Analgesic Drugs

Department of Pharmacology Gamal Soliman

Pain
Pain is subjective and difficult to quantify
Pain scale, 1-10 McGill Pain Q. Analog scale

What do we know about ANALGESICS?

aka painkiller are used to relief pain From the GREEK an-(without) and algos (pain) occurs either by blocking pain signals going to the brain or by interfering with the brain's interpretation of the signals, without producing anesthesia or loss of consciousness. Basically has TWO kinds: NON-NARCOTICS and NARCOTICS

Types and degree of pain:

Acute pain of a headache considered mild (aspirin and acetaminophen (dextropropoxyphene)) Severe pain of dental surgery or trauma more potent narcotic analgesics (codeine and oxycodone) Excruciating chronic pain of arthritis and cancer frequent administration of the potent narcotics is recommended So SEVERE!!! (like cancer) - morphine

Types of Pain
Superficial:

- Stimulation of skin & mucous membranes

- Fast response

Deep:

- Arises from muscles, joints, tendons, heart ..etc.

- Slow response

What is Pain?
Pain can be defined as a somatic sensation of acute discomfort, a symptom of some physical hurt or disorder, or even emotional distress. It is a common human experience therefore the idea of pain and pain management appear throughout history

What is Pain?
Pain is a crucial aspect of the bodys defense mechanisms Pain is a part of a rapid warning relay instruction the motor neurons of the central nervous system to minimize detected physical harm (2). Pain can be classified into two types

Acute Pain
Acute pain is short-term pain or pain with an easily identifiable cause Acute pain is the body's warning of present damage to tissue or disease. It is often fast and sharp followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. This type of pain responds well to medications (2).

Chronic Pain
Chronic pain is pain that last much longer than pain normally would with a particular injury. Chronic pain can be constant or intermittent and is generally harder to treat than acute pain. Pain can also be grouped by its source and related pain detecting neurons such as cutaneous pain, somatic pain, visceral pain, and neuropathic pain Opioid Analgesics can be used to treat many types of pain

What Causes Pain?

Pain is caused by the stimulation of pain receptors which are free nerve endings. Nocireceptors are pain receptors that are located outside the spinal column in the dorsal root ganglion and are named based upon their appearance at their sensory ends. These sensory endings look like the branches of small bushes( 2). There are two types of nocireceptors that mediate fast or slow pain signals The perception of pain is when these receptors are stimulated and they transmit signal to the central nervous system via sensory neurons in the spinal cord.

http://staff.washington.edu/chudler/gif/spi

Pain Signaling
These neurons release excitatory neurotransmitters which relay signals from one neuron to another. The signals are sent to the thalamus, in which pain perception occurs. From the thalamus, the signal travels to the somatosensory cortex in the cerebrum, at which point the individual becomes fully aware of the pain (2).

Mechanisms of Nociception and Pain

Nociception is the mechanism by which noxious peripheral stimuli are transmitted to the CNS. Pain is a subjective experience , not always associated with nociception.

Mechanisms of Pain and Nociception

Polymodal nociceptors (PMN) are the main type of peripheral sensory neurons that responds to noxious stimuli. The majority are non-myelinated fibres whose endings respond to thermal, mechanical and chemical stimuli.

Mechanisms of Pain and Nociception

Chemical stimuli acting on PMN to cause pain include bradykinin, 5-HT, and capsaicin. PMN are sensitised by prostaglandins, which explains the analgesic effect of aspirin-like drugs, particularly in the presence of inflammation. Nociceptive fibres terminate in the superficial layers of the dorsal horn, forming synaptic connections with transmission neurons running to the thalamus.

Mechanisms of Pain and Nociception

PMN neurons release glutamate (fast transmitter) and various peptides (especially substance P) which act as slow transmitters. Peptides are also released peripherally and contribute to neurogenic inflammation. Neuropathic pain, associated with damage to neurons of the nociceptive pathway rather than an excessive peripheral stimulus, is frequently a component of chronic pain states, and may respond poorly to opioid analgesics.

Modulation of Pain Transmission

Transmission in the dorsal horn is subject to various modulatory influences, constituting the gate control mechanism. Descending pathways from the midbrain and brainstem exert a strong inhibitory effect on dorsal horn transmission. Electrical stimulation of the midbrain periaqueductal grey (PAG) causes analgesia through this mechanism.

