Analgesia and Drugs Flashcards
(145 cards)
1
Q
Two types of tolerance
A
Innate and acquired
2
Q
Three types of acquired tolerance
A
Pharmacokinetic (related to concentration of drug)
Pharmacodynamic (related to response to the drug)
Learned (related to Pavlovian cues)
3
Q
Tolerance
A
The reduction in response to a drug after repeated administration
4
Q
Sensitisation
A
The increase in response to a drug after repeated administration
5
Q
Physical/psychological dependence
A
The state that develops as a result of tolerance produced by resetting of homeostatic mechanisms in response to repeated drug abuse
6
Q
Withdrawal syndrome
A
The only evidence of physical dependence. Caused by the removal of the drug and characterised by CNS hyperarousal. Characteristic of the particular category of drug and tends to be opposite to the effects of the drug.
7
Q
Factors that affect the likelihood of drug abuse or dependence
A
Agent: the drug
Host: the user
Environment: the setting
8
Q
Drug abuse
A
A behavioural syndrome including one or two symptoms as listed in the DSM under substance dependence syndrome. Often refers to non-medical use of the drug to alter a state of consciousness.
9
Q
Drug addiction
A
A behavioural syndrome including three or more symptoms as listed in the DSM under substance dependence syndrome. Refers to the medical diagnosis causing a change in behaviour and tolerance.
10
Q
Drug misuse
A
Inappropriate medical use e.g. for too long, not long enough, incorrect dose etc.
11
Q
Compulsive drug use
A
A technical term that distinguishes behavioural problems from physical dependence.
12
Q
Reinforcement
A
The property which makes the user want to use the drug again – related to the abuse potential of the drug and the rapidity of onset of action.
13
Q
“Asian flush”
A
An informal term for the phenomenon of asian populations having high levels of alcohol dehydrogenase which converts alcohol to acetylaldehyde, the compound that causes the negative effects of alcohol use such as increased body temperature, headache, red face, nausea, etc. Individuals that are prone to this rarely experience the desired effects of alcohol due to increased metabolism speed, so rarely become alcoholics.
14
Q
1 standard drink
A
14 g ethanol
15
Q
Average alcohol elimination rate
A
7 g per hour
16
Q
Michaelis–Menten kinetics of alcohol elimination
A
The first drink(s) are cleared very quickly according to 1st order kinetics but after multiple drinks the rate of elimination slows and starts to follow 2nd order kinetics.
17
Q
3 types of CNS depressants
A
Alcohol
Benzodiazepines
Barbituates
18
Q
3 types of psychedelic agents
A
LSD
Ecstasy
Mesciline
19
Q
2 types of psychostimulants
A
Cocaine
Amphetamine
20
Q
Properties of alcohol
A
CNS depressant
Impaired recent memory and blackouts in high doses
Mild intoxication associated with motor incoordination, sleepiness, then stimulation
Severe intoxication can lead to sedation, coma and death.
21
Q
Alcohol tolerance
A
As tolerance develops, sedation is reduced but lethal dose is unchanged so the therapeutic index is reduced.
