Mbchb3 Pharmacology



Pain Overview
• Tis irritation or injury releases chemicals such as prostaglandins, kinins and K+ that stimulate nociceptors
• Pain may persist even after a pain-producing stimulus is removed bec pain mediating chems linger and bec nociceptors exhibit v little adaptation
• Asprin and ibuprofen – block formation of prostaglandins which stimulate nociceptors
• Local anesthetics – provide ST pain relief by blocking nerve conduction of nerve impulses along the axons of first order pain neurons
• Morphine and other opiate drugs alter the quality of pain perception in the brain – the pain is still sensed but it is no longer perceived as being so noxious

Kumar – Clinical Medicine
• Pain perception mediated by free nerve endings – the termination of finely myelinated a-delta and of non-myelinated c fibers
• Chems released locally as a result of injury either produce pain by direct stim or by sensitizing the nerve endings
• A-delta fibers – give rise to sharp immed pain which is followed by slower-onset duller mre diffuse and prolonged pain (mediated by the slower conducting C fibes
• Sensory impulses enter the cord via dorsal spinal roots
• Within it, impulses asc either in each dorsal column or in each spinothalamic tract
• Sym activity ↑ pain eg ↑ blood flow
Endogenous Opiates
• Endorphin family of peptides have opioid activity
• Probably account for the v real effects of placebo stress reducers and acupuncture analgesia
• They are NTs acting at inhibitory synapses via mu, kappa and sigma receptors
• Primary use in conditions other than pain but also useful for tx in pain
• Eg NSAID, tricyclic anti-depressants, anticonvulsants

Rang Pharmacology
Modulation of Pain Transmission
• Transmission in dorsal horn subject to various modulatory influences (gate control theory)
• Desc pways from midbrain/brain stem exert strong inhibitory effect on dorsal horn transmission (electrical stim activates this pway)
• The desc inhibiton is mediated mainly by enkephalins, 5HT and nor-adr – opioids cause analgesia partly by activating these desc pways, partly by inhibitng transmission in dorsal horn and partly by inhibing excitation of sensory nerve terminals in the periphery
• Repetitive c fiber activity facilitates transmission through the dorsal horn (wind up) by mechanisms involving activation of NMDA and substance p receptors
Mechanisms of Pain and Nociception
• Polymodal nociceptors PMN are the amin type of peripheral sensory neuron that responds to noxious stimuli – the majority are non-myelinated c fibers
• Chem. Stimuli act on PMN to cause pain
• PMN are sensitized by prostaglandins which explains the analgesic effect of aspirin like drugs esp when inflame is present
• PMN neurons release glutatmate (fast transmitter) and various peptides (substance p) which act as slow transmitters
• Neuropathic pain, assoc w damage to neurons of the nociceptive pway rather than an excessive peripheral stimulus is freq a component of chr pain states and respond poorly to opioids


Analgesics include –
• Nitrous oxide (entonox)
• Opioid analgesics (morphine and pethidine)
• Paracetamol
• NSAIDs (incl COX2 inhibitors)
• Analgesic combination drugs (digesic)
• Tramadol
• Acupan
• Gabapentin
• Tricyclic anti-depressants
• Alcohol

Non-Pharm methods –
• Hypnosis
• Acupuncture
• Spinal cord stimulation

Mgt of Pain
• Successful pain mgt involves –
o Accurate dx of underlying cause of pain
o Assessment of the severity and nature of the pain
o Explanation
o Tx of underlying pathology
o parmacotherapy
o Other forms of tx
Assessment of Pain
• VAS – Visual analogue scales
o Typically 10cm lines whose ends are anchored with eg no pain at one end to worst possible pain at the other
o Pt marks the line at the point representing the severity of pain
o Widely used in pain research
• Likert scales
o Numeric scales often with words to anchor the numbers
o A little easier to administer than vas and probably as reliable
• McGill Pain Questionnaire
o List of descriptors in groups form which the pt chooses those which describe the quality of their experience of pain
o Typically used for chronic pain


Non-Pharmacological Methods
• Electrical Analgesia
o TENS – transcutaneous nerve stim
 Widely used
 Justified on the basis of gate control theory
 In some pts w chronic pain – appears useful but probably due to placebo effect
o SCS – Spinal cord stimulation
 Expensive high-tech therapy
 Widely accepted as v effective in some forms of chr pain
 Success rates – typically 50%
 Reasonable duration of action (benefit in excess of 10 yrs is not uncommon)
 Provided in the context of a multi-disciplinary pain clinic as part of a wider mgt strategy
 Mech action – complex and not well understood
 Pt selection critical
 Particulary effective in tx of chr refractory angina pectoris in which it has an anti-ischaemic effect as well as an analgesic effect
 SCS produces vasodilation and has been used for peripheral vascular dis w good results
• Hypnosis
o Popn splits into approx into thirds on the basis of hypnotisability
o Mech action unclear
• Acupuncture
o No valuable evidence to support this as an analgesic
o One exception – acupuncture valuable as an anti-emesis (vomit)
o Acupuncture does release endorphins (but so does a placebo) – effect is transient

