CNS, pain, drug dependence and analgesics/anaesthetics Flashcards
1
Q
What are the three main neurotransmitter classes?
A
- amino acid and derivatives (glutamic acid, GABA, aspartic acid, glycine)
- peptides: vasopressin, somatostatin, neurotensin
- monoamines: NA, DA, 5-HT
2
Q
What is the nature of the CNS environment regarding synapses?
A
The CNS has a multi-synaptic environment where neurotransmitters affect multiple receptor targets with varying subunit conformations.
3
Q
How do glial cells contribute to CNS function?
A
Glial cells, which outnumber neuronal cells by about 10:1, play major roles in supporting neuronal function through receptor expression, electrical coupling, and affecting neuronal activity.
4
Q
What are secondary adaptive effects in the CNS?
A
Secondary adaptive effects may occur on receptors as a response to the presence of drugs, affecting the CNS response over time.
5
Q
Why do individual experiences of drug effects in the CNS vary?
A
Individual experiences of drug effects vary due to the unique responses in the CNS, and this variation is often a key criterion for assessing drug effectiveness.
6
Q
What types of changes occur in the CNS over time?
A
Changes occur via neurotransmitter, neuromodulator, and neurotrophic compounds, influencing CNS function over time.
7
Q
What are neuromodulators?
A
- Cause complex responses/ modulation
- Alter sensitivities of synapses
- Modify post synaptic responses;
- Change pre-synaptic handling of NT
- Changes occur over minutes, hours or days; associated with slower events, e.g. growth, learning, protein synthesis
8
Q
What is the blood brain barrier?
A
A system of tight junctions between the endothelial cells and surrounding astrocytes (glia) of the capillaries. You need to cross this to affect the CNS. It creates a challenge as it can prevent many therapeutic drugs from reaching the brain. It is tightly regulates the CNS and protects it from toxins, bacteria, etc.
9
Q
What are the effects of agonist drugs
A
- bind to autoreceptors and blocks their inhibitory effect on neurotransmitter release
- binds to post-synaptic receptors and either activates them or increases the effect on them of neurotransmitter molecules
- blocks the deactivation of neurotransmitter molecules by blocking degradation of reuptake
10
Q
What are the effects of antagonist drugs?
A
- activate autoreceptors and inhibits neurotransmitter release
- is a receptor blocker, it binds to the postsynaptic receptors and blocks the effect of neurotransmitter
11
Q
What is glutamate?
A
Glutamate within the CNS usually comes from either glucose or glutamine; there is relatively little entering the CNS directly from the periphery after the first few weeks of life.
12
Q
Describe the cycle of glutamate in the CNS.
A
Glutamine is converted by glutaminase to form glutamate.
Glutamate is then, using a pump, concentrated into a synaptic vesicle. This will require energy because we’re increasing concentration. If an action potential comes along that neuron, that vesicle will move to the end and fuse with the presynaptic membrane and release into the synaptic cleft.
Released Glu is captured partly by neurons and partly by astrocytes, which convert most of it to Gln.
Gln is tranported out of the astrocyte and taken up by neurons which use it to synthesis glutamate.
13
Q
What is EEAT?
A
excitatory amino acid transporter
14
Q
What is GlnT?
A
Glutamine transporter
15
Q
What is VGluT?
A
Glutamate transporter
16
Q
What is glycine?
A
Glycine is a positive allosteric modulator of NMDA receptor glutamate responses.
(glycine is not an agonist but can bind to the NMDA receptor and when it does it might change the affinity of that receptor)
It is manufactured premondinalty in spinal chord, packed into vesicles, released, have diversity of receptors post synaptically, chloride ion channel down central pore, no metabotropic forms (all ionotropic). Then cleared again using transporters located on nearby astrocytes
17
Q
What are the issues with the glutamate receptor?
A
Penetration of BBB is a challenge
Difficult to selectively block function as glutamate is so generally used throughout CNS
only two drugs in current medicinal use and they are lipid soluble and can cross the BBB:
- ketamine (anaesthesia, depression)
- memantine (alzheimers)
18
Q
What are PCP and ketamine?
A
Both are drugs which bind to the same site within the NDMA receptor pore, blocking ion movement down the concentration gradient.
This is a different site than where glutamate binds, so they are non-competitive antagonists of the NMDA receptor.
PCP used to be used as an anaesthetic but is now illegal.