22
Q
Alcohol withdrawal syndrome
A
Alcohol craving, tremor, irritability, nausea, tachycardia, sweating, seizures
Treat with wine
23
Q
ABCDE
A
Airway Breathing Circulation Disability Exposure
24
Q
Most common cause of liver failure in NZ
A
Hepatitis
25
Most common cause of liver failure in UK
Paracetamol overdose
26
Delirium tremens
Severe agitation, confusion, hallucinations, fever, nausea, diarrhoea
More likely with infection, malnutrition and electrolyte imbalance
27
Cross-tolerance with alcohol
Other sedatives e.g. benzodiazepines produce additive sedation which can be fatal
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Full agonist opioids
Morphine
Oxycodone
Hydromorphone
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Partial agonist opioid
Buprenorphine
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Antagonist opioid
Naloxone
31
Benzodiazepine withdrawal symptoms
Anxiety, agitation, increased light and sound sensitivity, paresthesia, muscle cramp, myoclonic jerks, seizure, delirium
32
Prolonged solvent use effects
Cardiac arrhythmia, bone marrow depression, liver damage, peripheral nerve damage, renal damage, cerebral degeneration
33
3 short-acting rapid onset opioids
Morphine
Fentanyl
Pethidine
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2 longer-acting slower onset opioids
Sustained release morphine
| Methadone
35
Opioid withdrawal syndrome
Characterised by sweating, dilated pupils and piloerection
Symptoms include craving, restlessness, irritability, increased sensitivity to pain, nausea, cramps, muscle aches, insomnia, anxiety, tachycardia, vomiting, diarrhoea, hypertension, fever
36
Heroin
Diamorphine
Rapidly metabolised to 6-monoacetyl morphine causing analgesia
Also associated with abnormal pituitary function, dysmenorrhea, reduced sexual performance and high mortality
37
Clonidine
Alpha2 adrenergic agonist which reduces adrenergic neurotransmission and decreases autonomic symptoms of withdrawal
38
Cocaine cause of death
Usually through cardiac arrhythmia or CNS toxicity
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Proprfolol
Most widely used anaesthetic induction agent
| Narrow therapeutic index
40
Opioids vs opiates
Opiates are natural
| Opioids are partly or fully synthetic
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3 types of pain
Nociceptive (tissue damage)
Inflammatory (inflammation)
Neuropathic (nerve damage)
42
Possible routes of narcotic administration
Oral
Parenteral (injectable)
Transmucosal
Transdermal
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2 methods of parenteral administration
Intramuscular and intravenous
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Opium
The dried latex from opium poppies containing narcotic alkaloids and non-narcotic alkaloids
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Narcotic alkaloids in opium
Morphine and codeine
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Non-narcotic alkaloids in opium
Papaverine
Thebaine
Noscapine
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Opioid receptors
Essential pre-synaptic and belong to GPCR family
| Mu, Kappa and Delta
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Opioid mechanism of action
Activate G proteins which inhibit adenylate cyclase, decreasing calcium channel permeability. Calcium can't enter nerve terminals so transmitter release is blocked. Potassium conductance increases causing hyperpolarisation of post-synaptic neuron which decreases the response.
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Mu receptors location
Spinal cord
Periaqueductal grey
Thalamus
Cortex
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Kappa receptors location
Limbic system
Hypothalamus
Periaqueductal grey
Spinal cord
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Delta receptors location
```
Olfactory bulb
Cerebral cortex
Nucleus accumbens
Amygdala
Pontine nucleus
```
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Mu-1 receptor activation response
Analgesia
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Mu-2 receptor activation response
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Analgesia
Respiratory depression
Euphoria
Decreased GI motility
Physical dependence
```
54
Kappa receptor activation response
Analgesia
| Dysphoria
55
Antagonist–Agonist opioids
Nalorphine and pentazocine
| Have agonist activity on one receptor type and antagonist activity on another
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3 semi-synthetic opioids
Buprenorphine
Oxycodone
Diamorphine
57
4 fully-synthetic opioids
Fentanyl
Pethidine
Methadone
Tramadol
58
4 endogenous opioid peptides and the receptors they act on
Endorphins (mu)
Endomorphins (mu)
Enkephalins (delta)
Dynorphins (kappa)
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Adjuvants
Used to enhance opioid analgesia and reduce side effects e.g. NSAIDs
60
Cross-tolerance
A type of opioid management in which one opioid is replaced with another and then slowly withdrawn
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Rapid opiate detoxification treatment
Patient is put under general anaesthesia and given high doses of naltrexone to rapidly induce detoxification while blocking the severe symptoms of opiate withdrawal
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Morphine metabolism
By glucuronidation in the liver
70% to morphine 3-glucoronide
Rest to morphine 6-glucoronide
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Pethidine elimination
Metabolism in the liver via ester hydrolysis to pethidinic acid and N-demethylation producing norpethidine
