Becase ACLY is also at a branch point feeding fatty acid synthesis, bempedoic acid can reduce both cholesterol and TAG synthesis. It also increases LDLR on the liver cell surface and lowers hs-CRP.
Another key difference from the slides: bempedoic acid is a prodrug activated in the liver but not muscle, which may reduce both muscle-related adverse effects compared with statins.

How do BAS affect plasma levels of some drugs?

Cholestyramine and other bile acid sequestrants can interfere with absorption of other drugs and vitamins. That means they can lower the absorption of co-administered oral drugs, which would tend to decrease their plasma levels. This happens because BAS are binding agents in the GI tract and are not themselves absorbed.

How can you prevent BAS DDI's?

The prevention principle is to avoid coadministration at the same time, because BAS interfere with absorption of other drugs and vitamins. In exam wording: separate the administration of BAS from other medications to reduce binding in the gut and prevent reduced absorption/plasma levels.

What is the mechanism of action of PCSK9i?

1.    PCSK9 normally binds to the LDL receptor and target it for degradation in liver cells. PCSK9 inhibitors reduce this process, so more LDL receptors are recycled back to the hepatocyte surface. That increases LDL uptake from plasma and lowers plasma LDL-C.
- Evolocumab: a monoclonal antibody against PCSK9 that binds and neutralizes PCSK9 activity.
- Inclisiran: a small interfering RNA-based therapy against PCSK9.

How do the adverse effects of evolocumab differ from those of rosuvastatin?

Evolocumab adverse effects in the slides are mainly:
- Injection site reaction
- Hypersensitivity reaction
- Nasopharyngitis, URTI, influenza
- Back pain, myalgia, arthralgia, diarrhea
- Dizziness and hypertension listed specifically for evolocumab

Rosuvastatin adverse effects include:
- Myopathy/rhabdomyolysis
- Hepatotoxicity
- Systemic lupus erythematosus
- Pancreatitis
- Acute renal failure listed specifically for rosuvastatin
- Abdominal pain, constipation, arthralgia, and musculoskeletal pain.

Evolocumab has a more biologic/injection-related adverse effect profile, while rosuvastatin has the more classic statin toxicities, especially muscle, liver, and renal toxicity.

Why might evolocumab be a bad choice for a patient with Parkinson's disease or dementia?

Evolocumab may be less favorable choice in a patient with Parkinson’s disease or dementia because the slide lists dizziness as an adverse effect, and dizziness could worsen safety or functional problems in patients who already have neurologic or cognitive impairment.

What are similarities between evolocumab and inclisiran?

- Are PCSK9 inhibitor
- Reduce PCSK9 activity
- Increase LDL receptors on the liver cell surface
- Lower LDL-C
- Are used for heterozygous familial hypercholesterolemia (HeFH) and clinical ASCVD requiring additional LDL-C lowering

- Evolocumab is a monoclinal antibody
- Inclisiran is an siRNA-based therapy
So… same target, same physiologic outcome, different modality

What are basic causes of hypertension?

- Primary (essential) HTN
- Renal HTN (kidney dysfunction affecting volume/RAAS)
- Hormonal HTN
 - Catecholamines
 - Cortisol
 - Aldosterone
- Other causes
  - Cardiovascular
  - Neurogenic
  - Drug-induced (NSAIDs, steroids, decongestants, erythropoietin)

These reflect dysregulation of volume, vascular tone, or hormonal control.

What are the main factors contributing to mean arterial pressure?

- MAP = CO x TPR
- CO = SV x HR
- SV depends on:
  - Cardiac contractility
  - Venous return

So MAP is determined by:
- Cardiac output (CO)
- Total peripheral resistance (TPR)

How do hydrochlorothiazide and chlorthalidone decrease blood pressure?

- Block Na+/Cl- symporter (NCC) in DCT
- inc Na+ in lumen -> increase water excretion -> dec blood volume -> dec CO
- Chronic use -> vasorelaxation (mechanism not fully defined)

Net:
- dec volume (initial)
- dec TPR (chronic)

How do hydrochlorothiazide and chlorthalidone increase the risk of gout?