Pharmacological Methods of Analgesia

1. Opioid Analgesics
Opiods – large group of drugs acting at opioid receptors
• Opium – major side effect is constipation (contains 20 alkaloids)
• Morphine – active ingredient of opium
• Omnopon – a mixture of opioid alkaloids but no advantage over pure morphine
• Pethidine – synthetic drug intended to be like atropine, hence side effects of dry mouth and tachycardia tendency
• Fentanyl – and similar synthetic drugs such as phenoperidine, alfentanyl, remifentanyl – v potent, pure opioids used in anaesthesia
• Codeine – can be used orally, often added to paracetamol
• Methadone – long acting, active orally
• Oral morphine preparations – kapanol
• Powerful analgesia – opioids are the most potent analgesics avail – but they are not effective in all forms of pain - limited use in neurogenic pain
• Anxiolysis
• Sedation
• Cough suppression
• Meiosis
• Altered mood – euphoria and tranquility
Side Effects
• Resp depr – this may be fatal in even moderate overdose – there is consid potential for additive resp depr w other depressant agents
• Nausea – v common – tolerance tends to develop w persistence but this is probably the biggest single limitation of the use of opioids in acute pain
• Vomiting
• Constipation
• Addiction
• Pruritis (itching)
• Biliary colic (pethidine does not cause this)
Routes of Admin
• PCA (pt controlled analgesia – devices which allow the pt to personally titrate the amount of opioid he or she uses)
• Epidural/spinal
• IV
• IM (intramuscular)
• PO
• PR (peri rectal)

2. Tramadol
• Synthetic codeine analogue
• Weak u-opioid receptor agonist which also inhibits uptake of nor-adr and serotonin
• Non-addictive
• Causes little resp deprs or constipation
• May be counter productive to use it combo w morphine due interaction w ondoansetron (zofran) which makes both drugs less effective when used in combo
Side Effects
• Nausea and vomiting
• Dizziness
• Dry mouth
• Sedation (mild)
• Headache
• Can cause seizures (rare)
Routes of Admin
• IV
• IM
• PO

3. Misc Analgesics

Nitrous Oxide
• Gas
• Mech action unknown
• High doses can lead to anaesthesia
• Entonox – 50/50 mixture of of NO and O2 (insufficient to induce anesthesia)
• Often used during labour for acute pain mgt and in the wards for brief painful procedures
• Pt experiences an alteration in perception
• The effect is disinhibiting – hence known as laughing gas
• Pt perceives a change in their voice wich appears to become squeaky – but not apparent to observers
• Nausea and vertigo may occur
• Used in postoperative nausea and vomiting
• On discontinuation – effects wear off rapidly even if gas has been administered for some time
• NO is not addictive – repeated exposure may have LT ill-effects incl bone marrow depr

Nefopam (acupan)
• Centrally acting analgesic
• Useful alternative when NSAIDs are contraindicated
Side effects (not usu troublesome)
• Nausea
• Nervousness
• Dry mouth
• Light headedness
• Urinary retention
Routes of Admin
• PO (large tablets) – effervescent formulations avail
• IV

Gabapentin (Neurontin)
• Anti-convulsant
• Effective in some pts w neurogenic pain
• May act by facilitating GABA activity and by preventing glutamate release
• Should be used in the setting of a chr pain clinic
• Evidence inconclusive
• Other anti convulsants have also been used for neurogenic pain

Tricyclic Anti-depressants
• Prolong the actions of nor-adr and serotonin
• These and the selective serotonin-uptake inhibitors may alleviate certain forms of chr pain in some pts
• These agents are often called co-analgesics


• Aspirin – prototype
• Traditional NSAID – inhibit COX1
• COX2 inhibitors – more specific for this enzyme (ratios still 50:1)
Mech Action
• Most NSAID compete reversibly w arachidonate to modulate cyclo-oxygenase activity non-specifically
• Arachidonate (arachidonic acid) – precursor converted into protaglandins, prostacyclins and thromboxanes by cyclo-oxygenase (cox) and also precursor for leukotrines
• Inhibition seldom complete
• Analgesic effect of NSAID is attributable to their anti-inflam effect related to inhibition of cyclo-oxygenase
• However – there is some evidence for a central anti-nociceptive mechanism for at least some NSAIDs
• This means that one NSAID is not necessarily equivalent to another in terms of analgesic potency even if the two drugs have similar anti-inflam activity
Aspirin - selectively acetylates a single serine residue and inactivates the enzyme irreversibly
Paracetamol – produces v weak inhibition of cox and other mechanism probably predominate

• COX1 – constitutive (normally present) and inhibiton leads to many side effects
• COX2 – induced in settings of inflame and inhibition mediats anti-pyresis, analgesia and anti-inflam
• Eicosanoids
o 20C compounds derived from linoleate
• Autacoids – evanescent and local
o Paracrine (on neighboring cells)
o Autocrine (on cells actually secreting the substance)
• Often involved in response to injury
• Classified by number of double bonds in side chains
• Major prostaglandins are dienoic – eg PGG2 (derived from arachidonate)
Main Actions of Prostaglandins
• PGG2/PGH2 – unstable intermediaries converted rapidly to other PGs
• PGE2 – vasodilator in most beds, bronchodilator, increase rennin release from JG apparatus, decrease ADH secretion
Other Eicosanoids
• TXA2 (thromboxane) – produced by platelet endothelium etc, mediates platelet aggregation, vasoconstrictor and bronchoconstrictor
• PGI2 (prostacyclin) – produced by blood ves endothelium – the most potent inhibitor of platelet aggregation known, vasodilator
• Leukotrienes – produced by leucocytes, platelets, and mphages – attract and activate leucocytes vasc perm, bronchoconstrictors

Traditional NSAID
• Aspirin
• Diclofenac (voltaren)
• Indomethacin (indocid)
• Tenoxicam (tilcotil)
• Ketorolac (toradol)
Side Effects
1. Bleeding
2. GI tract
3. Renal
4. Water and electrolytes
5. Asthma
6. Liver
7. Immune

