Advanced Pharm Exam 1

rectal drugs and first-pass effect

50% of drug absorbed will bypass liver/first-pass effect

low albumin states result in

lower total drug levels and a higher fraction of free drug

major determinant in ability to cross blood-brain barrier

lipid solubility

volume of distribution

extent of drug distribution into blood and tissues

Vd and drug type

lipophilic drugs have large Vd, hydrophilic drugs have small Vd

phase 1 reactions

oxidation, reduction, and hydrolysis

usually leads to drug inactivation, sometimes causes drug activation

decreased in elderly

phase 2 reactions

conjugation of substrate to make it more hydrophilic and improve elimination

preserved in elderly

what most commonly determines duration of drug action

hepatic metabolism and renal elimination

how many doses are required to reach steady state

5

(unless a loading dose is given)

acetaminophen MOA, Use, dosing

MOA: weak cox-1 and cox-2 inhibition, some central activation of 5HT

Use: analgesic and antipyretic, mild-moderate pain or adjunct for severe, first line for OA

Dosing/admin: Max 4g/day for healthy adults, max 2g/day for cirrhosis, max 5 doses/day for peds (10-15mg/kg/dose)

acetaminophen adverse effects/warnings/pregnancy

AE: rash/hypersensitivity

contraindications: severe hepatic impairment or liver disease

warnings: chronic alcoholism, hepatic impairment, malnutrition

OK for pregnancy and lactation

acetaminophen overdose

4 stages: asymptomatic/nonspecific; hepatic injury onset; hepatic failure/coma/death; recovery phase

acetaminophen converted to toxic NAPQI metabolite, glutathione normally detoxifies NAPQI but is depleted in overdose

**antidote: N-acetylcysteine (synthetic glutathione)

NSAIDS class-wide MOA and use

MOA: inhibition of COX, inhibiting PG synthesis

cox1: gastric epithelium protection and clotting

cox2: inflammation

Use: anti-inflammatory/pyretic, analgesic; first-line for inflammatory MSK and RA, mild-moderate pain or adjunct, NOT chronic use

NSAIDS AE/warnings/contraindications

GI upset and bleeds

bruising and bleeding

Na/K/water retention, edema

MI/stroke/clots

Contraindication: <6 mo

warnings: asthma, HF, CAD/MI, renal/hepatic impairment

NSAIDS and renal dysfx

NSAIDS inhibit PG which normally dilate afferent arteriole

NSAIDS decrease renal blood flow and GFR

caution with ACEs/diuretics

NSAIDS and cardio risk

cause edema, HTN, MI, CHF

**cox-2 selective (celecoxib and meloxicam) big risk for MI/stroke/clots

NSAIDs and bleeding risk

from lack of good PG from cox1

combine with PPI or misoprostol for LT use

NSAIDS pregnancy/lactation

contraindicated in 3rd trimester

small amounts in breast milk but OK

NSAID drug interactions

ACES—renal issues

SSRIS/SNRIS—GI

steroids—GI

warfarin—bleeding

lithium—toxicity

ketorolac

limited to 5 days duration

reduce dose by ½ in >65 yo or mild-moderate renal impairment, don’t use in severe renal impairment

meloxicam and celecoxib

cox-2 selective

NO CABG patients

aspirin

MOA: irreversible inhibition of COX enzymes—prevents formation of txA2 (needed for platelet agg)

*reyes syndrome in children

neuropathic pain agents

first line: gabapentin/pregabalin

second line: lidocaine patch, tramadol, capsaicin

lidocaine patch

local

12 hr on, 12 hr off

capsaicin

depletes substance p from nociceptive pain fibers

burning/stinging/erythema

diclofenac gel

topical NSAID

less systemic effects

when is preventive migraine therapy indicated

>5 attacks/mo

migraine rescue therapeis

NSAIDS

excedrin (aspirin + acetaminophen + caffeine)

butalbital compounds (fioricet/fiorinal)

antiemetics

fiorecet/firoinal

combination butalbital products

abortive migraine therapy

AE: hangover, GI upset, CNS depression

overuse leads to tolerance and dependence

**not first line

antiemetics/prokinetics for migraines

metoclopramide or prochlorperazine

MOA: anti-5HT, Ach, DA, Histamine

AE: akasthisa (+ others)

Triptans

selective 5HT1D and 5HT1B agonist

MOA: inhibits release of vasodilating peptides—>vasoconstriction

AE: chest discomfort/pain

contraindications: CAD, uncontrolled HTN, cerebrovascular disease

drug interactions: other 5HT drugs/MAOIS (serotonin syndrome)

Ergot alkalodis

Nonselective 5HT receptor agonists—>vasoconstriction

AE: peripheral/myocardial/brain ischemia; N/V

contraindicated: renal/hepatic failure, any vascular disease, uncontrolled HTN, pregnancy/lactation