- They are organic acids secreted via OAT transporters
- They compete with uric acid secretion
- dec uric acid excretion -> hyperuricemia -> gout

Which diuretics are NOT organic acids?

- Thiazides = organic acids
- Loop diruetics = organic acids (use OAT1)
- Spironololactone/eplerenone = steroid-based
- Amiloride = NOT organic acid
(Spironololactone, eplerenone, amiloride)

Compare and contrast spironolactone and eplerenone.

Similarities:
- Both = aldosterone (mineralocorticoid) receptor antagonists
- dec Na+/H2O reabsorption, dec K+ secretion -> K+-sparing
- Used in HTN, HF, edema

Differences:
- Spironolactone
  - Less selective
  - Binds androgen/progesterone receptors
  - -> gynecomastia, impotence, menstrual changes
- Eplerenone
  - More selective (epoxide group)
  - dec endocrine side effects
  - Less potent

Both:
- Risk of hyperkalemia + metabolic acidosis

Which diuretics use the organic acid transporter 1?

- Thiazides (HCTZ, chlorthalidone)
- Loop diuretics (furosemide, bumetanide)

Used for secretion into renal tubule

Draw the RAAS pathway, then label the steps with their inhibitors (drugs)

Pathway:
- Angiotensinogen -> (Renin) -> Ang I
- Ang I -> (ACE) -> Ang II
- Ang II -> AT1 receptor -> vasoconstriction + aldosterone

Drugs:
- Aliskiren -> inhibits renin
- ACE inhibitors (lisinopril, enalapril, captopril) -> block Ang I -> Ang II
- ARBs (losartan, valsartan) -> block AT1 receptor

Effects:
- dec vasoconstriction (dec TPR)
- dec aldosterone -> dec Na+/H2O -> dec CO

Compare and contrast adverse effects of hydrochlorothiazide and lisinopril.

HCTZ:
- Hypokalemia
- Hyponatremia
- Hypercalcemia
- Hyperuricemia (gout)
- Hyperglycemia
- Volume depletion

Lisinopril:
- Hyperkalemia
- Dry cough (inc bradykinin)
- Angioedema
- dec GFR
- Teratogenic

HCTZ -> low K+
Lisinopril -> high K+ + cough

Compare and contrast adverse effects of metoprolol and lisinopril.

Metoprolol:
- Bradycardia
- AV block
- HF worsening
- Sexual dysfunction

Lisinopril:
- Hyperkalemia
- Dry cough
- Angioedema
- Renal impairment

Beta block = cardiac effects
ACEi = RAAS + bradykinin effects

Compare and contrast adverse effects of metoprolol and prazosin.

Metoprolol:
- Bradycardia
- AV block
- dec CO

Prazosin:
- Orthostatic hypotension
- Reflex tachycardia
- Dizziness
- Blood pooling

Metoprolol -> dec HR
Prazosin -> reflex inc HR

Is carvedilol or labetalol a better choice for a patient with extensive liver disease and why?

- Carvedilol
  - Extensive hepatic metabolism (CYP2D6, 2C9)
- Labetalol
  - Not metabolized
  - Excreted unchanged

- Labetalol (avoids hepatic metabolism)

Which calcium channel blockers are “cardio selective”?

- Verapamil
- Diltiazem

Act on:
- SA node
- AV node
- Contractility

Which cardiac calcium channel blockers are vascular only?

- DHPs (dihydropyridines)
- Nifedipine
- Amlodipine

-> Primarily act on vascular smooth muscle

How do second generation CCB's differ from first generation CCB’s?

- Second generation:
  - Longer half-life
  - More sustained effect

- Also:
  - Differences in tissue selectivity (cardiac vs. vascular)

Which CCB has the biggest effect on coronary arteries?

Nifedipind (DHP) -> greatest coronary vasodilation

Why is AV-block an adverse effect of verapamil and diltiazem?

- Block L-type Ca2+ channels in SA/AV node
- dec conduction velocity

-> Leads to AV block and bradycardia

Which antihypertensive medications are used in pregnancy?

- Labetalol
- Methyldopa
- Hydralazine

Which antihypertensive medications are teratogens?