1. Bleeding
• Platelet aggregation is modulated by balance betw
o TXA2 (thromboxane) – constriction and aggregation
 Synthed from platelet phospholipids
 Stimulates platelet aggregation
 Constricts large blood vessels
o PGI2 (prostacyclin) – dilation and inhibition
 Synthed from endotehelial cell phospholipids
 Vasodilator
 Most power known inhibitor of platelet aggregation
• Aspirin – acetylation inactivates COX irreversibly
• Platelets do not synth new proteins so effect on platelet COX is permenant and cumulative
• Low dose provides complete inactivation of platelet thromboxane and partial sparing of endothelial prostacyclin
• High dose aspirin provides complete inhibition with a less profound effect on platelets and more side effects
• Thromboxane synth mediated by COX1 so COX2 inhibitors would probably not have any useful anti-thombotic activity
• Some concern over ↑ CV events for the COX2 inhibitors
• Bleeding time is typically ↑ in pts on aspirin or NSAID but not usu beyond normal limits

2. GI Tract
• Prostaglandins found throughout the gut
• Prostaglandin production ↑ by mucosal injury and irritants causing
o ↓ HCL secretion
o ↑ Bicarbonate secretion
o ↑ mucosal thickness
o ↑ pH gradient betw epithelial cell surface and lumen
• these effects are more pronounced with COX1
• NSAID dual mechanism of enteral toxicity
o Direct toxicity
o Central prostaglandin inhibition (therefore gastropathy may occur w rectal or parenteral admin
• NSAID gastropathy serious public health problem – less common w ST tx, advanced age ↑ risk

3. Renal + Water and Electrolytes
• Prostaglandin function in kidney regional
o Cortex – renal vascular resistance and rennin secretion
o Medulla – salt and water homeostasis
• NSAID – sodium, water and k may be retained leading to –
o Oedema
o Oliguria
o Hyperkaleamia
o Possibly hyponatraemia
• NSAID have been clearly assoc w renal failure in several diff manifestations –
o Papillary necorosis and chr interstitial nephritis (analgesic nephropathy)
o Acute tubular necrosis
o Acute interstitial nephritis

• Aspirin induced asthma – affects 8-12% of asthematics
• Typically adults 30-40 but rare in children
• Aspirin triad – asthma, aspirin intolerance and nasal polyps
• Cross-sensitivity w most other NSAIDs

5. NSAID – pregnancy and lactation
• Most NSAID cross the placenta and excreted in milk
• Prostaglandins involved with establishing and maintaining labour and maintain patency (openness) of the ductus arteriosus
• NSAID can be used to tx premature labour, for closure of patent (open) ductus arteriosus in premature infants

6. Reye’s Syndrome and Aspirin
• Acute metab encephalopathy w acute microvesicular hepatic stenosis and hyperammonaemia in infants and young children
• Acute viral illness (typically flu or chickenpox) followed by damage to mitochondria leading to massive cytotoxic cerebral edema
• Rare
• Often used to be fatal but pts now recover
• Role of aspirin unclear and controversial
• Hence avoid using aspirin or NSAID in children who have a viral illness

COX2 Inhibitors
• Celecoxib (celebrex)
• Valdecoxib
• Rofecoxib (vioxx)
• Parecoxib
These agents assoc w gastric side effect and may also be assoc w increase serious adverse events overall
• Too early to tell

Paracetamol (acetaminophen)
• Analgesic and anti-pyretic
• Weakly anti-inflam
• Mech action unknown
• Few side effects (acute overdose → fatal hepatic damage)
Routes of Admin
• PO – large tablets
• PR
Underrated as an analgesic
• Should be the mainstay of analgesia for most pts
• Often combined w other drugs – eg codeine but this is often sub-therapeutic and if high dose → constipation



• The reduction in response to a drug after repeated administrations
• Cf Sensitization – the increase in response to a drug
• Tolerance may be innate (eg ethnic differences) or acquired
• Acquired Tolerance
o Pharmokinetic – related to distbn and metabolism → therefore conc of a drug
o Pharmacodynamic – related to receptor density or coupling efficiency → therefore response of a drug
o Learned or behal – related to pavlovian cues, this type of tolerance may be reduce din a novel evt

Physical Dependence
• The state that develops as a result of tolerance produced by resetting of homeostatic mechanisms in response to repeated drug abuse

Withdrawal Syndrome
• The only evidence of physical dependence
• Caused by the removal of the drug and characterized by CNS hyperarousal
• It is characteristic of the category of drug and tends to be opposite to the effects of the drug (eg opioids cause miosis and bradycardia and thus withdrawal leads to dilated pupils and tachycardia)

Abuse and Addiction
• These are behal syndromes
• Defined and redefined over many years and related to societal norms
• There is a continuum betw minimal abuse and addiction
• Lay def of addiction should be distinguished from the medical dx of addition
Substance Dependence Syndrome – DSM 4: a cluster of sx incl –
• Continued use despite substance related probs
• Tolerance
• Withdrawal sx
• Others
• Three or more sx indicate dependence (ie addiction) while one or two indicates abuse
Compulsive Drug Use
• Distinguishes behal probs from physical dependence
• This term is non-perjorative (non-critical)
• Abuse – best defined as the non-medical use of a drug commonly to alter the user’s state of consciousness
• Misuse – means inappropriate medical use eg for too long, or not long enough or too high or low a dose