Ketamine has an affect on opiod receptors.
19
Q
What is memantine?
A
It is a non-competitive antagonist of the NMDA receptor and is clinically useful drug to treat alzheimers disease.
20
Q
Describe the lifecycle of GABA
A
Glutamine can be converted enzymatically to glutamate.
Glutamate can then be converted to GABA via glutamic acid decarboxylase.
GABA is then pumped and concentrated into a synaptic vesicle and then exocytosis upon an action potential, you release GABA into that synaptic gap.
If there happens to be an astrocyte sitting nearby you have the enzymes to take that GABA, convert it to glutamate, convert it to glutamine and shuttle it across and start the whole cycle again.
If you’re presynaptic, you might take that GABA up through that transporter to repackage and recycle.
21
Q
What are benzoadiapines?
A
They are positive allosteric modulators. When bnz binds it does not activate the receptor, it simply enables it to be more responsive when a GABA is present. Barbiturates have another positive allosteric binding site, and so do neurosteroids and alcohol.
22
Q
What problems can arrive when some drugs are mixed?
A
If you mix BNZs and alcohol, they have different binding sites, and they are positive allosteric modulators so its not just a summative effect, the net hyperpolarisation possible is significantly greater. Mixing drugs that have a common action is potentially dangerous particularly if it’s inhibitory.
23
Q
What are GABA a receptors?
A
Most GABAA receptors are post-synaptic, and activation
leads to hyperpolarization due to the inward movement of Cl- ions, making it less likely that an AP will occur.
24
Q
What are GABA b receptors and what are some useful drugs?
A
Baclofen is a derivative of GABA and is an agonist of GABA b receptors. Like GABA it decreases neurotransmitter release in excitatory spinal pathways and increases inhibitory pathway activity by working presynaptically …
25
Are GABAB receptors drug targets?
Baclofen is a derivative of GABA and is an agonist of GABAB receptors.
Like GABA, it decreases neurotransmitter release in excitatory spinal pathways and increases inhibitory pathway activity by working presynaptically.
Spasticity, which leads to involuntarily tight or stiff muscles, can be treated with baclofen as it reinforces inhibitory input in the CNS.
26
What is γ-Hydroxybutyrate (GHB)?
GHB is also an agonist at GABAA receptors. GHB effects are similar to those of alcohol and ecstasy, such as euphoria, disinhibition, and enhanced sensuality. At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, visual disturbances, depressed breathing, amnesia, unconsciousness, and death.
27
What type of receptors are glycine receptors in the spinal cord?
Ionotropic receptors.
28
What is the structure of glycine receptors?
They are pentamers made of α and β monomers with an internal chloride ion channel.
29
How many known α subunits are there for glycine receptors, and are there any metabotropic forms?
There are 4 known α subunits, and no metabotropic forms.
30
How is glycine cleared from the synapse?
Via transporters: GlyT1 moves glycine into astrocytes, and GlyT2 moves glycine into presynaptic neurons.
31
Are glycine receptors pharmacological targets?
No therapeutic drugs currently being used on
these receptors, although there has been considerable interest in modulating NMDA-R function using glycine.
32
What is strychnine
A competitive antagonist for glycine receptors, blocking access of glycine to its receptors.
When blocking inhibitory receptors, the result is a greater excitatory response - normal stimulation leads to severe muscle spasms.
33
Define anaesthesia.
A state characterized by loss of sensation; the result of pharmacological depression of nerve function or of neurological disease.
34
What is local anaesthesia?
The ability to have anaesthesia (loss of sensation) in a defined region of the body. Produced by direct application of a drug into the operative site. The goal is a reversible block of sensory perception of pain, with the patient’s consciousness maintained.
35
What are the three structural requirements of local anaesthetics (LAs)?
1) Lipophilic groups (aromatic ring), 2) Intermediate bond (ester or amide linkage), 3) Hydrophilic group (basic amine side chain; either tertiary or quaternary amino group). Rule: if it has two "i"s in its name, it’s an amide; one "i" indicates an ester. Common LAs include procaine, lidocaine, bupivacaine, and tetracaine.
36
Describe Procaine (Novocaine).
One of the first synthetic LAs, procaine is less toxic and addictive than cocaine. It has a long onset time, wears off quickly, is less potent than cocaine, and causes vasodilation (which limits its local effect). It is an ester and has a high potential to cause allergic reactions.