- ACE inhibitors (lisinopril)
- ARBs
- Aliskiren

-> Cause fetal toxicity

How does isosorbide dinitrate treatment acute anginal attack?

Mechanism:
- NO donor
- inc NO -> inc cGMP
- -> smooth muscle relaxation (venodilation)

Effects:

- dec preload
- dec cardiac oxygen demand
- improves supply / demand mismatch

Used for:
- Acute anginal attacks

Compare and contrast 2 mechanisms of triggered activity in the heart. (EAD and DAD)

Early Afterdepolarizations (EAD):
- Occur before repolarization is complete
- Due to Na+ channel reactivation
- Can trigger a new action potential prematurely
- More likely in damaged tissue (eg. Ischemia)

Delayed Afterdepolarization (DAD):
- Occur after repolarization is complete
- Caused by intracellular Ca2+ overload
- Excess Ca2+ -> NCX exchanges Ca2+ out for Na+
- Na+ influx -> triggers new action potential

Key difference:
- EAD = Na+-driven, during repolarization
- DAD = Ca2+-driven, after repolarization

What are the four basic classes of anti arrhythmics and which channels do they affect?

- Class I: Na+ channel blockers
- Class II: Beta-blockers (affect beta-blockers -> dec automaticity)
- Class III: K+ channel blockers
- Class IV: Ca2+ channel blockers

Compare and contrast various Class 1 antiarrhythmic agents.

Class IA (Procainamide)
- Moderate Na+ block
- Also block K+ channels
- inc AP duration + refractory period
- inc QT interval

Class IB (Lidocaine)
- Weak/short Na+ block
- Preferentially affects rapidly firing/ischemic tissue
- dec automaticity
- Shortens refractory period slightly
- No QT prolongation

Class IC (Flecainide)
- Strongest Na+ block
- dec conduction velocity significantly
- No effect on refractory period
- High pro-arrhythmic risk

Key comparison:
- IA: moderate + inc QT
- IB: weak + ventricular specific
- IC: strong + dangerous

Why are beta blockers first line anti-arrhythmics?

Because they:
- Decrease SA node automatically
- dec HR (Beta-1 blockade)
- dec conduction velocity (AV node)
- dec Ca2+ via dec cAMP

Also:
- Reduce sympathetic stimulation, which drives arrhythmias

Net: stabilize rhythm by reducing excitability and conduction

Why use esmolol (given IV) rather than propranolol (given IV) in an acute emergency?

Esmolol:
- IV only
- Very short t1/2 (~2 min)
- Rapid onset/offset
- Cardio-selective (Beta-1)

Propranolol:
- Longer t1/2 (3.5-6hr)
- Non-selective

In emergencies:
- Esmolol is safer and controllable
- Effects can be quickly stopped

How does Propranolol act as an anti-arrhythmic?

- Beta-1 blockade -> dec SA node firing (dec HR)
- dec AV node conduction
- dec contractility -> dec O2 demand
- dec cAMP -> dec Ca2+ influx

Net:
- dec automaticity
- dec conduction velocity

What are the adverse effects of propranolol?

- Bradycardia
- AV block
- Heart failure
- Bronchospasm (Beta-2 blockade)
- Arrhythmias, stroke
- GI upset
- Sleep disorders
- Severe skin reactions (SJS)

What is the mechanism of action of amiodarone as it is used in arrhythmia?

Primacy:
- Blocks K+ channels -> prolongs repolarization

Effects:
- inc action potential duration (APD)
- inc effective refractory period (ERP)

Also:
- Has Class I, II, III, and IV effects
  - Na+ block
  - Beta-blockade
  - Ca2+ block

Net:
- Prevents re-entry
- Suppresses EADs

Which calcium channel blockers are used in arrhythmia?

- Verapamil
- Diltiazem
(Non-DHP, cardio-selective)

What is the mechanism of action of CCB’s in cardiac arrhythmia?

- Block L-type Ca2+ channels in:
  - SA node
  - AV node

Effects:
- dec SA node firing -> dec HR
- dec AV node conduction -> prevents rapid conduction
- dev contractility

Also:
- Inhibit EADs and DADs
- Prevent re-entry circuits

Net:
- dec automaticity
- dec conduction velocity

What is the mechanism of action of clopidogrel/prasugrel?