Origins of Substance Dependence
1. Agent – The Drug
• reinforcement is the property which makes the user want to use the drug again
• it is related to the abuse potential of the drug
• it is assoc w certain central NTs (eg dopamine)
• it is related to the rapidity of onset of the drug’s action
• Ex – Cocaine
o Inhaled crack (goes straight to brain is more addictive than snorting cocaine which is more addictive than chewing coca leaves in the Andes
o Inhalation helps explain addictiveness of smoking and nicotine
2. Host – The User
• People show wide variability in their -
o Pharmacokinetic response to drugs (distbn, metab and hence blood levels)
o Pharmacodynamic response to drugs
o Learned or behal reponses to drugs
• Predisposition for addiction shows polymorphic inheritance
• Concordance for alchoholism is greater in identical than fraternal twins
• Innate tol occurs – sons of alcoholics are less sensitive to alcohol, have greater tol and may be more prone to alcoholism
• Alcohol dehydrogenase converts alcohol to acetaldehyde – it is increased in Asian popns who never become alcoholic
• Anxiety, depr and insomnia are subjectively helped by alcohol but objectively made worse – drugs of abuse produce more psychiatric sx than they relieve
3. Evt – the Setting
• Societal norms v sig in colouring our view of addiction
• Factors impt in addiction incl peer pres, low employment and low educational levels

• CNS depressants
o Alcohol
o Benzodiazepines
o barbiturates
• Nicotine
• Opioids
• Psychostimulants
o Cocaine
o Amphetamine
o fenfluramine
• Cannabinoids
• Psychodelic agents
o Mesciline
o Ecstasy
o phencyclidine
• Inhalants
o Solvents (vapors)
o Gases

CNS Depressants
Alcohol (ethanol)*
• Lifetime prev of alcohol abuse and addiction – 5-10% (men) and 3-5% (women)
Properties of alcohol
• CNS depressant – but low doses perceived as stimulant
• Recent memory impaired
• Blackouts in high doses
• Mild intoxication is assoc w motor inco-ordination, sleepiness and then stimulation and garrulousness
• Incr dose leads to sedation, coma and death
As tol develops, sedation is ↓ but lethal dose unchanged so therapeutic index is reduced
Withdrawal Sx
• Alcohol craving
• Tremor, irritability
• Nausea
• Sleep disturbance
• Tachycardia
• HT
• Sweating
• Perceptual disorders
• Seizures
Delirium tremens (DT – a severe sometimes fatal form of delirium due to alcoholic withdrawal following a period of sustained intoxication)
• More likely w infection, malnutrition and elyte imbalance
• Severe agitation
• Confusion
• Visual hallucinations
• Fever
• Profuse sweating
• Tachycardia
• Nausea, diarrhea
• Dilated pupils
Other sedatives (eg benzos) – show cross tol and may produce additive sedation
Chr use of alcohol – assoc w depr, ↑ suicide risk, cog deficits even when sober, nutritional deficiencies and organ toxicity
Alchoholic organ toxicity
• Liver (cirrhosis)
• CVS – myopathy
• Endocrine
• GI (gastritis, malnutrition)
• Fetal alcohol syndrome
• Mental retardation
Alcohol is cardio-protective
• Dose-effect rship follows j- curve
• Optimal dose – 1 glass wine per day women and 2-3 glasses for men
• Benefit – confined to older and middle aged people
Benzodiazepines and other sedatives
• Tx – anxiety and insomnia
• Little tol or withdrawal up to several weeks use
• LT tol varies widely
• Intermittent use preferable to continuous use
• Contraindication – hx of alcohol or other abuse
• Sedatives – not great for insomnia as they don’t address underlying cause, alter sleep physiology and r assoc w rebound
• Benzo withdrawal after chr use
o Anxiety
o Agitation
o Sleep disturbance

• Inhalation – v rapid effect (7 secs)
• Stimulant and depressant actions – smokers feel alert but some mus relaxation
• Activates the nucleus accumbens reward sys and ↑ dopamine levels
• ↑ endogenous opioids and glucocorticoids
• tol develops
• depr ↑ during withdrawal
• NRT – nicotine replacement therapy – suppresses withdrawal sx and is best combined w behal tx
• Patches or gum used – slower uptake and lower peak levels of nicotine
• Benefit seen at 6 wks but diminishes over time

• Produce well being and euphoria
• Useful for tx of acute pain
• Analgesic use rearely leads to addiction or abuse so fear of addiction does NOT justify withholding morphine in ca pain
• Opioids for chr pain of non-malignant origin may be justifiable w appropriate caveats and controls – should be prescribed and monitored in liason w specialized services (multi-dis pain clinic)
• Short acting rapid onset good for acute pain – morphine iv or elixir, Fantanyl iv or pethidine iv/po
• Injection – gives rush of warmth and then period of sedation and tranquility (3-5 hrs)
• Withdrawal – leads to irritability and aggression
• Use is assoc w abnormal pituitary func, irregular menses, reduced sexual performance in men, high mortality
• Opioid withdrawal syndrome
o Craving
o Restlessness, irritability
o Nausea, cramps
o Mus aches
o Insomnia, anxiety
o Dysphroia
o Signs – papillary dilatation, sweating, piloerection, tachycardia, vomiting, fever
o Tx – specialist units with methadone (slow onset, long action), clonidine (↓ adrenergic NT), behal and regulatory approaches

• Blocks the transporter that recovers dopamine from the synapse → dopaminergic stim at critical brain sites
• Blocks nor-adr and serotonin reuptake
• Produces dose dependent ↑ in HR, BP
• Produces arousal, enhanced performance, self-confidence and wellbeing
• Produces desire for more after 10-30 mins
• Repeated doses lead to irritability, violence, addiction in some
• Toxicity – cardiac arrhythmias, myocardial ischaemica, aortic dissection, cerebral vasoconstriction and seizures, short term incr orgasm but LT reduced sexual drive, anxiety, depr, psychosis
Methamphetimine – Speed
• Addictive stimulate drug closely related to amphetamine
• But has greater CNS effects
• Releases high levels dopamine – enhances mood and body mvment
• Neurotoxic damaging dopamine and serotonin containing cells – may produce a parkinsons like disorder
• Toxicity – CNS damage, incr wakefulness, incr physical activity, decr appetite, incr respiration, hyperthermia, euphoria, irritability, insomnia, confusion, tremors, convulsions, anxiety, paranoia and aggressiveness
• Hyperthermia and convulsions can result in death

