Pharmacokinetics and Pharmacodynamics of Acetaminophen and Aspirin; By Vincenzo Crawford

VINCENZO CRAWFORD ID# 1005315 BS. FORENSIC SCIENCE

FOSS – SONAS [University of Technology, Jamaica]

DRUGS AND TOXICOLOGY

PHA-4021

Pharmacodynamic/Pharmacokinetic of

ASPIRIN AND ACETAMINOPHEN [COMPARISON BETWEEN ASPIRIN (ASA) AND ACETAMINOPHEN (APAP)]

Prepared by:

Vincenzo Crawford

Student at:

University of Technology (U-Tech)

Bs. Forensic Science

[NOVEMBER 21, 2014]



ASPIRIN/Acetylsalicylic Acid (ASA)

Aspirin or acetylsalicylic acid (ASA) is known as a salicylate and a nonsteroidal anti-

inflammatory drug (NSAID) which is generally used as an analgesic for minor aches and pains,

to reduce fever (antipyretic), and also as an anti-inflammatory drug (“MNT news desk,” 2014).

USES OF ASA

Aspirin is used to reduce fever and relieve mild to moderate pain from conditions such as muscle

aches, toothaches, common cold, and headaches. It may also be used to reduce swelling in

conditions such as arthritis etc.

Aspirin also tends enable easier blood flow through narrowed blood vessels, and help to prevent

blood from clotting. This drug is used to relieve discomfort caused by numerous medical

problems, including infections, it is also used to reduce the risk of a second heart attack or stroke.

Larger doses of aspirin are used to treat gout (a disease in which defective metabolism of uric

acid causes arthritis, especially in the smaller bones of the feet).

PHARMACODYNAMICS OF ASA

NSAIDs such as aspirin benefits some patients greatly in alleviating their discomforts

caused by pain, inflammation, fever, etc. However, serious side effects can occur and generally

tend to be dose related. Therefore, it is advisable to use the lowest effective dose to minimize

side effects.

The most common side effects of aspirin involve:

1. Stomach ulceration and bleeding can occur without any abdominal pain.

2. Black tarry stools, weakness, and dizziness upon standing may be the only signs of

internal bleeding.

3. Rash, kidney impairment, vertigo, and light-headedness can also occur

4. Gastrointestinal system and ringing in the ears.

5. Ulcerations, abdominal burning, pain, cramping, nausea, gastritis, and even serious

gastrointestinal bleeding and liver toxicity.



Fig. 0.1 – Showing Side Effects Of ASPIRIN (ASA)

Serious side effects can occur and generally tend to be dose related. Therefore, it is advisable to

use the lowest effective dose to minimize side effects.

Fig. 0.2 – Showing Overdose Of ASPIRIN (ASA)



PHARMACOKINETICS OF ASA

ABSORPTION OF ASA

Aspirin is absorbed rapidly from the stomach and intestine by passive diffusion. Aspirin

is a prodrug, which is transformed into salicylate in the stomach, in the intestinal mucosa, in the

blood and mainly in the liver. Salicylate is the active metabolite responsible for most anti-

inflammatory and analgesic effects (but acetylsalicylate is the active moiety for the antiplatelet-

aggregating effect). Gastrointestinal intolerance to salicylate observed in some patients has

prompted the development of formulations with enteric coating (UNIL, 2014).

DISTRIBUTION OF ASA

Salicylate distributes rapidly into the body fluid compartments. It binds to albumin in the

plasma. With increasing total plasma salicylate concentrations, the unbound fraction increases.

Salicylate may cross the placental barrier and distributes into breast milk.

METABOLISM OF ASA

Aspirin is rapidly biotransformed into the active metabolite, salicylate. Therefore, aspirin

has a very short half-life. Salicylate, in turn, is mainly metabolized by the liver. This metabolism

occurs primarily by hepatic conjugation with glycin or glucuronic acid, each involving different

metabolic pathways. The predominant pathway is the conjugation with glycin, which is

saturable. With low doses of aspirin approximately 90% of salicylate is metabolized through this

pathway. As the maximum capacity of this major pathway is reached, the other pathways with a

lower clearance become more important. Therefore, the half-life of salicylate depends on the

major metabolic pathway used at a given concentration and becomes longer with increasing

dosage. Salicylate is said to follow nonlinear kinetics at the upper limit of the dosing range.

Studies have shown that there is much inter-subject variation with respect to the relative

contribution of the different salicylate metabolic pathways (Klaassen, 2008).

