ESAR

Federal vs State Controlled Substance Laws

• Federal law establishes minimum nationwide standards

• States may enforce stricter, but not looser, regulation

• When laws conflict, pharmacists must comply with the more restrictive law

DEA numbers

• 2 letters + 7 numbers

• First letter = registrant type (A, B, F, M)

Checksum calculation

Step	Action
1	Add digits 1, 3, 5
2	Add digits 2, 4, 6 and multiply by 2
3	Add results
4	Last digit must match final DEA digit

Medicare Part D quality measures.

• Major focus areas:

  • Medication adherence (PDC ≥ 80%)

  • Statin use in diabetes

  • Avoidance of high-risk medications in older adults

• Poor performance can affect plan enrollment and reimbursement

Medication Error

Preventable event that may cause harm

ADE

Injury resulting from medication use

Near Miss

Error caught before reaching patient

Sentinel Event

Unexpected event causing death or serious harm

ISMP Categories

• Category A: Circumstances or events that have the capacity to cause error.

• Category B: An error occurred but the error did not reach the patient.

• Category C: An error occurred that reached the patient but did not cause patient harm.

• Category D: An error occurred that reached the patient and required monitoring and/or required intervention

• Category E: An error occurred that contributed to or resulted in temporary harm to the patient and required intervention.

• Category F: An error occurred that may have contributed to or resulted in temporary harm to the patient and required initial or prolonged hospitalization.

• Category G: An error occurred that may have contributed to or resulted in permanent patient harm.

• Category H: An error occurred that required intervention necessary to sustain life.

• Category I: An error occurred that may have contributed to or resulted in patient death. 

Premium

Monthly cost for coverage

Deductible

Amount paid before coverage starts

Copay

Fixed patient payment

Coinsurance

Percentage-based patient payment

Out of pocket max

Annual spending cap

CII refills

No refills; partial fills allowed under specific rules

CIII–CV refills

Up to 5 refills within 6 months

Schedule CI

Abuse Potential	Medical Use
High	None

Schedule CII

Abuse Potential	Medical Use
High	Accepted

Schedule CIII-CV

Abuse Potential	Medical Use
Decreasing	Accepted

DEA Form 222

• Required to order Schedule II controlled substances

• Available in paper and electronic (CSOS) formats

• Must be completed accurately — errors invalidate the order

• Records must be kept for 2 years
  

HMO Plan type

Strength	Limitation
Lower cost	Requires referrals

PPO Plan type

Strength	Limitation
Provider Flexibility	Higher Cost

ACO plan type

Strength	Limitation
Coordinated Care	limited network

Prospective DUE

Timing	Purpose
Before dispensing	Prevent errors

Concurrent DUE’s

Timing	Purpose
During therapy	Optimize treatment

Retrospective DUE’s

Timing	Purpose
After therapy	Improve systems

Medicare Part A covers

Inpatient hospital

Medicare Part B covers

Outpatient, DME (med equipment) , some vaccines

Medicare Part C covers

Medicare Advantage A+B

Medicare Part D covers

Outpatient prescriptions

REMS

• Used for drugs with serious safety risks

• Common examples:

  • Isotretinoin (iPLEDGE)

  • Clozapine

  • Thalidomide
    

USP 795

Nonsterile compounding

USP 797

Sterile Compounding

USP 800

Hazardous drug handling

QH (hepatic blood flow):

delivery of drug to liver

Clint (intrinsic clearance):

enzymatic ability of liver

fu (fraction unbound):

free drug available for metabolism

What can decrease QH?

Diseases

• Heart failure → weak pumping → less blood to liver

• Cirrhosis → scarring blocks blood flow

• Shock → poor organ perfusion

Drugs

• Beta-blockers

• Calcium channel blockers
  (these lower cardiac output)

Lower QH = lower clearance

What changes Clint?

Drugs

Some drugs slow enzymes down:

• Azoles

• Macrolides

• Amiodarone

decrease clearance

Some drugs speed enzymes up:

• Rifampin

• Carbamazepine

• Phenytoin

increase clearance

Herbal products

• St. John’s wort → speeds enzymes up

• Grapefruit juice → slows enzymes down

Diseases

• Liver disease → damaged enzymes → slower metabolism

• Hepatitis → inflammation → ↓ Clint

What increases fu?