37
Describe the properties of Lidocaine/lignocaine.
Lidocaine is an amide, hypoallergenic, has a quick onset of anaesthetic effect, but causes vasodilation at the injection site, leading to rapid absorption away from the area.
38
How do we address the vasodilation issue with non-cocaine local anaesthetics?
Cocaine blocks NA reuptake transporters, increasing NA and causing vasoconstriction. Synthetic LAs lack this NA effect, leading to vasodilation and increased absorption before the LA effect completes. Synthetic LAs are often mixed with low concentrations of adrenaline to cause vasoconstriction, slowing blood flow and prolonging numbness.
39
What are some toxicity issues with lidocaine?
Side effects include drowsiness, tinnitus, dysguesia, dizziness, and twitching. At higher doses, seizures, coma, respiratory depression, and arrest may occur. Signs of toxicity can be remembered by "SAMS": Slurred or difficult speech, Altered cardiovascular system, Muscle twitching, and Seizures.
40
How and when are local anaesthetics used based on duration?
Ultra-short: 2% lignocaine (without vasoconstrictor)
Short: Procaine, lignocaine (1:100,000 epinephrine)
Intermediate: Articaine, mepivacaine, prilocaine, 2% lignocaine (1:200,000 epinephrine)
Long: Bupivacaine, etidocaine, 2% lignocaine (1:200,000 epinephrine)
41
What are examples of local anaesthetics (LAs) categorized by type?
Esters:
- Long action: tetracaine
- Short action: procaine
- Surface action: cocaine, benzocaine
Amides:
- Long action: bupivacaine, ropivacaine
- Medium action: lidocaine
42
Why is the pKa of a local anaesthetic important?
All LAs are weak bases that can exist as ionized (BH+) or unionized (B) forms. Acidic environments increase BH+ (ionized), while alkaline conditions increase B (unionized). LAs with a lower pKa are mostly unionized at pH 7.4, crossing membranes more easily for rapid onset. Higher pKa LAs are mostly charged and have a slower onset.
43
Why is membrane crossing important for local anaesthetics?
The binding site of LAs is on the inner surface of voltage-dependent Na+ channels, which can be in closed, open, or inactivated states. LAs bind to the inactivation gate, preventing channels from returning to the closed or open states.
44
Describe the Na+ channel block mechanism of LAs.
The block is concentration-dependent (effective in charged form), reversible, voltage-sensitive (greater with depolarization), and use-dependent (better access to inactivated channels).
45
How are local anaesthetics metabolized?
Amide LAs: Metabolized by cytochrome P450 enzymes in the liver, excreted in urine or stool. Caution needed in hepatic disease.
Ester LAs: Inactivated by plasma esterase enzymes.
46
Which nerve fibres are most affected by local anaesthetics?
LAs primarily affect small-diameter afferent neurons, especially myelinated (Aδ) and non-myelinated (C) fibres, making them effective for pain reduction. Larger motor neurons are less affected due to their larger diameter and surface area.
47
What are the adverse effects of local anaesthetics?
Temporary weakness or paralysis of the affected area. In high concentrations, CNS effects include tingling, visual disturbances, and tremors, followed by convulsions. Cardiovascular effects include reduced myocardial contractility and Na+ channel inhibition.
48
Describe bupivacaine’s binding affinity and cardiotoxicity.
Bupivacaine provides prolonged anaesthesia with sensory over motor block, making it ideal for labor or post-op analgesia. It is more cardiotoxic than lidocaine, causing severe ventricular arrhythmias at high systemic levels due to its slow dissociation from cardiac Na+ channels.
49
What factors influence the choice of local anaesthetics in dentistry and medicine?
Factors include procedure duration, vasoconstrictor use, cardiovascular health, infection presence, and potential for self-mutilation (e.g., in children). For post-op pain, long-acting LAs like bupivacaine are beneficial.
50
When would local or regional anaesthesia be preferred by anaesthetists?
Local anaesthesia avoids some risks (nausea, vomiting) of general anaesthesia, often lasts longer than the surgery for post-op relief, and may reduce blood loss.
51
In which cases might local anaesthesia not be suitable?
It may be unsuitable for major surgeries (e.g., abdominal), certain surgeons might prefer patients under general anaesthesia, and some patients cannot cope with being awake during surgery.