Cannabinoids (marijuana)
• Cannabinoid receptors widespread in brain
• Produces a high (lasts about 2 hrs) and a ↓ cog func, reaction time, learning, mem which outlasts the high
• Anxiety attacks and hallucinations may occur
• Acute psychosis is possible which may precipitate recurrence of schizophrenia
• Amotivational syndr has been attributed to cannabis
• Cessation of chr high dose usage – gradual improvement in mental state
• Medicaul use of cannabis proposed for – appetite stim, to tx chemo nausea, tx glaucoma, for mvment disorders, an analgesic esp for neuropathic pain
• Withdrawal is mild and short lived – restlessness, irritability, mild agitation, insomnia, sleep EEG disturbance nausea, cramping

Pyschodelic Agents
LSD – lysergic acid diethylamide
• Produces variable perceptual distortion – hallucinations, mood changes (elation, paranoia, arousal), dilated pupils, ↑ BP, salivation, lacrimation
• Onset of effects is 40-60 mins – may last 6 hrs
• A bad trip may occur w severe anxiety and depr
• Risk of accidents and suicide
• LSD may precipaitate psychosis

• Inhaled agents volatile at rom temp
• Prolonged exposure may cause cardiac arrhythmias, bone marrow depr, liver damage, peripheral n damage, cerebral degen, renal damage



• Episodic, recurrent illness w periods of spontaneous remission
• 2% popn affected
• affective d/os = mood d/os
two main types
• unipolar = depression → mood, appetite, libido, tiredness, negative self concept
o endogenous depression – unknown origin
o reactive depression – assoc w etal event
• bipolar = manic depression
o strong genetic basis
o mood fluctuates betw depression and mania
o Mania = heightened mood/euphoria, irritability, poor insight into conseqs of sudden irrational decisions and in severe cases - delusions and hallucinations (manic-depressive psychosis)

Biochemical Theories - Simple Monamine Theory
• Depression a result of a ↓ in brain monoamines – nor-adr, serotonin, dopamine
• Evidence –
o Reserpine – depletes monoamine stores can cause depr in some people
o Amphetamine/cocaine - ↑ monoamine levels by blocking re-uptake ↑ mood
o Anti-depressants produce an acute ↑ in brain monoamines by blocking reuptake or metab (causation of depr unclear but the drugs still work!)
 Monoamine NTs such as nor-adr, serotonin and dopamine are inactivated by two main mechanism –
 Reuptake into neuron
 Breakdown by monoamine oxidases (MAOa and MAOb)
 MAOa breaks down nor-adr and serotonin
 MAOb breaks down dopamine
 Catechol-o-methyltransferase (COMT) also degrades monoamines
 Anti-depressant drugs work acutely by inhibiting either of the above two syss – ie reuptake or MAOs
• Problems w the simple monoamine theory –
o Although anti-depressants produce an immediate ↑ in monoamine levels (nor-adr and serotonin) in the brain, the therapeutic action of these drugs is delayed and only becomes apparent 2-3 wks after chr use
o Therefore perhaps the therapeutic effect of anti-depressant drugs results from a change in brain chem./func after chr use (LT adaptive changes)
Neurochemistry of Depr in human brain
• There are NO strong consistent changes in brain chemistry that have been discovered so far in the brains of depressed people that might account for depression

Anti-depressant Drugs

First Generation
• Tricyclics – Amitriptyline, Imipramine (TCAs)
o Acute effects – block nor-adr and serotonin reuptake
o Chr effects - ↓ in B1 adrenoceptors ???
o Side effects – antimuscarinic effects (like atropine – dry mouth, ↓ secretions, dilated eyes etc)
 Muscarinic response – due to post-ganglionic parasympathetic stimulation
o Benefit – 75% of pts (cf placebo response 30-40%)
• MAO Inhibitors - phenelzine
o Irreversibly inhibits MAOs and ↑ levels of nor-adr, serotonin and dopamine
o Less widely used due to toxicity
Second Generation
• Moclobemide
o Reversible MAOa selective inhibitor which produces an acute ↑ in nor-adr and serotonin
• Fluoxetine (Prozac)
o Potent, selective serotonin reuptake inhibitor (SSRI)
o Its use has shifted depr research to the serotonin area
o Better tolerated than TCAs
o Paroxetine – a fluoxetine analogue (also widely used and even better tolerated than prozac)

Lithium and Manic-Depression
• Lithium carbonate – most effective tx
• 2-3 wk onset of action latency
• no effect on unipolar depr
• stabilizes both the manic and depressive phases
• overdose → tremor, seizures, coma, death
• Mechanism
o Dampening of phosphoinositide-mediated neurotransmission may explain its normalizing effects in tx of both mania and depr
o This is a 2nd mesngr pway
o Not really understood how drug works though
• Anti-convulsant
• Also used in manic depr esp for rapid cyclers (4-5 cycles per year)
• Sodium valproate can also be used

Recent Research
• MRI – lithium tx of pts w manic depr ↑ grey matter vol
• Studies have shown that lithium stimulates neurogenesis in the brain
• Other anti-depressants (eg fluoxetine) can also promote neurogenesis
• Suggestion – impaired neurogenesis may play a role in depr and anti-depressant drugs may act to promote endogenous neurogenesis
• Lithium is also neuroprotective (esp after chr tx) suggesting that this may also somehow be involved in its me


