Pain and Analgesics (background)
Pain
→ an unpleasant sensory or emotional experience associated with actual or potential tissue damage.
Pain receptors → nerves in our bodies that transmit pain signals along nerves, to the spinal cord and brain for interpretation.
The skin has more pain receptors than the GI tract so it is harder to pinpoint the precise location of a tummy ache than a bruise or burn.
Pain receptors are attached to two main types of nerves
 one that relays messages quickly sharp, acute pain
 the other that relays messages slowly  dull, throbbing pain
The spinal cord receives the message, and then sends it to a brain structure called the thalamus.
The thalamus also contributes to mood and arousal, which helps to explain why our interpretation of pain partly depends
on our state of mind. The pain message is then delivered to the brain's cerebral cortex. Interestingly, some people who
have injuries to areas of their cerebral cortex still experience pain, but don't care about it that much.
Analgesics are medicines that reduce pain. Analgesics relieve symptoms not the cause of the pain
Four classes of analgesics:
1. mild analgesics – NSAIDs (ibuprofen and aspirin) and acetaminophen
2. strong analgesics - narcotics (opioids)
3. local anesthetics (lidocaine)  block nerve conduction an decrease blood supply
4. general anesthetics (chloroform, ether, N2O)  induce unconsciousness
Mild Analgesics function by intercepting the pain stimulus at the source, often by interfering with the production of
substances that cause pain, swelling or fever.
1. Acetaminophen
→ relieves pain by elevating the pain threshold; more pain needed before it is felt. → antipyretic
2. NSAIDs, non-steroidal anti-inflammatory drugs
 Corticol Steroids (Cortisone, Prednisone) – steroids used to reduce inflammation
 NSAIDs (ASA, ibuprofen) – reduce production of prostaglandins and the inflammatory response
Table 1. A comparison of aspirin and paracetamol (acetominophen).
AntiAnti-pyretic
Pros
inflammatory
Best pain relief of mild
Acetylsalicylic acid
√
√
analgesics
(ASA) Aspirin
Anticoagulant
No stomach irritation
Acecaminophen
√
Fewer interactions
Tylenol
Fewer side effects
Cons
Reye’s syndrome in children
Increases stomach bleeding
Potential damage to liver
Reduced pain relief
Same pain relief as ibuprofen
D.2 Aspirin
 Willow bark contains salicin which the body converts to salicylic acid (SA).
 Aspirin is prepared from salicylic acid. Acetylsalicylic acid (ASA) is a ester of SA.
 ASA is less irritating to the stomach than SA
Prostaglandins
Prostaglandins are chemicals, similar to hormones, which trigger physiological changes like increased temperature and
dilation of blood vessels.
 Damaged tissue cells naturally produce prostaglandins to initiate the response
Prostaglandins cause:
 pain receptors to fire, sending pain signals to the brain
 dilation of blood vessels causing inflammation (swelling, redness, heat) at the injury
Mode of Action of Aspirin
 ASA is a COX inhibitor  ASA binds to cyclooxygenase enzyme to prevent creation of prostaglandins.
 ASA reduces the production of prostaglandins and the inflammatory response
 If prostaglandin production is blocked, then fever and inflammation is reduced.
 Prostaglandins also help the stomach lining to resist gastric acid
 This is why aspirin can cause stomach irritation and bleeding in some people
Other Therapeutic Attributes
Antipyretic
→ reduces fever
Antipyretics affect the temperature-regulating centre of the brain (hypothalamus)
Aniticoagulant = blood thinner  prevents abnormal blood clotting.
Prostaglandins cause platelets to stick together to form clots
Aspirin can be used as an anticoagulant, in prevention of the recurrence of heart attacks and strokes and as a prophylactic.
A prophylactic is something taken to try to prevent a disease happening in the first place.
Ethanol


ETHANOL IS A DEPRESSANT
interferes with neurons and slows down normal brain function.
lower blood pressure, blood vessels dilate
Brain Area
Cerebral cortex (Frontal Lobe)
Cerebellum
Parietal Lobe
Motor cortex
Hippocampus
Hypothalamus
Medulla (brain stem)
Vasodilation
Common Short Term Effects of Ethanol
poor judgment, personality change, inhibition, talkative
staggering
do not drink and drive
only ride with a sober driver
sleepy  sleep  coma  death
smooth muscles of blood vessels relax
 capillaries near skin dilate  flushing, warmth