Modulation of Pain Transmission

The descending inhibition is mediated mainly by enkephalins, 5-HT, noradrenaline and adenosine. Opioids cause analgesia partly by activating these descending pathways, partly by inhibiting transmission in the dorsal horn, and partly by inhibiting excitation of sensory nerve terminals in the periphery.

Modulation of Pain Transmission

Repetitive C-fibre activity facilitates transmission through the dorsal horn (wind-up) by mechanisms involving activation of NMDA and substance P receptors.

The descending control system, showing the main sites of action of opioids on pain transmission

Clinical Use of Analgesic Drugs

The choice and route of administration of analgesic drugs depends on the nature and duration of the pain. A progressive approach is often used, starting with nonsteroidal anti-inflammatory drugs, supplemented first by weak opioid analgesics, and then by strong opioids.

Clinical Use of Analgesic Drugs

In general, severe acute pain (e.g. trauma, burns, post-operative pain) is treated with strong opioid drugs (e.g. morphine, fentanyl) given by injection. Mild inflammatory pain (e.g. arthritis) is treated with non-steroidal anti-inflammatory drugs (e.g. aspirin) supplemented by weak opioid drugs (codeine, pentazocine) given orally if required. Severe pain (e.g. cancer pain, severe arthritis or back pain) is treated with strong opioids given orally, intrathecally, epidurally or by subcutaneous injection.

Clinical Use of Analgesic Drugs

Chronic neuropathic pain is often unresponsive to opioids, and treated with tricyclic antidepressants (e.g. amitriptyline), or other drugs, such as carbamazepine.

New Approaches
Enkephalinase inhibitors, such as the experimental drug RB120 act by inhibiting the metabolic degradation of endogenous opioid peptides, and have been shown to produce analgesia, together with other morphine-like effects, without causing dependence. Various neuropeptides, such as somatostatin and calcitonin, produce powerful analgesia when applied intrathecally, and there are clinical reports suggesting that they may have similar effects when used systemically to treat endocrine disorders.

New Approaches
Non-peptide antagonists of substance P, which modulates transmission through the dorsal horn, have recently been developed and may prove to be useful analgesic drugs. Adenosine analogues, and adenosine kinase inhibitors, which mimic or enhance the inhibitory effect of adenosine on nociceptive pathways.

New Approaches
Agonists at nicotinic ACh receptors, based on epibatidine (an alkaloid from frog skin, which is a potent nicotinic agonist, andunexpectedly a potent analgesis as well). Derivatives with fewer side-effects are under investigation. Transplantation of enkephalin-secreting adrenal medullary cells into the spinal canal.

What is pain?
An

unpleasant sensory and emotional experience associated with actual or potential tissue damage.

What are pain receptors and their functions.

Pain receptors in our bodies are nerves that transmit pain. These are free nerve endings located in various body tissues that respond to thermal, mechanical and chemical stimuli. When stimulated, these pain receptors generate an impulse. The pain results of various impulses arriving at the spinal cord and the brain. When tissues become injured, they release chemicals called prostaglandins and leukotrienes that make the pain receptors more sensitive and thus causing pain.

Definition of analgesics and categories

Analgesics are drugs that relieve pain. These are: Mild analgesics: used for relief of mild pain. (aspirin, acetaminophen) Strong analgesics: used for relief of severe pain.(morphine, heroin, codeine) Local anesthetics: used as pain killers in localized areas.(lidocaine, procaine) General anesthetics

I. Mild analgesics

They work by blocking the enzyme-controlled synthesis of prostaglandins.

1) 2) 3)

The main effects prostaglandins are: The constriction of blood vessels, which helps increase the body temperature. Direct effect on the bodys heat regulating centre, hypothalamus, which produces fever. Increase of the permeability of capillaries which allows water to pass to the tissue and cause pain and swelling.

Natural painkillers

They are produced naturally in the body. Endorphins and enkephalins are the natural opiates found in the part of the brain and the spinal cord that transmit pain impulses. They are able to bind to neuro-receptors in the brain and produce relief from pain. The temporary loss of pain immediately after an injury is associated with the production of these chemicals.

Salicylic acid-Aspirin

Salicylic acid was widely used as a fever reducer However, it is relatively strong acid so it was unpleasant to take orally and it damaged the membranes lining the mouth, esophagus and stomach. Sodium salicylate (salt of salicylic acid) was used but it was also highly irritating to the stomach. Acetyl Salicylic Acid (ester of salicylic acid) named aspirin retains the beneficial properties of salicylic acid but is less irritating to the stomach. ASA is relatively tasteless so it can be taken orally.