- Irreversible, non-competitive antagonists of P2Y12 (ADP) receptor
- Both are prodrugs -> require activation
- Blocking P2Y12:
  - Prevents ADP-mediated Gi activation
  - inc adenylyl cyclase -> inc cAMP
  - inc VASP phosphorylation
  - -> dec platelet aggregation

Net: inhibit platelet activation/aggregation permanently for platelet lifespan

How can the PPI omeprazole affect the action of clopidogrel/prasugrel?

- Both drugs are prodrugs
- Require activation via CYP enzymes (CYP2C19, CYP3A4)
- Omeprazole inhibits CYP2C19 (and CYP3A4)

Result:
- dec activation of clopidogrel/prasugrel
- dec antiplatelet effect -> treatment failure risk

If you wanted to block P2Y12 in a patient taking omeprazole, which agent might you use and why?

- Ticagrelor

Why:
- NOT a prodrug (active as administered)
- Does not require CYP activation

So avoids PPI interaction and maintains P2Y12 inhibition

Why would GPIIb/IIIa antagonists eptifibatide /tirofiban only be used in acute thrombosis?

(Eptifibatide, tirofiban)
- Block final common pathway of platelet aggregation
- Prevent fibrinogen binding to GPIIb/IIa

BUT:
- Very potent
- High risk of:
  - Major hemorrhage
  - Intracranial bleeding
  - Thrombocytopenia

Therefore:
- Used only inactive settings (ACS, PCI) where rapid, strong inhibition is needed

Why does aspirin’s effect on platelet COX-1 last so long?

- Irreversibly acetylates COX-1
- Platelets cannot synthesize new enzyme (no nucleus)

Effect lasts:
- 7-10 days (platelet lifespan)
Even though drug t1/2 is short (~20 mins)

Which drugs do the following reversal agents reverse and how do they do it?

a.    Prothrombin complex concentrates (PCC)
- Reverse: Warfarin (and others)
- MOA:
   - replace clotting factors II, VII, IX, X
   - Restore coagulation

b.    Protamine sulfate --
- Reverse: Heparin (especially UFH)
- MOA:
  - Positively charged protein
  - Binds negatively charged heparin -> inactive complex

c.     Andexanet alpha
- Reverse: Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)
- MOA:
  - Factor Xa decoy protein
  - Binds drug -> restores Xa activity

d.    Idarucizumab
- Reverse: Dabigatran
- MOA:
  - Monoclonal antibody
  - Bind dabigatran -> neutralizes it

e. Ciraparantag
- Reverse: Heparin + DOACs (Xa inhibitors)
- MOA:
  - Broad binding -> neutralizes anticoagulants

Compare and contrast heparin and warfarin.

Heparin:
- IV/SC
- Immediate effect
- MOA:
  - Enhances antithrombin
  - Inactivates Factor IIa (thrombin) + Xa
- No monitoring delay
- AE:
  - Bleeding
  - HIT (thrombocytopenia)

Warfarin:
- Oral
- Delayed onset (36-72 hrs)
- MOA:
  - Inhibits VKORC1
  - dec synthesis of Factors II, VII, IX, X
- Requires INR monitoring
- AE:
  - Bleeding
  - Skin necrosis
- Many CYP interactions

Key contrasts:
- Heparin = fast, direct, injectable
- Warfarin = slow, indirect, oral, monitored

List the direct oral anticoagulants (DOAC’s) and their mechanisms of action.

Direct Thrombin Inhibitor
- Dabigatran
  - Directly inhibits Factor IIa (thrombin)

Direct Xa Inhibitors
- Rivaroxaban
- (Also implied: apixaban, edoxaban)
Mechanism:
- Directly inhibit Factor Xa
- dec conversion of prothrombin -> thrombin

Indirect Xa Inhibitor:
- Fondaparinux
  - Enhances antithrombin -> inhibits Xa

Summary:
- Dabigatran -> IIa inhibitor
- Rivaroxaban -> Xa inhibitor