*do not use within 24 hours of triptan

CGRP receptor antagonists

ubrogepant/rimegepant

block CGRP receptors—>blocks neuroinflammation and vasodilation

migraine prophlyaxis

anticonvulsants, beta-blockers

new CGRP antagonists

CGRP antagonists

for migraine prophylaxis

erenumab, fremanezumab, galcanezumab,

inactivate/block CGRP

Opioids class wide MOA and AE

Therapeutic: reduce pain perception in CNS, cough suppression

AE: miosis, itching, constipation (tolerance does not develop so bowel regimen needed for LT use), N/V

severe AE: respiratory depression, hypotension, bradycardia, allergy

opioid contraindication/precautions

contra: respiratory disease, comatose patients, allergy

warnings: bowel obstruction, CNS depression, delirium tremens, head trauma, renal impairment, seizure disorders

opioids pregnancy and lactation

fetus dependent in utero—>requires withdrawal treatment with morphine and clonidine

lactation—excreted in breast milk (can try to dose around feedings)

codeine

metabolized to morphine (active)

---

contraindicated in pediatrics because of fatal risk from ultrametabolizers

morphine

active and inactive metabolites are toxic

at risk: elderly/renal dysfx/dialysis

avoid long-acting in high-risk groups

hydromorphone

metabolized in liver to inactive metabolites

oxycodone

metabolized in liver to weakly active and active compounds

hydrocodone

metabolized to hydromorphone (active, highly potent) and norhydrocodone

fentanyl

various routes of admin

NOT for opioid naive

NOT coverted 1:1 between products

metabolized in liver to inactive product

for patch: applied for 72 hours at a time in opioid tolerant only, requires adipose depot, caution with edema and do not use heat

methadone

opioid agonist, MAOI, NMDA antagonist

used for analgesia but mainly for detox/opioid misuse

AE: QT prolongation, seizures

tramadol

opioid agonist, increase 5HT, inhibits 5HT/NE reuptake

metabolized to active and inactive products

greatest seizure potential

buprenorphine

partial opioid agonist

anlagesic ceiling

used for opioid dependence with naloxone as Suboxone

Schedule 2 prescribing

• no refills

• no time limit for filling of prescription (does not expire)

• only one prescription per blank

• up to 90 day supply

schedule 3-5 prescribing

• max 5 refills

• Prescriptions expire 6 months after issue

dispensing narcotics for treatment

• normally need to have additional training and register to provide meds as part of narcotic treatment program

• exceptions made if to relieve acute withdrawal—-only one days med at a time for max 3 days

• OR to maintain/detoxify someone inpatient when they are there for other medical issues (to prevent withdrawal)

opioid tolerance vs dependence

tolerance—repeated dosing has reduced effect, occurs within 2-3 weeks of continued use; does not develop to constipation/miosis

dependence: discontinuation leads to withdrawal (due to DA dysfunction)

Naloxone

competitively inhibits binding of opioids to receptors

precipitates withdrawal

can administer additional doses if needed

AE: significant n/v—>aspiration risk

Nicotine

1. nicotine replacement—>use combination and dose based on number of daily cigarettes and time of first cig

2. vareniciline—>blocks reward system of nicotine, start 1 week before quitting and can use for up to 24 weeks

3. burproprion—can use for up to 6 months (also blocks reward)

benzo withdrawal

occurs within days and lasts 1-2 weeks

no good treatment, requires tapering

alcohol withdrawal

delirium tremens within 48-72 hours (can be fatal)

requires benzos for treatment

alcohol dependence treatment

1. naltrexone (opioid antagonist)—reduces cravings

2. acomprosate (NMDA antagonist, GABA agonist)—reduces cravings, avoid in renal impairment

3. disulfiram (causes severe discomfort with alcohol ingestion)

anticoagulation monitoring

PTT: heparin, bivalirudin, argatroban

Xa: LMWH, fondaprinux

PT/INR: warfarin

Aspirin antiplatelet

irreversibly inhibits COX—>inhibits PG synthesis (specifically TXA2)