Uses of derivatives of salicylic acid

As mild analgesic for minor aches and pains. As an antipyretic. As an anti-inflammatory agent when there is swelling from injuries. As an anti-clotting agent in the prevention of abnormal blood clotting and as an anti clotting agent after heart surgery.

Disadvantages of Aspirin

Aspirin can cause stomach upset and internal bleeding due to its acidic nature. There is a risk of developing severe gastrointestinal bleeding following use of alcohol. 0,5% are allergic to aspirin leading to skin rashes, respiratory difficulty and even shock Aspirin is one of the most frequent causes of accidental poisoning in infants. The taking of aspirin by children under twelve has been linked to Reyes disease (a fatal liver and brain disorder with the symptoms of vomiting, lethargy, irritability and confusion.)

Aspirin substitutes (Acetaminophen)

Acetaminophen is the metabolic byproduct of phenacetin and is active ingredient of many over-the-counter drugs (OTC) It is like aspirin as it is an anti-pyretic. It is an analgesic to reduce mild pain. It does not upset the stomach or cause bleeding. It is not an effective anti inflammatory drug. It is a safe drug when it is used in the correct dose BUT can rarely cause side effect such as blood disorders and kidney damage. In great dose (>20 tablets) can cause serious liver damage, brain damage, coma and even death.

Aspirin substitutes(Ibuprofen)

Ibuprofen has many of the same effects as aspirin but seems to cause fewer stomach problems. It is an anti-inflammatory drug. It is effective in low doses and has a wide margin of safety. In great dose has similar side effects as ASA.

II. Strong analgesics

They temporarily bind to the opiate receptor sites in the brain preventing the transition of pain impulses

-The opium alkaloids: Opiate: it is a natural or synthetic drug that exerts actions on the body similar to those induced by morphine. Narcotic: is a term generally used for drugs that have both a narcotic and analgesic action.

Admin Methods
Oral Injection IV - Continuous or intermittent

Common Analgesics
Narcotic
Morphine Codeine Propoxyphene Oxycodone Meperidine Pentazocine

Non-Narcotic
Aspirin Acetaminophen Ibuprofen

Acetaminophen
Tylenol or Datril Antipyretic & analgesic effects Minimal AI activity Minimal side effects

ANALGESICS

Non-narcotic Analgesics
Paracetamol (Alaxan, Biogesic, Calpol) Ibuprofen (Alaxan, Restolax, Mefanamic Acid (Ponstan, Ponser, Ritemed)

Narcotic Analgesics

Tramadol (Dolcet, Dolmal, Gesidol, Newdorphin) Morphine (Morin, Relimal CR)

Analgesics
Definition
Drugs that selectively inhibit the perception (sensation) of the pain

Classification
1- Peripheral (miscellaneous):
- Causal - Non-causal

2- Central:
- Narcotic - Non-narcotic

Peripheral Analgesics
Causal
-Treat the cause Example: Atropine (antispasmodic)

Non-causal
- Not treat the cause Examples: 1- Local anaesthetics (for superficial tumor) 2- Counter-irritant (apply pain that counteract or mask the original one e.g. acupuncture)

Central Analgesics
Narcotics
The class - Opioids (morphine & morphine like drugs) Examples 1- Natural (as codeine) 2- Semi synthetic e.g. di-hydromorphine& diacetylmorphine (heroin) 3- Synthetic e.g. pethidine 4- Endogenous opiates as endorphins & encephalins

Non-narcotic
- NSAID
1- Aspirin 2- Paracetamol 3- Diclofenac 4- Piroxicam 5- Ibuprofin 6- Ketoprofin

Central Analgesics
Narcotics
Site of action Antagonist Uses Cortex & thalamus Naloxone, nalorphine & levallorphan Sever & deep pain e.g. cancer, MI & anginal pian High Addiction

Non-narcotic
Subcortical thalamus No antagonist Dull pain e.g. headache, toothache & backache

Potency Side effect MOA

Low No addiction. in bleeding tendency & ulcer

Inhibits prostaglandin synthesis by inhibition of cycloxygenase enzyme

of opiates receptors (m, k ,s, d) and relief the pain through the release of endorphines & encephalins

Screening Methods For Analgesics

Principle
Pain is induced to a suitable animal and the response of the animal to the painful stimuli is recorded before and after administration

Screening methods
Narcotics: 1- Thermal method a- Hot plate b- Tail flick
2- Mechanical method