Conjugation of pethidinic acid and norpethidine, then excretion via urine
64
Pethidine
Originally designed as synthetic anticholinergic
| Miosis, dry mouth, tachycardia, less biliary spasm
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Norpethidine
Toxic metabolite of pethidine
| Accumulates in renal failure and causes hallucinations and seizures
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Pethidine drug interactions
MAOIs
| Causes coma, convulsions, labile circulation and hyperpyrexia
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Fentanyl administration
```
Intravenous
Intramuscular
Transdermal patches (slow and difficult to alter dose rapidly)
Transmucosal lozenges
Nasal and sublingual sprays
Sublingual tablets
Iontophoresis
```
68
Iontophoresis
Method of transdermal PCA of ionisable drugs in which the electrically charged components are propelled through the skin by an external electric field
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Methadone
Fully synthetic opioid that can block NMDA transmission, preventing glutamate activity and easing neuropathic pain
No significant cognitive impairment or euphoria
70
Tramadol
Synthetic codeine analogue
Weak mu opioid receptor agonist that inhibits NE and serotonin uptake
Caution in patients with history of epilepsy
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Codeine
Mild to moderate pain
Cough suppressor
Anti-diarrhoeal
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Codeine metabolism
By CP450 2D6
Ultra-rapid metabolisers at higher risk of toxic opioid effects, slow metabolisers may not experience adequate analgesic effect
73
6 types of co-analgesics
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TCAs
Anticonvulsants e.g. Gabapentin
Anxiolytics
Corticosteroids
Ketamine
Clonidine
```
74
3 classifications of NSAIDs
Carboxylic acids
Enolic acids
Non-acidic compounds
75
NSAID mechanism of action
Inhibit cyclo-oxygenase enzymes leading to suppression of prostanoid production in cells
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Aspirin mechanism of action
Selectively acetylates a single serine residue of a cyclo-oxygenase enzyme and irreversibly inactivates it
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Main effects of NSAIDs
Decrease Inflammation by decreasing PGs
Relieve mild pain by decreasing PGs
Anti-pyretic by decreasing PG E2
Anticoagulation by decreasing TXA2
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Prostaglandins
A large group of highly potent lipid compounds derived rom fatty acids with a wide spectrum of biological actions. They have very short half lives, are produced by almost all cells and are involved in autocrine signalling.
79
Arachidonic acid
Synthesised from essential fatty acid lineolate or taken in by diet
Esterified to cell membrane phospholipids which then synthesise eicosanoids
80
Eicosanoids
Prostanoids and leukotrienes
| Synthesised from arachidonic acid
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3 types of prostanoid
Prostaglandins
Prostacyclins
Thromboxane
82
Why are some newer NSAIDs selective COX2 inhibitors?
Old NSAIDs, which are COX1 and COX2 inhibitors, have undesirable side effects due to the inhibition of COX1, which has important homeostatic functions in producing prostanoids for the GI tract, renal system and for platelets and macrophages. Newer NSAIDs have been created to selectively target COX2, which is normally dormant, but, when activated, produces excess inflammatory prostaglandins, leading to the symptoms of inflammation. Unfortunately, these newer NSAIDs also seem to carry so undesirable gastric and cardiovascular side effects.
83
Pharmacokinetics of NSAIDs
Highly lipophilic
Rapid and complete absorption after oral administration
High bioavailability due to little first-pass metabolism
High degree of protein binding, so small volumes of distribution
Slow onset of action
Variability in half life, therefore varying clearance rates
Metabolised by liver into inactive products
84
Drug interactions of NSAIDs
```
Oral anticoagulants
Methotrexate
Oral anti-diabetics
Thyroid hormones
Digoxin
```
85
Why can NSAIDs exacerbate gout?
They compete for active renal tubular secretion with other organic acids like uric acid, which is responsible for gout. Without filtration of uric acid, it collects in the joints, causing gout flare-ups.
86
CYP2C9 inhibitors
Cimetidine
| Valproic acid
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CYP2C9 inducers
Carbamazepine
| Phenobarbitone
88
NSAID excretion
Excreted in urine as phase II glucuronides, sulfate conjugates and a small percentage unchanged
89
Aspirin excretion
Aspirin is absorbed in the stomach and the upper intestine by passive diffusion. Once in the blood, most of it is deacetylated to salicyclic acid which binds to serum albumin and is conjugated in the liver with glycine and glucuronic acid. It is then excreted in the urine.
90
How does aspirin prevent clots?
It irreversible acetylates COX1 which is responsible for TXA2 formation. Without this key factor, platelets cannot aggregate.
91
NSAIDs effects on gastric cytoprotective prostanoid
This is a prostaglandin produced by gastric epithelium to protect against acid damage. NSAIDs inhibit synthesis, leading to mucosal damage, ulceration, nausea/vomiting and dyspepsia.
92
Aspirin triad
Aspirin intolerance, including rhinitis and flushing
Severe asthma
Nasal polyps
93
Aspirin-induced asthma
inhibition of COX1/2 leads to decreased PGE2, a bronchodilator, and activation of the lipoxygenase pathway. This increased inflammatory mediators and induces bronchospasms. Together, these provide the symptoms of asthma.