EXCRETION OF ASA

Urinary excretion of unchanged salicylate accounts for 10% of the total elimination of

salicylate. Excretion of salicylate results of glomerular filtration, active proximal tubular

secretion through the organic acid transporters and passive tubular reabsorption. Urinary

excretion is markedly pH dependant and as the urinary pH rises from 5 to 8, the amount of free

ionized salicylate excreted increases from 3% of the total salicylate dose to more than 80% (by

ion trapping in the urine). Salicylate metabolites are also excreted in the urine.



Mechanism Of Action Of ASA

Aspirin targets the nerves throughout your body (Klaassen, 2008). When tissues are

damaged, it creates prostaglandin, a chemical which magnifies the message to your brain

sent by the nerves, making the pain felt more intense; aspirin works through the nerves of

the body to reduce the painful and inflammatory effect being felt.

Prostaglandin is made by enzymes called cyclooxyygenase-2 (COX-2).

Prostaglandin, as well as amplifying the pain signal to your brain cause swelling

(inflammation) in the damaged area.

Aspirin sticks to the enzyme that makes prostaglandins (COX-2) so that prostaglandins

cannot be made. This means that the pain signal to your brain isn’t amplified so that the

pain felt is less intense. It also means swelling is reduced.



ACETAMINOPHEN/PARACETAMOL (APAP)

PHARMACODYNAMICS OF APAP

Acetaminophen also known as paracetamol, us a synthetic compound (drug), which is commonly

used for its analgesic and antipyretic effects. Its therapeutic effects are similar to salicylates.

(APAP) is a nonsteroidal anti-inflammatory drug with potent antipyretic and analgesic actions

but with very weak anti-inflammatory activity. When administered to humans, it reduces levels

of prostaglandin metabolites in urine but does not reduce synthesis of prostaglandins by blood

platelets or by the stomach mucosa.

Dose of APAP – Acetaminophen is believed to be an effective antipyretic at serum

concentrations of 10–20 mg/L and these concentrations have been extrapolated to those that

provide analgesia.

APAP is a safe drug when used at therapeutically recommended doses. . However, an

overdose can cause severe liver injury and even liver failure in experimental animals and in

humans. An acetaminophen-related overdose, even accidental, may cause the liver to accumulate

a toxic substance (a reactive intermediate metabolite), bind to liver cells and damage them. This

can lead to serious liver damage, subsequent liver failure or even death if immediate medical aid

is not administered. If patient already have liver disease, their liver may worsens if APAP is

being administered.

Signs and symptoms of an acetaminophen overdose may entail:

First 24 hours: o Nausea, vomiting, stomach pain, and loss of appetite

o Paleness

o Tiredness

o Sweating

24 to 72 hours after the overdose: You may have any of the symptoms listed above, plus:

o Pain in your upper right side

o Dark-colored urine

o Urinating less often than normal

o Skin and the whites of the eyes turn yellow

72 to 96 hours after the overdose: This is the most serious stage. You may have any of the

symptoms listed above, plus:

o Blood in your urine

o Fever, lightheadedness, fainting



o Fast breathing, trouble breathing

o Extreme weakness or tiredness

o Feeling very hungry, shaking

o Blurred vision, a fast heartbeat, headache that will not go away

o Trouble staying awake

o Confusion

o Coma

PHARMACOKINETICS OF APAP

ABSORPTION & DISTRIBUTION OF APAP

Absorption and distribution of acetaminophen occurs similar to that of aspirin. The rate of

absorption of acetaminophen has a pKa of 9.5 and in the alkaline medium of the duodenum

acetaminophen is non-ionized. Consequently, absorption of the non-ionized form from the

duodenum to the systemic circulation is rapid in children.

After oral administration, APAP is rapidly absorbed by the GI tract; its volume of distribution is

roughly 50 L. The bioavailability of acetaminophen results from low first-pass metabolism, and

the hepatic extraction ratio is 0.11–0.37 in adults. The relative bioavailability of rectal compared

with oral acetaminophen formulations has been reported as 0.52 (range 0.24–0.98) and even as

low as 0.3. The relative bioavailability is higher in neonates and approaches unity. The relative

bioavailability of rectal formulations appears to be age related.

Metabolism

Acetaminophen is metabolised primarily in the liver, into toxic and non-toxic products.

Three metabolic pathways are notable:

Glucuronidation (45-55%)

Sulfation (sulfate conjugation) accounts for 20–30%.

N-hydroxylation and dehydration, then GSH conjugation, accounts for less than 15%.

The hepatic cytochrome P450 enzyme system metabolises Acetaminophen, forming a

minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzoquinone

imine-also known as N-acetylimidoquinone. NAPQI is then irreversibly conjugated with

the sulfhydryl groups of glutathione.