52
Define general anaesthesia and its components.
General anaesthesia is a state of loss of sensation, pain, and consciousness, usually achieved with intravenous or inhalation agents. It involves unconsciousness, analgesia, amnesia, muscle relaxation, and hemodynamic control.
53
What are the four stages of general anaesthesia?
Stage 1: Analgesia (loss of pain)
Stage 2: Excitement/delirium with heightened reflexes
Stage 3: Surgical anaesthesia with reflex loss
Stage 4: Medullary paralysis leading to respiratory failure (monitoring essential)
54
How is general anaesthesia typically induced and maintained clinically?
General anaesthesia (GA) is usually induced by an intravenous GA drug to achieve unconsciousness, followed by maintenance with an inhaled GA drug, often combined with opioids and neuromuscular blockers as needed.
55
What are the stages of general anaesthesia during clinical induction?
Analgesia: Preliminary introduction with sedatives or inhaled GA; preoxygenation.
Excitement (transition): Induction of GA with IV or inhaled agents, airway secured.
General Anaesthesia: Maintenance with adjusted IV or inhaled GA; avoiding under or overdosing.
Excitement (transition): Emergence from GA by stopping GA agents, reversing neuromuscular blockers, and managing potential issues like vomiting and shivering.
56
What is the mechanism of action (MOA) of general anaesthetics?
Early theories, like the "lipid theory," suggested that GAs worked by dissolving into nerve membranes. Modern understanding indicates GAs have specific receptor targets and isomer-specific potency, disproving the theory of a purely nonspecific membrane mechanism.
57
List common modern anaesthetic drugs.
Intravenous (PET): Propofol, Etomidate, Thiopental
Volatile (SIN): Sevoflurane, Isoflurane, Nitrous Oxide
Note: Inhaled GAs like halogenated hydrocarbons are volatile at room temperature, affecting synaptic transmission and neuron hyperpolarization.
58
How do GABAA receptors serve as targets for general anaesthetics?
Most GAs, except cyclopropane, ketamine, and xenon, act as positive allosteric modulators of GABAA receptors. They prolong channel opening, increasing postsynaptic inhibition, often with affinities for α- and β-subunits.
59
What is the effect of GAs on GABAA receptor subunits?
GAs modulate GABAA receptors, with varying affinities for different subunits, particularly at α- and β-subunit interfaces, which influences their effects on the receptor.
60
How do GAs interact with glycine receptors?
Certain inhalation anaesthetics are positive allosteric modulators of glycine receptors, which modulate responses to noxious stimuli in the spinal cord and brainstem. However, this effect is not universal across GAs; propofol and barbiturates do, while etomidate and ketamine do not.
61
How do NMDA glutamate receptors act as targets for some GAs?
Xenon, nitrous oxide, and ketamine primarily affect NMDA receptors instead of GABAA or glycine receptors. Xenon competes with glycine at an allosteric site, while ketamine blocks the NMDA pore, resulting in inhibition of excitatory transmission.
62
What role do two-pore domain K+ channels play in GA mechanisms?
TREK and TASK K+ channels, activated by low GA concentrations, reduce neuron excitability by promoting hyperpolarization. They are found pre- and post-synaptically and are usually open at rest, though IV GAs do not affect this mechanism.
63
What brain regions are affected by general anaesthesia?
Anaesthesia mainly reduces cerebral metabolic rate and blood flow in the thalamus, a sensory input hub. This suppression facilitates the transition to anaesthesia and affects natural sleep pathways. GAs also reduce hippocampal activity, contributing to amnesia.
64
Describe the ADME process of inhaled general anaesthetics.
Inhaled GAs move according to partial pressure gradients. Less soluble drugs cross the blood-brain barrier faster, while the brain, a blood-rich organ, equilibrates quickly. Poorly perfused areas have minimal influence on GA diffusion in most surgeries.
65
What is the Minimum Alveolar Concentration (MAC) unit in inhalation anaesthesia?
One MAC is the drug concentration at which 50% of patients show no motor response to surgical incision. Lower MAC values indicate higher potency, unaffected by duration, gender, or size, but lower in the elderly and higher in infants.
66
Describe the properties and action of Isoflurane.
Isoflurane, a clear liquid at room temperature, is vaporized for use. It modulates GABAA receptors, inhibits glutamate, potentiates glycine receptors, reduces gap junction activity, and antagonizes certain acetylcholine receptors, impacting multiple CNS pathways.