94
Reye's syndrome
An acute metabolic encephalopathy following aspirin administration in children. Most often affects children and teenagers recovering from a viral illness and seems to be linked to underlying fatty oxidation disorders, causing increased ammonia and increased liver enzymes.
95
Analgesic nephropathy
In compromised patients, NSAIDs are associated with renal failure, specifically:
Papillary necrosis
Interstitial nephritis
Acute tubular necrosis
96
Prostaglandins in pregnancy
Establish and maintain labour
Increase uterine smooth muscle contraction
Maintains patency of ductus arteriosus
NSAIDs can prevent premature labour and close patent ductus arteriosus in premature infants
97
Paracetamol antidote
N-acetylcysteine
98
Why isn't paracetamol considered an NSAID?
It doesn't exhibit significant anti-inflammatory activity – only analgesic and antipyretic
99
Triad of anaethesia
Immobility
Hypnosis/amnesia
Autonomic areflexia
(+ physiological stability)
100
How do inhaled anaesthetics work?
GABA modulation in the brain and glycine modulation in the spinal cord
These are both inhibitory neurotransmitters, so we want to increase their activity to dampen the body's response to stimuli
101
MAC
Minimal alveolar concentration producing immobility on standard surgical stimulus in 50% of patients, or the percentage of drug that you need to be in the alveoli to prevent movement in 50% of patients in a standard forearm incision
A means of describing potency and dose
102
How does MAC relate to potency?
More potent drugs will have a lower MAC, because a lower percentage is required to be in the alveoli to prevent movement in 50% of patients in a standard forearm incision
103
Factors that increase the MAC of a drug in a patient
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Young age
Hyperthermia
Hyperthyroid
Amphetamine
Heavy alcohol
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104
Factors that decrease the MAC of a drug in a patient
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Old age
Hypothermia
Hypothyroid
Opioids
Pregnancy
Low O2
```
105
Why isn't the setting of the MAC on a machine completely accurate?
Blood flow tends to decrease the fraction of a drug in the alveoli, so, even though a machine setting may say 6% concentration, you would actually need to increase the dose to get the desired concentration.
106
What other effects do inhaled anaesthetics have on the body?
Decreased cerebral metabolic rate for O2
Increased cerebral blood flow and ICP
Peripheral vasodilation and decreased BP
Respiratory depression
107
Which inhaled anaesthetic has the least respiratory depression effect?
Sevoflurane
108
Which inhaled anaesthetic is pro-arrhythmogenic?
Halothurane
109
Which inhaled anaesthetic causes increased heart rate?
Desflurane
110
Which inhaled anaesthetic are you most likely to give a child?
Sevoflurane, because it tastes sweet and can be inhaled with irritation.
111
Nitrous oxide
Odourless, non-flammable gas with low potency. Also has low blood-gas solubility, rapid onset and many adverse effects.
112
Halothane
Sweet, non-pungent halogenated alkane
HIghly potent but slow onset
Highly chlorine substituted, so less stable than the fluranes
113
Isoflurane
Pungent, potent anaesthetic
Intermediate blood-gas solubility, medium rate of onset
Cardiovascular stability, so often used for cardio surgeries
114
Sevoflurane
Non-pungent and least respiratory depression, so good for gaseous inductions and commonly used in children
Intermediate potency, low solubility and rapid onset
Little airway stimulation
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Desflurane
Pungent, intermediately potent anaesthetic
Low blood-gas solubility with rapid onset and offset, so great for long surgeries that require a rapid wakeup
Sympathetic stimulation
116
5 types of IV anaesthetics and examples
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Barbiturates – Thiopentone
Phenols – Propofol
Imidazoles – Etomidate
Phenycyclidine derivatives – Ketamine
Benzodiazepines – Midazolam
```
117
Ketamine mechanism of action
Binds and blocks PCP receptors in the CNS, antagonising glutamate and suppressing excitation
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Thiopentone mechanism of action
Enhances GABA, prolonging Cl- current and causing hyperpolarisation
(Same for propofol, etomidate and midazolam)
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Pharmacokinetics of IV anaesthetics
Highly lipid soluble and can cross the BBB
| Rapidly distributed so patient wakes up quickly even though metabolism is slower
120
Thipentone
Incredibly rapid onset due to redistribution but slow clearance (liver metabolism). Hangs around in plasma leading to a hangover effect
Causes respiratory depression and loss of airway reflexes
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Propofol
Rapid onset, but not as quick as thiopentone
Faster clearance than thiopentone – no hangover effect
Causes respiratory depression and loss of airway reflexes
122
Etomidate
Remarkable CV stability
Less respiratory depression than thiopentone and propofol
Rapid clearance and good recovery profile
Cons include adrenocortical inhibition, myoclonus and epiliptogenesis
123
Ketamine
Phencyclidine derivative
Analgesic and cardiovascular stimulant
Preserves respiratory drive and airway reflexes
Increases CMRO2, CBF and ICP so not good for neurosurgery
Dissociative state and dysphoria
124
Midazolam
Reduces CMRO2 and CBF
Potent anti-epileptic
Slow onset and offset
Relatively safe
125
Pros and cons of IV anaesthesia
Avoids inhalation and complications of vapours (e.g. malignant hyperthermia and intracranial hypertension)
Expensive and hard to monitor
126
How do local anaesthetics work?