Screening methods
Non-narcotic: 1- Electrical method 2- Chemical ( Writhing method)

Hot plate
Material Animal: Mouse
Instrument: Hot plate analgesiometer

Painful stimulus: Heat (55C) Drug used: Morphine

Tail-flick
Material Animal: Mouse Instrument: Tail-flick analgesiometer Painful stimulus: Heat (by apply a beam of light 130C) Drug used: Morphine

Writhing Method
Principle: The painful stimulus is induced by IP injection of an irritant substance (e.g. acetic acid)
Writhing: Stretching of the body, withdrawing of the limb, retraction of the abdomen & the stomach touches the ground

Writhing Method
Material Animal: Mouse Painful stimulus: Chemicals e.g. acetic acid Drug used: NSAID e.g. Na salicylate

Drug Acetic acid (control) Na salicylate (100mg/kg) Na salicylate (200mg/kg)

Onset of writhing

No. of writhing

Neuromodulation of nociceptive pathways

The body possesses its own analgesic system which is centred in the periaqueductal grey matter of the brain Efferent neurons from this area synapse in the reticular formation of the brain stem and then to the first order afferent neurons in the spinal cord Here they release neurotransmitters which block the synaptic transmission of the afferent fibres and so attenuate the experience of pain This area is a key target for analgesic drugs including opioids and (probably) paracetamol

Neuromodulation of nociceptive pathways

Inhibitory neurotransmitters include GABA, norepinephrine and a family of endogenous opioid peptides

The endogenous opioid peptides vary in influence with location and include Brain b-endorphin, dynorphin and enkephalins
Spinal cord interneurons - esp. dynorphin descending pathways esp. enkephalins

Neuromodulation of nociceptive pathways

Endogenous opioid peptides bind to several sub-types of opioid receptor m (mu) d (delta) k (kappa) Opioid drugs can bind to these receptors as agonists and produce similar effects to the endogenous opioid peptides Most analgesic effects associated with m receptors

Neuromodulation of nociceptive pathways

Most analgesic effects associated with m receptors The following opioid analgesics are specific for m receptors morphine codeine methadone buprenorphine Fentanyl d and k receptors also contribute to analgesia Nalbuphine and pentazocine also have specificity for d and k receptors

Mechanism of Neuromodulation
The binding of endogenous or exogenous opioids to opioid receptors promotes the opening of K+ channels and inhibits the opening of Ca2+ channels Opening K+ channels hyperpolarises membranes and reduces neuronal activity Closing Ca2+ channels inhibits synaptic activity by reducing the release of neurotransmitters

Ca2+ Primary afferent nociceptor terminal

Ca2+ m opioid receptor

Neurotransmitter glutamate m opioid receptor K+ K+

Secondary ascending neuron

Synapses between afferent nociceptive neurons and secondary ascending neurons relay pain signals to the brain. The entry of Ca2+ into the pre-synaptic primary neuron and the release of K+ from the post-synaptic secondary neuron are processes involved in signal transmission across the synapse.

Mechanism of Neuromodulation
Opioids bind to m receptors associated with these channels
This firstly enhances the opening of K+ channels and secondly inhibits the opening of Ca2+ channels This hyperpolarises the membrane and inhibits the release of neurotransmitters respectively Both of these events inhibit the transmission of nociceptive signals to ascending pathways to the brain

Ca2+

Ca2+ Opioid m opioid receptor

Primary afferent nociceptor terminal Opioid

Neurotransmitter glutamate m opioid receptor K+ K+

Secondary ascending neuron

Opioids binding to ion channel associated m receptors inhibit the influx of calcium ions into the pre-synaptic terminal and increase the outflow of potassium ions from the postsynaptic membrane. This has the effect of reducing the release of the neurotransmitter glutamate and hyperpolarising the post-synaptic membrane. Synaptic transmission is inhibited.