67
What are the effects of Desflurane?
Desflurane, a rapid-onset, rapid-recovery GA used in outpatient surgery, modulates GABAA, glycine, and potassium channels, and antagonizes glutamate receptors. It irritates airways, causing coughing and bronchospasm, so induction is typically via IV.
68
Describe the properties of Nitrous Oxide (N2O).
N2O, or "laughing gas," is a colourless, odourless gas with weak anaesthetic but strong analgesic effects. It modulates GABAA, glycine, and glutamate receptors and activates opioid receptors. It is insoluble in blood, enabling rapid induction and emergence.
69
What are the characteristics of Halothane?
Halothane is a non-explosive, pleasant-smelling anaesthetic with moderate induction speed. While potent, it is a poor analgesic, so it's often combined with N2O or opioids. It can cause postoperative hepatitis and hyperthermic crisis in genetically susceptible patients.
70
How are inhaled GAs cleared from the body?
Inhaled GAs are eliminated through exhalation, allowing rapid drug removal from the body. Oxygen is administered to displace the GA, reversing its effects without needing metabolism for clearance.
71
Why are intravenous anaesthetics primarily used for induction?
Intravenous GAs, due to their lipophilicity and rapid distribution, cause quick onset and short duration with a single bolus. They’re generally unsuitable for maintenance due to slower elimination compared to inhaled agents.
72
What are the properties of Propofol?
Propofol modulates GABAA receptors and slightly antagonizes glutamate receptors. It has a narrow therapeutic window and can cause respiratory depression, hypotension, and bradycardia. It's metabolized in the liver, with slower clearance in neonates and elderly.
73
Describe the concentration-response relationship of Propofol.
Propofol's effect depth correlates directly with plasma concentration, necessitating careful patient monitoring. Overdosing can lead to severe metabolic issues, especially in ill patients, so careful dosing is critical.
74
What are the properties of Thiopental sodium?
Thiopental is a barbiturate, modulating GABAA receptors. It provides rapid, smooth onset and short action, making it less ideal for long procedures. It is slowly metabolized in the liver and excreted in urine.
75
What are the effects of Etomidate?
Etomidate, a non-barbiturate hypnotic, modulates GABAA receptors without providing analgesia. It induces unconsciousness rapidly with minimal respiratory depression, but common side effects include nausea and vomiting.
76
What does a steep concentration-response curve indicate in GA?
GA-induced loss of consciousness occurs over a narrow concentration range, with genetic variability, pharmacokinetics, and age broadening this range across populations. Older patients often require lower doses for effectiveness.
77
What are the risks of being conscious but paralyzed during surgery?
This rare event is usually prevented by monitoring vital signs. Drug and alcohol abusers may need higher doses due to cross-tolerance, but brain wave monitoring helps ensure adequate anaesthesia levels during surgery.
78
Describe the components of a pharmacological "symphony" in general anaesthesia.
- Sedative or anxiolytic premedication (e.g., benzodiazepine)
- IV anaesthetic for induction (e.g., propofol)
- Perioperative opioid analgesic (e.g., remifentanil)
- Inhaled anaesthetic for maintenance (e.g., nitrous oxide)
- Neuromuscular blocker for muscle relaxation (e.g., vecuronium)
- Antiemetic (e.g., ondansetron)
- Muscarinic antagonist for bradycardia and secretion reduction (e.g., atropine)
- At end of procedure: anticholinesterase (e.g., neostigmine) and analgesic for post-op pain (e.g., morphine).
79
How is the innate immune system activated, and what are DAMPs and PAMPs?
The innate immune system is activated by molecular patterns associated with injury (e.g., ischemia, trauma) or infection.
DAMPs: Damage-Associated Molecular Patterns from cellular damage (e.g., K+, DNA, H+, ATP, warning proteins).
PAMPs: Pathogen-Associated Molecular Patterns from pathogen components (e.g., viral proteins, bacterial cell walls).
80
Define the innate immune system and its purpose.
he innate immune system is a "non-specific" first line of defense against cell injury or infection.
Purpose:
- Localize and eliminate the injurious agent.
- Remove damaged tissue components.
- Allow the body to begin healing.
81
What are the 5 cardinal signs of inflammation?