Local anaesthetics are sodium channel blockers, so stop sodium from leaving cells and preventing nerve conduction
They are all weak bases that must be in the unionised form to cross the axonal membrane and are then converted into the ionised form inside the cell
127
Why are most local anaesthetics amides?
Locals are either esters or amides. Esters are rapidly metabolised, shorter acting and more allergenic due to the less stable ester bond.
128
2 important ester locals
Cocaine and tetracaine (eye anaesthetic)
129
4 important amide locals
Prilocaine
Lignocaine
Bupivacaine
Ropivacaine
130
Structure–activity relationship of local anaesthetics
Lengthening the alkyl chain increases lipid solubility
In general, the more lipid soluble a compound is, the more potent it is
Fast-acting anaesthetics have pKas closer to physiological pH (lower)
131
Why don't local anaesthetics work very well in hypoxic tissues?
Hypoxic tissues are acidic tissues with pHs below the normal physiological pH. Local anaesthetics, which are weak bases, work faster and better when their pKa is closer to the physiological pH, so having this lower than normal means they can't work as effectively as they could in a more neutral environment.
132
Ester anaesthetic metabolism
Metabolised by plasma cholinesterases
133
Amide anaesthetic metabolism
Metabolised in the liver, rate most dependent on liver blood flow because of high extraction rate
134
Lignocaine
Amide
Low lipid solubility, potency, pKa and protein binding
Short duration of action, fast onset
Ideal for short surgical procedures
135
Bupivacaine
Amide
High lipid solubility, potency, pKa and protein binding
Long duration of action, slow onset
Can cause cardiotoxicity and neurotoxicity
Ideal for analgesia nerve blocks
136
Cocaine
Ester
Topical to nose
Causes vasoconstriction
137
Prilocaine
Amide
Regional IV anaesthesia
Safest agent
138
Ropivacaine
Amide
Slow onset with long duration of action
Less cardiotoxicity than bupivacaine
139
Local anaesthetic toxicity
Allergic reaction (rare with amides)
CNS toxicity followed by cardiotoxicity
Involves CC:CNS ratio – How much more drug is needed to cause cardiotoxicity than CNS toxicity e.g. lignocaine is 7, therefore 7x more drug is needed to cause cardiotoxicity than CNS toxicity
140
EMLA
Eutectic mixture of local anaesthetics
Mixture of lignocaine and prilocaine as an oil preparation that allows most drug to be free base and able to cross skin
Used for IV insertion in children
141
Peripheral nerve block
Local anaesthetic infiltrated around a specific nerve for surgery without general anaesthesia or for post-op analgesia
142
Spinal anaesthesia
Local anaesthetic injected into intrathecal space – only below L2 where the spinal cord terminates (same rules apply for lumbar puncture)
Profound distal motor and sensory block for major surgery
143
Epidural
Small catheter inserted into epidural space, local anaesthetic infused through. Affects spinal nerves passing through space. Can be done at any level.
144
Local anaesthesia adjunct for vasoconstriction
Adrenaline
145
Local anaesthesia adjuncts for co-analgesia
Opioid agonists or alpha2-adrenergic agonists