What is Analgesia?
Analgesia simply means the absence of pain without loosing consciousness. The analgesia system is mediated by 3 major components : the periaquaductal grey matter (in the midbrain), the nucleus raphe magnus (in the medulla), and the pain inhibitory neurons within the dorsal horns of the spinal cord, which act to inhibit pain-transmitting neurons also located in the spinal dorsal horn. (2) These areas are the areas in which the chemical mechanisms of opioid analgesics will take place

Locations involved in Pain Signaling and Analgesia

http://www.georgiapainphysicians.com/downloads/m1_slides/12.%20opioid%20receptors

The Anatomy of a Neuron

The -receptor
Morphine and its analogues bind strongly to this receptor. Most used opioid analgesic drugs are selective for this type of receptors. Binding of opioids to the mu-receptor produces analgesia. The mu-receptor is also associated with other effects such as sedation, reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation (5). When an opioid binds to the mu-receptor it induces a change in shape which in turn induces a change in the ion channels of the associated cell membrane

The -receptor
The mu-receptor opens up the ion channel allowing potassium ions to flow out of the cell causing hyperpolarization of the membrane potential. This hyperpolarization causes it to become extremely difficult for an action potential to be reached and therefore the firing of the neuron become far less frequent and the neurons excitability decreases (3). The release of potassium ions also causes less calcium ions to enter the terminal end of the neuron. This is where neurotransmitters are stored and as a result this significantly reduces neurotransmitter release.

The -receptor
These effects of a ligand binding to a mu-receptor essentially turn off the neuron and in doing so block the relaying of pain signals from pain receptors. They are seen in significant amounts in all areas of the central nervous system associated with pain control There are two subtypes of the mu-receptor. The 1-receptors seem to be associated with its analgesic activities and the 2receptors seem to be associated with the effects of respiratory depression and constipation. Respiratory depression is considered the deadly side effect of opioid analgesic drugs. It is the cause of death in all overdose cases.

The -receptor
The kappa receptor is very different from the mureceptor in the fact that there are not many significant agonist of the kappa receptor known The kappa receptor is associated directly with analgesia and sedation but with none of the undesired side effects associated with the mu receptor. Because of this, it is an area of focus in current research and shows promise in the development of a safer analgesic.

The -receptor
When and agonist or ligand binds to the kappa receptor it induces a conformational change that results directly in the closing of the calcium ion channels in the terminal of the neuron and the neuron can not relay pain messages. Another difference between the kappa and mu receptors is that the kappa receptors only effect nerves that relay pain produced by non-thermal stimuli (3), and mu receptors inhibit all pain signals. There are three subtypes of the kappa receptor however the difference between these subtypes is not clearly known.

The -receptor
The delta receptor is the strongest binding site of the bodys natural pain killer, the class of opioid peptides called the enkephalins. Morphine and other commonly used opioid analgesics also bind to this receptor strongly and act as an agonist much like they do with the mu receptor. The delta receptor is a G-protein linked receptor. When an agonist binds to the delta receptor is induces a conformational change that causes the activation of a specific G-protein.

The -receptor
This G-protein inhibits the membrane bound enzyme adenylate cyclase and prevents the synthesis of cAMP. The transmission of the pain signal requires cAMP to act as a secondary messenger, and so inhibition of this enzyme blocks the signal ( 3). The delta receptor is found in larger cells than the other receptors and seems to be important in spinal analgesia.

The ORL-1 receptor

the ORL-1 receptor or the orphan receptor was very recently discovered. The natural opioid peptide that is a ligand for this receptor is nociceptin which is also called orphanin. The ORL-1 receptor is associated with many different biological effects such as memory processes, cardiovascular function, and renal function. It is thought to have effects on dopamine levels and is associated with neurotransmitter release during anxiety.

Objectives
Upon completion of this course the participant will:
Identify three groups of analgesics used for pain management. Identify the 3 most common opioid analgesics used at Passavant Hospital for pain management. Be familiar with the side effects/adverse reactions of opioid analgesics. Identify nursing considerations for opioid analgesics. Identify reversal agents for selected opioid analgesics.

Clinical Practice Analgesics

Clinical practice analgesics are divided into 3 groups (McCaffery & Pasero, Pain: Clinical Manual,1999)
Nonopioids (use to be called nonnarcotic) Opioids (use to be called narcotic)
Mu agonists (morphine like agonist) Agonist-antagonists Adjuvants (diverse group of drugs whose analgesic effect is secondary to their primary effect)

Summary
This course has provided you with a concise review of opioid analgesics. You have been encouraged to review corresponding policies and procedures related to the administration of opioid analgesics. A more in-depth review of the policies and procedures for pain management will be assigned to you in October.

 Thank you for taking the time to read this material. To complete this course you need to complete the post test. Click on the take test button to the left. If you have any questions please contact your nurse manager, supervisor, or clinical director.