• Ether – revolutionized the practice of medicine and surgery
Triad of Anaesthesia
1. analgesia (pain relief) – opioid agonist
2. hypnosis – propofol/volatile
3. immobility (areflexia) – muscle relaxant
Meyer-Overton Hypothesis
• anaesthetic potency correlates w lipid solubility
• suggests unitary mechanism at hydrophobic site
• exceptions include – isomers, convulsant actions, cutoff effect, nonimmobilisers
Hydrophilic Site
• postulated hydrophilic site in addition to main hydrophobic site
• amenable to alteration in H bonds
• however substituting Hydrogen for deuterium does not change potency
• xenon and argon are anesthetics but do not form H bonds
Volume Expansion Hypothesis
• anesthesia occurs when lipid membrane expands beyond critical volume
• predicts pressure reversal of anesthesia
• this effect is incomplete for some anesthetics
• does not explain why not all lipid soluble agents are anesthetics
Protein Receptor Hypothesis – Modern
• specific anesthetic binding sites have been found on membrane proteins
• action on ligand gated ion channels is probably indirect
• many ion channels have common subunits
• many ion channels affected eg Ach, GABA, NMDA etc and voltage gated channels
• non-immobilizers do not have these effects
• this theory explains the ability of general anaesthetics to act at many different ion channels incl the GABA receptor, the Acetylcholine receptor and the NMDA receptor
Evidence against a unitary mechanism
• differential effects of agents
• evidence of action at more than one receptor – eg partial antagonism of general anesthetic effect

Physiology of Inhalational Anaesthetics
Physiochemical Properties
• boiling point, blood-gas solubility (onset/offset), oil-gas solubility (potency), minimum alveolar concentration
• most are halogenated ethers
• physico-chemical properties largely determine their utility
• most are liquids at room temp and are delivered to pt by custom-made vaporizers
• drugs w a low blood gas solubility have rapid onset and offset ↑ oil gas solubility and ↑ potency
• potency of these drugs is described by the concept of minimum alveolar concentration (MAC) which is the conc of an anaesthetic vapour at which there is 50% chance of ablating a mvment response in a standard surgical incision

Pharmacodynamics - CNS
• largely similar pharmaco-dynamics - ↓ brain processing ability and subsequent effect on EEG
• ↓ the cerebral metabolic rate for O2 (CMRO2)
• ↑ cerebral blood flow and hence ↑ ICP – thus they can be used as cerebral protective agents
Pharmacodynamics – CVS (adverse effects)
• peripheral vasodilation and hypotension
• HR unchanged
• Little effect on SV (stroke vol)
• Halothane is pro-arrythmogenic
Pharmacodyanmics – RS (respiratory Sys)
• Most are potent respiratory depressants
• Impair ventilatory response to hypoxia and changes in PaCO2
• Airway stimulation
Pharmacodynamics – Other systems
• ↓ portal vein blood flow
• immune mediated hepatotoxicity w halothane
• ↓ renal blood flow, ↓ GFR, ↓ UO (urinary output)
• Nephrotoxicity from fluoride ions


1. Nitrous Oxide
• Odourless non-flammable gas
• low potency (MAC 101%) – ie in a concentration w O2, it must compose more than 100% (impossible!)
• Low blood gas solubility → rapid onset and offset
• Analgesic
• Many adverse effects
• ↑ risk of postoperative nausea and vomiting
• will expand air containing spaces such as bowel, middle ear and pneumothorax

2. Halothane
• sweet non-pungent halogenated alkane
• high potency (MAC 0.86%)
• intermediate blood gas solubility → slow onset
• 2% o drug is metab in-vivo (in the living body) and thus can rarely cause fetal hepatitis

3. Isoflurane
• pungent halogenated methyl ethyl ether
• MAC 1.1% - potent
• Probably the most stable CVS agents in common use
• Intermediate solubility and intermediate onset/offset

4. Sevoflurane
• Pungent fluorodinated methyl ethyl ether
• Intermediate potency 1.7% MAC
• Low solubility → rapid onset/offset
• Causes little airway stimulation but has a theoretical risk of being metabolized to compound A
• It can have neurotoxic side-effects

5. Desflurane
• Pungent fluorodinated methyl ethyl ether
• Intermediate potency MAC 6%
• Low blood gas solubility → rapid onset/offset
• Does cause some sympathetic stimulation → tachycardia and hypertension in some pts
• Low boiling point and has to be used w a specically designed vaporizer

Uptake and Disbribution
• Pi = PA = Pa = Pbr (Inspiration = alveolar = arterial = brain)
• Uptake = solubility (gamma) * Q (CO) * (Pa-Pv)

• Almost all eliminated unchanged
• Some agents metabolized in liver – methoxyflurane, halothane, sevoflurane
• Effects of metabolites – fluoride ions, compound A


• Intravenous agents like thiopentone, propofol and benzodiazepines act at the GABA channel
o They have an agonist action ↑ Chloride conductance and thus ↓ the excitablility of the post-synaptic neuron
• Intravenous agents such as katamine act at the NMDA receptor ↑ Na, Ca and K conductance thereby having an inhibitory action on the post-synaptic neuron
GABA Receptor
• GABAa receptor – ligand gated chloride channel
• Made of 5 subuntis that are transmembrane proteins
• GABA receptor is the main inhibitory receptor in the CNS
• Many anesthetic drugs have direct or indirect effects on the channel
NMDA Receptor
• Ligand gated Ca, Na and K channel
• Also made of 5 subunits