1. Redness
2. Heat
3. Swelling
4. Pain
5. Decreased function
(Systemic sign: Fever)
82
What are the two phases of acute inflammation?
1. Vascular phase
2. Cellular phase
83
Describe the vascular phase of acute inflammation.
1. Injured cells, sensory neurons, and resident immune cells release chemical mediators.
2. Chemical mediators cause vasodilation (warmth) and increase capillary permeability, leading to plasma protein influx and inflammation (swelling, redness).
3. Plasma proteins cause blood clotting, activate the complement system, and produce kinins.
4. The complement system and chemokines attract phagocytic white blood cells (e.g., monocytes, neutrophils) to the injury site.
84
Describe the cellular phase of acute inflammation.
Neutrophils and macrophages enter inflamed tissue through leaky blood capillaries.
Phagocytic cells: Ingest pathogens, dead cells, and debris; release cytokines to enhance inflammation and pyrogens to induce fever.
85
What is chronic inflammation, and what are some examples?
Chronic inflammation lasts for 2 weeks or more, often due to the inability to remove the cause.
Examples:
- Arthritis (osteoarthritis, rheumatoid arthritis)
- Crohn’s disease and IBD
- Asthma / COPD
- Tuberculosis: (It often involves lymphocytes and monocytes/macrophages, causing local tissue damage, fibrosis, and scarring).
86
List some inflammatory mediators.
- Eicosanoids: Arachidonic acid metabolites like prostaglandins (PGs), leukotrienes (LTs), thromboxane.
- Histamine: Stored in mast cells, mainly mediates allergic reactions.
- Platelet-activating factor (PAF) and C5a: These are synthesized and released in response to inflammatory stimuli.
87
Describe the inflammatory synthetic process.
- Inflammatory stimulus → arachidonic acid (esterified to membrane phospholipids).
- Phospholipase A2 enzyme releases free cytosolic arachidonic acid.
- Leads to production of prostanoids like PGs, prostacyclin (PGI2), and thromboxanes.
88
What is an overview of inflammatory mediators?
- COX (Cyclooxygenase): Produces prostaglandins (PGs) and prostacyclin (PGI2).
- LOX (Lipoxygenase): Produces leukotrienes (LTs).
- CYP (Cytochrome P450): Involved in epoxyeicosatrienoic acid (EET) and hydroxyeicosatetraenoic acid (HETE) production.
89
What are the roles of prostaglandins (PGs) in inflammation?
- Vasodilation
- Altered platelet function
- Hyperalgesia (increased sensitivity to pain)
- Bronchoconstriction
- Uterine contraction
- Fever
90
How do prostanoids bring about their effects?
Prostanoids act through G-protein coupled receptors (GPCRs).
Examples:
- PGE2, PGI2, PGD2: Cause vasodilation and lower BP.
- PGF2a: Causes constriction of pulmonary arteries and veins.
91
Which endogenous agents reduce PLA2 activity?
Endogenous corticosteroids (from adrenal cortex):
- Mineralocorticoids: Involved in water and electrolyte balance (e.g., aldosterone).
- Glucocorticoids: Influence metabolism and defense (e.g., cortisol).
Exogenous glucocorticoids (e.g., hydrocortisone, prednisolone, dexamethasone): Anti-inflammatory effects with reduced mineralocorticoid activity.
92
What are SAIDs, and what is their physiological role?
SAIDs: Glucocorticosteroids (e.g., prednisolone, hydrocortisone).
Role: Glucose homeostasis under stress.
Function: SAIDs reduce inflammation, have immunosuppressive effects, and can cause side effects due to their potency.
93
What is the main anti-inflammatory mechanism of action of SAIDs?
Lipocortin-1 inhibits phospholipase A2.
Reduces expression of COX enzymes.
Result: Reduced prostaglandin production and decreased inflammation.
94
Summarize the actions of corticosteroids (SAIDs).
Bind to intracellular glucocorticoid receptors.
Enter the nucleus, altering gene expression to upregulate anti-inflammatory genes (e.g., IL-10, lipocortin-1) and inhibit pro-inflammatory pathways.
Result: Immunosuppression, allergy control, reduced cytokines and chemokines.
95
What are some anti-inflammatory indications of corticosteroids?