Diseases

• Liver disease → low albumin

• Kidney disease → toxins knock drug off proteins

• Malnutrition → low protein levels

Drugs

• Some drugs push others off proteins (displacement)

High extraction drugs

High Clearance drugs

Only QH (blood flow to liver) can affect clearance

heart failure/shock effect can decrease clearance

low interaction risk

Low extraction drugs:

low clearance drugs

Clearance depends on how strong the liver enzymes are- Clint

High interaction risk

Liver disease damages enzymes

• Metabolism slows

Oral Bioavailability factors

• Bioavailability (F) = fraction reaching systemic circulation
  

• Reduced by:

  • First-pass metabolism (drug metabolized primarily in small intestine/ liver)

  • Poor solubility or permeability

  • Efflux transporters

• Increased by enzyme inhibition or food (drug-specific)
  
  

IV administration = 100% bioavailability

What is P-gp

• A drug efflux transporter

• Its job is to pump drugs OUT of cells

Think of P-gp as a bouncer.

limits absorption pumping drug back into gut out of cell (Ex. enterocytes)

P-gp inhibitors

increase drug absorption and toxicity

P-gp inducers

decrease absorption and efficacy

What happens to receptors with chronic agonist exposure, and what is the clinical consequence?

causes receptor down-regulation, leading to reduced responsiveness (tolerance) and the need for higher doses.

What happens to receptors with chronic antagonist exposure, and why is this clinically important?

receptor up-regulation; abrupt discontinuation can cause withdrawal or rebound effects (e.g., beta-blockers, opioids).

ED50 =

Effective dose 50%

It’s the dose that produces the desired effect in 50% of a population (for “quantal” data), OR sometimes the dose that produces 50% of the maximal effect (for “graded” data)

Lower ED50

→ you need less drug → more potent (in population terms)

TD50

Toxic Dose 50%

The dose that produces toxicity in 50% of a population.

• How much drug it takes before many people get side effects/toxicity

Therapeutic Index (TI)

TI = TD50 ÷ ED50

How to interpret it

• Large TI = big safety buffer (toxic dose far from effective dose)

• Small TI = narrow therapeutic window (dangerously close)

EC50

Effective Concentration 50%”
The concentration of a drug that produces 50% of Emax.

Key detail:

• EC50 is from a graded dose-response curve (effect size vs concentration)

• It’s a potency measure in a tissue/individual system

Emax

maximum effect a drug can produce (no matter how high you dose it)

What it tells you

• This is efficacy

• Higher Emax = drug can produce a larger maximum response

• Partial agonists have lower Emax than full agonists

KD

equilibrium dissociation constant
It reflects binding affinity between drug and receptor.

Lower KD = higher affinity (drug binds tighter)

What KD specifically represents

• The concentration at which 50% of receptors are occupied (in a simple model)

Potency

horizontal position

• How much drug is needed to get an effect

• Measured by EC50

• Curve further left = more potent

• Curve further right = less potent

Efficacy

vertical height

• Maximum effect the drug can produce

• Measured by Emax

• Higher curve = higher efficacy

• Lower curve = lower efficacy

Competitive Antagonists

What they do

• Compete with the agonist for the same receptor binding site

• Binding is reversible

Effect on the curve

• Curve shifts right

• Emax stays the same

• Higher agonist concentration can overcome the antagonist

What this means mechanistically

• More agonist is needed to achieve the same effect

• Maximum effect is still achievable

Interpretation

• Potency decreases (need more drug)

• Efficacy unchanged

Non-competitive Antagonists

What they do

• Bind irreversibly or bind to a different site

• Reduce the number of functioning receptors

Effect on the curve

• Emax decreases

• Increasing agonist concentration cannot restore max effect

• Curve gets shorter, not just shifted

What this means mechanistically

• Even with lots of agonist, fewer working receptors exist

• Maximum response is capped

Interpretation

• Efficacy decreases

• Potency may or may not change, but efficacy always does

Active metabolites

An active metabolite is a breakdown product of a drug that:

• Still has pharmacologic activity, and

• Can contribute to or prolong the drug’s effect

• prolong effect

• Increase risk of accumulation

• Important in renal impairment

• Examples: diazepam, codeine, amiodarone
  
  

Steady state

• Occurs when rate of drug in = rate of drug out

• Achieved after ~4–5 half-lives

• Independent of dose

• Depends only on half-life

Increasing the dose:

• Raises steady-state concentration

• Does NOT change time to steady state

Half life

time it takes for the amount or concentration of a drug in the body to decrease by 50%.

Half-life is determined by two physiological factors:

1. Clearance (CL) → how efficiently the body removes drug

2. Volume of distribution (Vd) → how widely the drug distributes into tissues

Mathematically:

t1/2= (0.693×Vd) /CL

Volume of Distribution (Vd)

how widely a drug distributes from the blood into the body’s tissues.

high VD

Parameter	Effect
Plasma concentration	Low
Half-life	Long
Loading dose	Large
Tissue storage	High
Dialysis	Poor

Low VD

Parameter	Effect
Plasma concentration	High
Half-life	Short
Loading dose	Small
Tissue storage	Low
Dialysis	Effective

Drug Distribution and Equilibrium

involves movement of drug from blood to tissues until equilibrium is reached, where concentrations are stable relative to each other despite ongoing bidirectional movement.