The Ideal IV Induction Agent
• Solubility – stability at 20 degrees C
• Potent, little variability of effect
• High therapeutic ratio
• Quick smooth onset
• Short duration action
• Suitable for total IV anesthesia
• Quick, smooth and complete recovery
• Fast redistribution
• Metab and excretion indep of liver or kidneys
• Inactive, non-toxic metabolites
• Amenable to hemodialysis
• Potential for anaphylactic and anaphylactoid reactions
• Sensitization
• Histamine release
Absence of Side Effects
• Hemodynamic instability
• Effects on myocardium
• Effects on ventilation
• Effects on CNS incl ICP
• Pain on injection
• Teratogenicity
• Endocrine
Other Properties
• No precipitation of porphyria
• Safe in malignant hyperthermia
• Identifiable onset of anesthesia
• Cheap
• Bacteriostatic

Types of IV Agents
A. Barbiturates (thiopentone, methohexitone)
B. Phenols (propofol)
C. Imidazole (Etomidate)
D. Phencyclidine derivates (ketamine)
E. benzodiazepines (midazolam)

1. Thiopentone
• GABAa receptor site of action
• GABAa agonist (ie mimics GABA) - ↑ Cl conductance hyperpolarizing and ↓ excitability of post-synaptic neuron
• Thiopentone binding prolongs GABA action mediating sedative-hypnotic effects
• At higher doses – direct stimulation of GABA receptor to mediate anesthetic effects
These effects above are similar to methahexitone and propofol as well
• A barbiturate
• Its action is terminated by redistribution to muscle rather than metabolism
• It is metabolized in the liver and induces liver enzymes
• Potent CVS and RS depressant
2. Methahexitone
• A barbiturate
• In some pts – produces excessive motor activity
• As well as being a CNS depressant, it also has some CNS excitatory properties and is often used during general anesthesia for electroconvulsive therapy in psychiatry
• Effect terminated by redistribution to muscle
• Action at GABAa – mimics GABA
• Metablised in the liver and induces liver enzymes
3. Propofol***
• A phenol that is highly lipid soluble so is formulated as an emulsion
• Action at GABAa – mimics GABA
• Rapid onset and offset
• Comes close to being the ideal agent for total intravenous anesthesia (TIVA)
• Metabolized in the liver by conjugation then excreted by the kidneys
• Most widely used IV induction agent in NZ
These three agents –
• ↓ cerebral metabolic rate for O2
• ↓ cerebral blood flow
• ↓ ICP
• are cerebrally protective
• thiopentone and propofol are potent anti-epileptics but methahixatone is epileptogenic
• all cause veno-dilation, moderate myocardial depression and reflex tachycardia
• Hypotension is common
• Central respiratory is common
Pharcodynamics – Other
• ↓ GFR by ↓ RBF
• ↓ cortisol but not adrenocortical stress response to surgery
• slight ↑ plasma Glucose

4. Etomidate
• An Imidazole formulated by an emulsion
• More CV stable than other intravenous agents
• less respiratory depression
• It has an excellent recovery profile but does cause adrenocortical inhibition in prolonged infusions → ↑ mortality in intensive care pts

5. Ketamine
• NMDA receptor antagonism mediates anesthetic effect as well as some analgesia
• S-(+) enantiomer has a gamma-opioid agonist activity mediating some of the analgesia
• No single antagonist reverses all the CNS effects of ketamine
• Phencyclidine derivative
• Slow redistbn half life
• Analgesic
• CV stimulant
• ↑ cerebral metab rate for O2
• ↑ cerebral blood flow
• ↑ ICP
• it acts on the NMDA receptor to cause a dissociative state and does not cause sig respiratory depression
• Excellent drug in shock or low CO states

6. Benzodiazepines
• act at the benzodiazepine receptor on the GABA channel
• ↓ cerebral metab rate ofr O2
• ↓ cerebral blood flow
• potent anti-epileptic agents and only cause modest hemodynamic and respiratory depr
• v high margin of safety as opposed to the other IV agents
• uncommon as single induction agent bec of prolonged hangover effect – often used as co-induction to minimize side effects of other induction agent

TIVA – Total IV Anesthesia
• modern technique uses computer controlled infusion pump w algorithm derived from popn characteristics for propofol
• algorithm estimates plasma conc based on three c/ment model
• avoids inhalation route
• avoids complications of vapours – malignant hyperthermia, PONV, Intracranial hypertension
• expensive
• no agent monitoring
Malignant Hypertension
• severe HT that runs a rapid course
• causing necrosis of arteriolar walls in kdney, retina etc
• hemorrhages occur and death most frequently is caused by uremia (excess urea in blood) or rupture of a cerebral vessel


• avoids many of the systemic side effects of general anesthesia
• cocaine was the first local anesthetic
• local anesthetics produce reversible conduction blockade of nerve impulses
• ester anesthetics like cocaine are prone to allergic reactions and have been largely replaced by amide local anesthetics
• lidocaine was the first representative of amide local anesthetics

• local anesthetics have a basic structure – hydrophilic and lipophilic end linked by an ester or amide group
o ie a polar molecule w one hydrophilic end and the other end being hydrophobic
o LAs w the pKa closest to physiological pH have fastest onset of action
o Las are weak bases and thus explains the poor quality of block when LA injected into acidic infected tis
o Lengthening alkyl chain ↑ lipid solubility
o Ester or amide bonds determine site of metabolism and potential for allergic reactions
• they block Na channels (H gate) in nerve cell membranes primarily in the inactivated closed state
• this slows the rate of depol so threshold potential is not reached
• resting membrane potential and threshold potential remain unchaged
• unwanted effects are reversible blockade of K and Ca channels that mediate some of the CVS and CNS side effects