Monitoring Drug-Related Behaviors

Probably more predictive of addiction Selling prescription drugs Forging prescriptions Stealing or borrowing drugs from another person Injecting oral formulation Obtaining prescription drugs from nonmedical source Losing prescriptions repeatedly Probably less predictive of addiction Aggressive complaining Drug hoarding when symptoms are milder Requesting specific drugs Acquiring drugs from other medical sources Unsanctioned dose escalation once or twice

Monitoring Drug-Related Behaviors (cont.)

Probably more predictive of addiction
Concurrent abuse of related illicit drugs Multiple dose escalations despite warnings Repeated episodes of gross impairment or dishevelment

Probably less predictive of addiction

Unapproved use of the drug to treat another symptom Reporting of psychic effects not intended by the clinician Occasional impairment

Monitoring Aberrant Drug-Related Behaviors: 2-Step Approach

Step 1:
Step 2:

Are there aberrant drug-related behaviors? If yes, are these behaviors best explained by the existence of an addiction disorder?

Chapter 10: Nonnarcotic, Anti-Inflammatory Analgesics

Treatment for: mild to moderate pain, fever, inflammation, stroke/heart attack prevention, arthritis, *? prevention of Alzheimers Dementia

Aspirin and related NSAIDs

display a ceiling effect for analgesia (not as effective as opioids) can be used in combination with opiate analgesics (summation effect)

History/Actions
Bark of willow tree: Pain relief from chemical in bark, salicin (chemically related to aspirin) NSAID prototype: Acetylsalicylic acid (ASA) = aspirin Action of NSAIDs: through either selective or non-selective blocking of enzymes involved in the synthesis of prostaglandins

NSAID= non-steroidal anti-inflammatory drug

PROSTAGLANDINS
Members of group of lipid-derived paracrines
Paracrines: chemicals secreted by a cell to act on cells in the immediate vicinity via process of diffusion

Can be released by all cells in the body

Cyclooxygenase
An enzyme involved in prostaglandin synthesis
cyclooxygenase-1 (COX-1): beneficial prostaglandins cyclooxygenase-2 (COX-2): harmful prostaglandins

COX Enzyme:Prostaglandin Effects

COX-1: beneficial COX-2: harmful Peripheral injury site Inflammation

Brain

Modulate pain perception Promote fever (hypothalamus)

protect mucosa aggregation

Stomach Platelets

Kidney

vasodilation

Effects of COX Inhibition by Most NSAIDS

COX-1 Gastric ulcers Bleeding Acute renal failure COX-2 Reduce inflammation Reduce pain Reduce fever

NSAIDs : anti-plateletdecreases ability of blood to clot

Pharmacokinetics: ASA
Absorption: from stomach and intestine Distribution: readily, into most fluids/tissues Metabolism : primarily hepatic ASA contraindicated for use in children with viral fever can lead to Reyes Syndrome Fatal overdose is possible
Similar pharmacokinetics for ibuprofen and related NSAIDs

Pharmacokinetic Variability of Non-Selective COX-Inhibitors

Name Aspirin Naproxen Oxaprozin Time to peak life parent (hours) life*active 1-2 0.25-0.33 (*3-10 L-H) 2-4 12-15 3-5 42-50 7.8 (*16.4) 3.8-8.6 1.8-2.5

*Sulindac (pro-drug) 2-4 Ketorolac (inj) Ibuprofen .5-1 1-2

Selective Cox-2 Inhibitors

Greater affinity for cyclooxygenase-2 Decreased incidence of negative effects associated with non-selective COX-inhibitors Name Time to peak life (hours) (hours) Celecoxib 3 11
Rofecoxib 2-3 17

Acetaminophen N-Acetyl-P-Aminophenol (APAP)

Classification: analgesic, antipyretic, misc. not an NSAID

Mechanism: inhibits prostaglandin synthesis via CNS inhibition of COX (not peripheral)---doesnt promote ulcers, bleeding or renal failure; peripherally blocks generation of pain impulses, inhibits hypothalamic heat-regulation center

APAP Liver Metabolism

1. Major pathway Majority of drug is metabolized to produce a non-toxic metabolite 2. Minor pathway Produces a highly reactive intermediate (acetylimidoquinone) that conjugates with glutathione and is inactivated. At toxic APAP levels, minor pathway metabolism cannot keep up (livers supply of glutathione is limited), causing an increase in the reactive intermediate which leads to hepatic toxicity and necrosis

Pharmacokinetics: APAP
Metabolism: major and minor pathways Half-life: 1-3 hours Time to peak concentration: 10-60 min

Treatment for overdose: Acetylcysteine (Mucomyst)