What defines steady state, what determines Css, and how can Css be reached faster

Steady state occurs when rate in = rate out; Css is proportional to infusion rate and inversely proportional to clearance (no peaks/troughs with continuous infusion), and a loading dose speeds attainment of Css without changing clearance or half-life.

What determines drug absorption from a physiological and pharmacokinetic perspective?

Drug absorption depends on physiology (blood flow, surface area, GI motility, pH) and pharmacokinetics (drug solubility, permeability, ionization, and transporters), which together control the rate and extent of drug entry into systemic circulation.

Absorption favors lipophilic, non-ionized drugs.

Clearance as a Central PK Parameter

• Clearance determines maintenance dose

• Directly affects half-life and Css

• Reduced in liver or kidney disease

• Most clinically relevant PK parameter

Goals of PAD therapy:

• Reduce cardiovascular events (MI, stroke)

• Reduce limb ischemia and amputation risk

• Improve walking distance (claudication)

PAD Core first-line therapies:

• Antiplatelet therapy (aspirin or clopidogrel)

• High-intensity statin

• Smoking cessation

• Exercise therapy
  
  

Cilostazol improves claudication symptoms (contraindicated in HF)

HFrEF definition

EF ≤ 40%

HFrEF Guideline-directed medical therapy (GDMT) includes

1. ARNI (preferred) or ACEI/ARB

2. Beta blocker (carvedilol, metoprolol succinate, bisoprolol)

3. Mineralocorticoid receptor antagonist

(spironolactone/ eplerenone)

4. SGLT2 inhibitor (emagliflozin/dapaglifolozin)
   

HFrEF drugs are titrated slowly to evidence-based target doses.

Duiretics vs GDMT in HFrEF

Diuretics relieve symptoms; GDMT saves lives (decreases mortality)

HTN first line agents

• ACEI/ARB

• Thiazide diuretics

(HCTZ)

• CCBs

(amlodipine, nifedipine,)

HTN Compelling indications guide selection:

• CKD → ACEI/ARB

• CAD → beta blocker + ACEi

• HF → ACEI/ARB/ARNI + beta blocker

• Stroke ACE/ARB/Thiazide

High-Intensity Statin Therapy

Atorvastatin	40–80 mg
Rosuvastatin	20–40 mg

LDL-C Goals in ASCVD

• LDL-C goal in ASCVD: <70 mg/dL

• If not achieved:

  • Add ezetimibe

  • Then consider PCSK9 inhibitor

• Lower LDL = lower CV risk

ACEi / ARB effect on Potassium

↑ K⁺ (hyperkalemia)

MRA effect on Potassium

↑ K⁺ (hyperkalemia)

Thiazides effect on Potassium

↓ K⁺ (hypokalemia)

Loop Diuretics (furosemide)

↓ K⁺ (hypokalemia)

Medications That Worsen Heart Failure

• Common offenders:

  • NSAIDs

  • TZDs

  • Non-DHP CCBs (verapamil, diltiazem)
    

• These cause:

  • Fluid retention

  • Negative inotropy

  • Renal dysfunction
    

Adverse Effects of Statins

• Myalgias

• Elevated AST/ALT

• Rare: rhabdomyolysis

• Baseline LFTs recommended

Key Point:
👉 Muscle symptoms are common; severe toxicity is rare.

Blood Pressure Goals

<130/80 mmHg

disease states that are examples of clinical ASCVD

• MI

• Stroke/TIA

• PAD

• Stable or unstable angina

• Used to determine statin intensity

Key Point:
👉 Clinical ASCVD automatically triggers high-intensity statin therapy.

Aspirin MOA

Cox-1 inhibition

Clopidogrel MOA

P2Y12 inhibition

GP IIb/IIIa inhibitors

Block platelet aggregation

a1 receptor

• smooth muscle

• vasoconstriction

• Increase Ca2

(alpha1 receprtor blocker would vasodilate)

a2 receptor

• found in CNS

• inhibit NE release

• decrease Ca2

B1 receptors

Found in Heart

Increase cardiac contractiity and frequency

B1 blocker would decrease HR and contrafrility

B1 specific blockers

• Metoprolol

• Atenolol

• Bisoprolol

b2 receptor

Found in heart and smooth muscle

increase cardiac contractility and frequency

smooth muscle relaxation

b2 blocker- bronchi dilation and vasodilation

Non selective beta blockers

Propranolol, timolol, carvedilol

Loop diuretics site of action

Thick ascending limb

Ex Furosemide

Thiazide diuretics site of action

Distal Convulated tubule

Ex HCTZ/ Chlorthalidone

Potassium Sparing Diuretic site of action

Collecting ducts

Ex. Spironolactone, Eplerenone

Carbonic anhydrase inhibitors site of action

proximal convoluted tubule

Ex Acetazolamide

Osmotic diuretics site of action

Proximal tubule and loop of henle

Ex Mannitol

SABA

short acting bronchodilator

Rescue

Albuterol / Levalbuterol