Local Anesthetics
• Na channels exist in activated-open, inactived closed, and rested closed states
• LA selectively bind to Na channels in inactivated closed states so are membrane stabilizing
• Reduce Na ion permeability slows depol so threshold potential is not reached
• Prevent of voltage dependent ↑ in Na ion conductance
Other sites of action
• Voltage dependent K channels
o Broadening of AP
• ATP sensitive K channels
o Cause of toxicity in other organs
• Voltage dependent Ca channels
o Possible cause of pro-arrhythmic activity
• G protein coupled receptors
o Muscarinic M3 receptor effects

Lipid Solubility
Drug Relative Potency Lipid Solubility
Procaine 1 100
Prilocaine 1.8 129
Lignocaine 2 366
Bupivicaine 8 3420

Drug Potency
• Drugs that have intrinsic vasodilator properties (eg lidocaine) have more rapid vascular uptake and fewer molecules available for neural block
• Lipid soluble drugs (eg eitdocaine) get taken up in adipose tis so fewer molecs avail for neural block

• Esters – plasmacholinesterase
• Amides – liver metab, most dependent on liver blood flow bec of high extraction ratio

Systemic Toxicity
• ↑ plasma concentrations of local anesthetics will result in systemic toxicity and may be due to –
o accidental overdose
o advertent IV injection
o injection into v vascular tissues
o impaired metabolism in severe liver failure
• sx of systemic toxicity incl –
o CNS Sx
 Circumoral numbness, restlessness, tinnitus, slurred speech
 Drowsiness, mus twitching, agitation
 Tonic-clonic seizures
 Coma, respiratory arrest
o CVS Sx
 Hypotension – arteriolar vasodilation
 Arrhythmia
 First degree heart block, conduction delay
 Cardiac arrest – myocardial depression
o Other
 Anaphylaxis
 Depress ventilatory response to hypoxia
 Methaemoglobinaemia (prilocaine)
 Tachycardia, HT, myocardial depression, addiction (cocaine)

• ester – tendency to cause allergy
• CVS and CNS stimulant
• Addictive
• Used in ENT as a vasoconstrictor
• Metab by plasma esterases

• Amide
• Standard agent against which others are compared
• Antiarrhythmic
• Vasodilator - ↑ in systemic toxicity
• Avail as 0.5%, 1% and 2% preparations

• Sequestered and metabolized in lungs
• Not vasodilating – safest drug in current use
• Equipotent w lidocaine – slightly longer duration action
• Hydrolysed to o-toluidine causing methaemaglobinaemia at doses over 600mg
• Agent of choice for IVRA

• Amide
• Long duration action
• Excellent w catheter based techniques
• May cause cardiotoxicity before neurotoxicity

Routes of Administration
• Topical – EMLA cream, ametop
• IV – IVRA or beir’s block
• Infiltration
• Nerve or plexus
• Subarachnoid – spinal anesthesia
• Epidural

• Adrenaline
• Opioid agonists
• A2 adrenergic agonists


Muscle Relaxants
• Act by binding at the acetylcholine receptor at the NMJ
• Main action is at skeletal muscle
Side Effects
• Mediated by effects at other acetylcholine receptor subtypes
• Two classes of drugs
o Depolarizing neuromuscular blocker
o Non-depolarizing neuromuscular blocker
• Original muscle relaxant was curare – south American arrow poison
• Modern non-depolarizing drugs have a shorter duration of action and fewer side effects
• Non-depolarizing muscle relaxants can be partially antagonized by anti-cholinesterases such as neostigmine which act by inhibiting the breakdown of acetylcholine
• Depolarizing muscle relaxants cause uncoordinated muscle contractions (fasciculations) before causing muscle relaxation
• Their onset of action if rapid, have a brief action but have numerous side effects including muscle pains, K release, anaphylaxis and malignant hyperpyrexia

NMJ - Slide 5/6
• Miniature end plate potentials (MEPPs) result in quantal release
• End plate depol is an all or none phenomenon
NMJ Physiology – Slide 9
• Receptor opening needs two Ach molecules
• Approx 200 quanta of approx 5000 Ach molecs needed
• One endplate per muscle fiber
• All or none contraction phenomena
• Curare binds where Ach binds thus inhibiting Ach receptor activation
• Attached to motor end plate by collagen
• Ach usu destroyed within 1 ms of release
• Usu only time for Ach to bind to one receptor
Pre-junctional Receptors
• Block of Na but not Ca channels
• Mobilization effected not release
• Fade is a prejunctional effect as is fasciculation and its prevention by NMBs
• Prejunctional receptors not as well typified
• Extrajunctional receptors v sensitive to Ach and suxamethonium

• Depolarizing v nondepolarizing
• Chemistry
o Benzylquinolones
o steroids
• Duration of effect
o Ultra-short
o Short
o Medium
o long

Non-depolarizing Muscle Relaxants
• Non-depolarizing muscle relaxants are quaternary ammonium compounds
• Positive chargers at these sites mimic the quaternary N atom of Ach
• NMBs are quite water sol and hence easily excreted via glomerular filtration
• NMBs do not cross lipid membranes such as cellular, bbb or placental barriers

Suxamethonium – Adverse Effects
o CVS - stimulates all nicotinic and muscarinic receptors, Bradycardia, nodal and ventricular dysrhythmias
o CNS - ↑ ICP
o Muscular – masseter spasm
o Metabolic – hyperkalemia
o GI – variable ↑ intragastric pressure
o Anaphylaxis
o Antagonism of blockade
o Neostigmine, pyridostigmine, edrophonium

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