Liver
Nerves
Pregnancy
Other Long Term
Controls / Affects
decision-making, personality, self-control, language
coordination and balance
depth perception, other sensory perception (pain)
voluntary muscle control, reaction time
memory and emotions
sexual arousal and performance
automatic body functions: heart rate, breathing
veins and arteries dilate  reduced blood pressure
o Heart pumps harder to maintain blood pressure  coronary heart disease
o Rebound high blood pressure  hypertension, strokes, coronary heart disease
 detoxifies harmful chemicals in the blood, especially those that entered the body from the digestive tract
Ethanol does not kill brain cells; it damages the ends of the neurons (dendrites) so the way the neuron communicates is altered.
increased risk of miscarriage, low birth mass, developmental problems, FAS (fetal alcohol syndrome)
gastritis, peptic ulcers, tolerance, dependence, anxiety, depression, malnutrition
Synergystic Effects of Ethanol
Synergism
the effect of the combination of two drugs which is greater either drug taken alone
Alcohol + other depressants  risk of heavy sedation, coma, death
Alcohol + Aspirin  increased risk of stomach bleeding (hemorrhage)
Alcohol + cocaine  vasoconstriction, high blood pressure, irregular heart rate
Synthesis of aspirin
Aspirin can be made from 2-hydroxybenzoic acid (salicylic acid) by warming with excess ethanoic anhydride (Figure D.6).
This addition [CH3COOC(O)CH3] and elimination [CH3COOH] reaction can be catalysed by sulfuric or phosphoric acid.
Isolation
The resulting ASA (aspirin) has less polar character than all other species present, so it is relatively insoluble in water.
Aspirin forms an insoluble white solid in water. Rinsing with cold water removes soluble impurities w/o dissolving the ASA.
Purification by Recrystalisation
Aspirin can be dissolved without reacting in ethanol or ethyl ethanoate; it tends to decompose in water.
The solubility of a solute (ASA) in a solvent (ethanol) is the maximum amount that can dissolve at a given temperature.
 Use the known solubility of ASA at a desired high temperature to form a near-saturated solution. Solid impurities are filtered.
 The ASA solution becomes supersatured when it cools then forms a solid precipitate. Soluble impurities are filtered.
o Vacuum filtration is a fast way of filtering so that impurities can be removed before it cools too much
Characteristics of Aspirin
Melting Point (test for purity)
MPpure = 139 ± 1ºC
MPimpure = 128 ± 3ºC
 Every pure substance has a distinctive narrow range of temperatures for changes of state.
 Impurities in the sample decrease the melting point and broaden the temperature range.
Chromatography (test for purity)
Chromatography is used to separate mixtures based on the different solubilities of each substance in a given solvent.
When a sample of the mixture is placed on chromatography paper which is then placed in a solvent, the different solutes will
migrate up the paper with the solvent at different rates; the more soluble will move faster.
Substances with similar solubilities in a given solvent are difficult to separate by chromatography.
IR (infrared) Spectrum  shows distinctive absorption peaks for bonds/functional groups
Solubility in Water

Aspirin is not highly soluble in water, so when it is swallowed not much of it will dissolve and be absorbed.

Ionic salts are more soluble in water than their carboxylic acids or their basic amine groups.

Bioavailability increases with increased solubility in water because more of the medication will be absorbed into the
blood stream and reach the target cells.
Carboxylic acid-containing compounds like aspirin are reacted
with strong alkali (NaOH) to form a more soluble salt.
Amine-containing compounds like Prozac are reacted
with strong acid (HCl) to form a more soluble salt.
Strong Analgesics - Narcotic analgesics (opioids) are all derived from opium.
 Natural Painkillers




– endorphins and enkaphalins
bind to neuro-receptors of the brain
responsible for runner’s high, rugby high,
temporary loss of pain for severe injury
produced through acupunture and chiropractic adjustments
 Opioids − morphine, heroin, codeine, Demerol, Methadone
 alter pain messages by influencing brain chemistry
 strong pain relief of severe pain
 heroin is 6x stronger than morphine and 36x stronger than codeine
 ALL tend to be addictive
Narcotic = “sleep inducing”
Alkaloid → nitrogen-containing drug or medicine
Opium alkaloids
All have effects on the body similar to morphine
All have the same basic structure
 phenyl ring
 2 x 6-carbon rings, one has a double bond
 6-membered ring including a nitrogen attached to a methyl group
 5-membered ring with an oxygen
Each drug has different functional groups:
Morphine – two hydroxyl (-OH) groups
Codeine - hydroxyl (-OH) and methyl group attached to oxygen
Heroin – two acetyl (CH3COO) groups - diester
Table 2.
Summary of the effects of narcotics
Usual short-term effects
sedation and stupor;
pain relief
euphoria
impaired functioning and coordination
temporary impotence
Typical long-term effects
loss of appetite
malnutrition and constipation
sterility
reduced tension, worry and fear
withdrawal, illness, loss of job, crime
reduced coughing reflex
diversion of energy and money
occasional death from overdose
risk of infection from shared needles (HIV, Hepatitis)