AE: dyspepsia, bleeding, asthma exacerbation, hepatotoxicity, thrombocytopenia

monitor: CBC, platelets, Scr

avoid in children

P2Y12 Inhibitors

clopidogrel, prasugrel, ticagrelor, cagrelor

MOA: inhibit ADP-induced platelet aggregation by blocking P2Y12 receptor

AE: bleeding dyspepsia, headache

monitor: CBC, platelets

timing: effects seen in 3-7 days

prasugrel

contraindicated after TIA or stroke

ticagrelor

dyspnea

reversible P2Y12 inhibitor

cagrelor

only IV
do not administer clopidogrel or prasugrel during infusion

PAR-1 antagonist

vorapaxar (in combination with aspirin or clopidogrel)

inhibits thrombin-induced and (TRAP induced)—platelet aggregation

effectively irreversible bc of long half life

for patients with prior MI or PAD

AE: bleeding, anemia, rash, depresssion

avoid in: hx of stroke, TIA, intracranial hemorrhage, severe hepatic impairment

monitor: CBC

Dipyridamole

in combinatioin with aspirin

vasodilator, inhibits platelet aggregation by inhibition adenosine uptake and cGMP activity

indication: stroke prevention after TIA

AE: bleeding, headache, abd pain, n/d, dyspepsia

monitor: CBC, platelets

**start with bedtime dosing first week to prevent headache

fibrinolytics

alteplase most commony used (also strepotkinase/reteplase/tenectaplase)

converts plasminogen to plasmin—>digests fibrin and causes fibrinolysis

**never exceed 100 mg

only for life threating clots

AE: bleeding

fibrinolysis inhibitors

aminocaproic acid and tranexamic acid

AE: thrombosis, myopathy, hypotension, abd discomfort, blood dyscrasias

monitor: CBC, fibrinogen, BUN, creatinine

unfractionated heparin

binds to antithrombin III—>inhibits factors IIa, IXa, Xa

AE: bleeding, thrombocytopenia, alopecia, hepatotoxicity

monitor: PTT or anti-Xa, CBC, platelets, potassium

antidote: protamine 1 mg per 100u, max 50 mg

low molecular weight heparin

enoxaparin and dalteparin

short chain heparin molecules, mainly affect factor Xa

**kinetics affected by renal fx

AE: bleeding, thrombocytopenia, skin necrosis/hypersensitivity

monitor: K+, CBC, platelets, SCr, anti-Xa

antidote: protamine 1mg per 1 mg

enoxaparin

dose rounded to nearest syringe size

LMWH black box

hold LMWH before and after spinal procedure

—can cause spinal/epidural hematomas and subsequent paralysis

heparin-induced thrombocyptopenia

UFH and LMWH can bind to platelet factor 4 and cause immune-mediated HIT

exposure to five days or more of heparin

can also have thrombosis (HITT)

HIT dx and management

diagnosed based on: thrombocytopenia, timing of platelet fall, thrombosis, other causes

*discontinue all heparin products, start with a direct thrombin inhibitor at therapeutic doses

once platelet count recovered, initiate warfarin

document allergy

Warfarin

vitamin k antagonist—decreases synthesis of factors 2, 7, 9, 10 and endogenous anticoagulant proteins C/S

takes at least 5 days for full effect

AE: bleeding, teratogenic

monitor: INR (2-3), CBC

antidote: vitamin K

warfarin bridge therapy

temporary hypercoagulable state upon inititaion due to depletion of C and S anticoagulant proteins

bridge therapy with injectable while waiting for full warfarin effect

bridge therapy must overlap warfarin until INR is within range for 2 consecutive days; minimum 5 days overlap

warfarin elevated INR

INR <10 without bleeding—hold dose until INR close to/in goal

with bleeding, regardless of INR, or INR >10 regardless of symptoms—-reverse with vitamin K

warfarin food interactions

maintain consistent vitamin K intake

warfarin dosing

lower initial dose (2.5 mg)—elderly, low weight, poor nutrition, hepatic impairment, CHF, coadministration w agent that decreases warfarin clearance

higher initial dose (7.5 mg)—young, overweight, admin wiht agent that increases clearnace

**adjust dose by 10-15% based on weekly warfarin dose

Xa inhibitors

rivaroxaban, apixaban, edoxaban, fondaparinux, betrixaban

inhibit factor Xa

AE: bleeding

monitoring: none (maybe CBC)

reversal: andexanet alfa

direct thrombin inhibitors

dabigatran, bivalirudin, argatroban

inhibits thrombin—prevent thrombin-induced conversion of fibrinogen to fibrin

AE: bleeding, hypotension, gastritis-like sx

monitor: PTT, INR (argatroban), CBC

antidote (idarucizumab) for dabigatran

dabigatran

contraindicated for mechanical heart valves, approved for non-valvular a-fib

reduce/avoid in renal impairment

Praxxbind/idarucizumab antidote

bleeding while on antiplatelet/anticoag

expected: gum bleeding, easy bruising with impact, nosebleeds, bleeding takes longer to stop

unexpected: hypotension, tachycardia, discolored urine/stool, headaches/faintness, hematemesis, head impact

DOACs vs Warfarin

-no routine monitoring, few drug interactions, rapid onset

better efficacy, probably safer

most should be avoided in renal impairment

rapid offset—>caution in non-adherent patients, consider anticoagulant bridge if temporarily held for any reason other than significant bleeding

cannot be used in mechanical valves