All three pathways yield final products that are inactive, non-toxic, and eventually

excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic.

NAPQI is primarily responsible for the toxic effects of Acetaminophen this constitutes an

example of toxication. Production of NAPQI is due primarily to two isoenzymes of cytochrome



P450: CYP2E1 and CYP3A4. At usual doses, NAPQI is quickly detoxified by conjugation with

glutathione

The toxic metabolite of acetaminophen, N-acetylp-benzoquinone imine (NAPQI) is

formed by the cytochrome P450s CYP2E1, 1A2 and 3A4. This metabolite binds to intracellular

hepatic macromolecules to produce cell necrosis and damage. Infants less than 90 days old have

decreased expression of CYP2E1 activity in vitro compared with older infants, children and

adults. CYP3A4 appears during the first week, whereas CYP1A2 is the last to appear. Neonates

(new-borns) can produce hepatotoxic metabolites (e.g. NAPQI), but the lower activity of

cytochrome P450 in neonates and higher glutathione stores may explain the low incidence of

acetaminophen-induced hepatotoxicity seen in neonates.

Fig. 0.3 – Showing the metabolism of ACETAMINOPHEN (APAP)/PARACETAMOL

EXCRETION OF APAP

Excretion of Acetaminophen occurs similar to that of Aspirin.

MECHANISM OF ACTION OF APAP

Analgesia is mediated through inhibition of prostaglandin synthesis within the central

nervous system (COX III, COX 2b). Analgesic effect also involves an inhibitory action on spinal

nitric oxide mechanisms and serotonergic pathways.



Vs ASPIRIN (ASA) COMPARED TO ACETAMINOPHEN (APAP)

Aspirin Basics Aspirin is a medication that is commonly used to treat different types of mild pain, including

headaches. When taken, aspirin is absorbed into the bloodstream and reacts with certain

chemicals in the blood to reduce the substances in the body that are causing the pain. Because it

also helps reduce inflammation and heat, aspirin is also useful in lowering fevers and to ease

minor muscle aches. In the past few years, aspirin has also been shown effective as a part of the

treatment regimen for heart disease because of its ability to thin the blood and allow it to flow

more freely through the body. Unfortunately, aspirin does have side effects; it can cause upset

stomach, heartburn, and indigestion, it’s generally not recommended for use in children, and

shouldn’t be used in some patients who have bleeding disorders.

Acetaminophen Basics Acetaminophen, on the other hand, is a medicine that works much like aspirin, but still has a few

differences. It also lowers fevers and helps with headaches, like aspirin, but it does not treat the

inflammation that can occur with muscle sprains or arthritis. However, acetaminophen is less

irritating to the stomach than aspirin, and usually does not cause as many side effects in the

digestive tract as aspirin does. Acetaminophen is safer for children and people with bleeding

disorders as well. People should be cautioned however, that taking acetaminophen in high doses

can damage the liver. Because it is found in many over-the-counter combination products,

patients should be extra cautious to make sure that they are not taking above the daily

recommended dose (4000 mg per day) without consulting their physician or pharmacist.

Comparison Summary

ASA and APAP are two entirely different drugs that in part treat similar symptoms. Both drug

reduces fever and pain. However, aspirin thins your blood and helps some with inflammation,

but is dangerous to be given to children under certain conditions, therefore a more suitable

alternative for certain children would be acetaminophen.

Aspirin acts on both inflammation and pain, while acetaminophen only relieves pain but have a

weaker anti-inflammatory property than to that of aspirin. Acetaminophen is easy on the gastric

pathway, while aspirin may cause gastric irritation and even bleeding.



REFERENCES

Klaassen, C. (2008). Toxicology "the basic science of poison". (Seventh ed.). NewYork: The

McGraw-Hill Companies, Inc.

MNT news desk. (2014, September 26). Retrieved from

http://www.medicalnewstoday.com/articles/161255.php

UNIL. (2014, September 26). Aspirin pharmacokinetics. Retrieved from

http://sepia.unil.ch/pharmacology/index.php?id=83

Read more: Difference Between Acetaminophen and Aspirin | Difference Between |

Acetaminophen vs Aspirin http://www.differencebetween.net/science/health/difference-between-

acetaminophen-and-aspirin/#ixzz3Jkvuehet

http://www.medicalnewstoday.com/articles/161255.php

http://sepia.unil.ch/pharmacology/index.php?id=83

http://www.differencebetween.net/science/health/difference-between-acetaminophen-and-aspirin/#ixzz3Jkvuehet




Pharmacokinetics and Pharmacodynamics of Acetaminophen and Aspirin; By Vincenzo Crawford

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