- Transplant rejection (with other immunosuppressants)
- Rheumatoid arthritis (injected into joints)
- IBD, Crohn’s disease, ulcerative colitis
- Psoriasis, lupus, asthma/allergies
- Septic shock (restores cardiac output and raises BP)
96
What are potential side effects of corticosteroids?
- Increased infection risk (immunosuppressive)
- Hyperglycemia (worsens diabetes)
- Na+ and water retention (hypertension, heart failure)
- Peptic ulcers, osteoporosis
- Ca2+ absorption issues, vitamin D inhibition
97
What are NSAIDs, and what effects do they provide?
NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): Inhibit COX-1 & 2 to reduce prostaglandin synthesis.
Effects: Anti-inflammatory, antipyretic, analgesic.
Common uses: Arthritis, fractures, soft tissue injuries, dental pain, menstrual pain, headaches.
98
Differentiate COX-1 and COX-2 enzymes.
COX-1: Produces protective PGs (gastric protection, platelet aggregation, renal blood flow).
COX-2: Produces inflammatory PGs (pain sensitivity, fever, cell recruitment).
99
Explain the antipyretic effects of NSAIDs.
NSAIDs inhibit PGE2 synthesis in the hypothalamus, returning the body's temperature set-point to normal and allowing normal thermoregulation.
100
Describe the antithrombotic effects of aspirin.
Aspirin permanently acetylates platelet COX-1, blocking thromboxane production, leading to reduced clotting and prolonged bleeding time (doubles with one dose for 5 days).
101
What are common side effects of NSAIDs?
Gastrointestinal: Reduced mucosal protection, irritation.
Renal: Decreased renal blood flow, nephrotoxicity.
Cardiovascular: Prolonged bleeding time.
Other: Skin rashes, photosensitivity.
102
What are the effects of aspirin, and what conditions should avoid its use?
Effects: Analgesic, anti-inflammatory, antipyretic, antiplatelet.
Conditions to avoid: Surgery (bleeding risk), late pregnancy, children under 12 with viral fever (Reye's syndrome risk).
103
What are major side effects of aspirin?
- Gastric irritation and ulceration
- Bleeding risk
- Nephrotoxicity
- Tinnitus, confusion, coma
- Reye’s syndrome in children with viral illness
104
What are the effects and uses of Naproxen?
Class: Propionic acids
Mechanism: Competitive, reversible COX-1 & COX-2 inhibitor (more selective for COX-1).
Effects:
- Strong anti-inflammatory effect (more than aspirin).
- Effective for menstrual pain (best if taken before pain sets in).
- Longer pain relief duration than ibuprofen.
- Used for headaches, arthritis, and menstrual pain.
Adverse effects:
- Increased thrombosis risk.
- Some gastric irritation (less severe than aspirin).
- Better tolerated than other NSAIDs but may affect liver more than ibuprofen.
105
Describe the effects and adverse effects of Indomethacin.
Class: Indolacetic acid
Mechanism: Competitive, reversible COX-1 & COX-2 inhibitor (more selective for COX-1).
Effects:
- Most potent anti-inflammatory effect among NSAIDs.
- 10x more effective as an analgesic than aspirin.
- Generally used for gout and arthritis due to toxicity.
Adverse effects:
- Severe GI toxicity and cardiovascular side effects.
- Contraindicated in children under 14 and during pregnancy.
106
What are the effects and risks associated with Diclofenac?
Class: Fenamate
Mechanism: Competitive, reversible COX-1 & COX-2 inhibitor (more COX-2 selective).
Effects:
- Potent analgesic (also inhibits lipoxygenase and phospholipase A2).
- Longest analgesic duration (6-8 hours).
- Used for chronic inflammatory conditions.
- Available as a topical gel (e.g., Voltaren).
Adverse effects:
- Increased cardiovascular risk.
- GI disturbances in 20% of patients.
- Risk of liver damage and hypersensitivity reactions with topical use.
107
What are the effects and uses of Ibuprofen?
Class: Propionic acids
Mechanism: Competitive, reversible COX-1 & COX-2 inhibitor (more COX-2 selective).
Effects:
- Strong anti-inflammatory effect, effective for arthritis.
- Good for menstrual pain, especially if taken before onset.
- Safe for use in children.
Adverse effects:
- Can increase thrombosis risk.
- Some gastric irritation (less severe than aspirin).
- Better tolerated than other NSAIDs.
108
What are the uses and adverse effects of Celecoxib?
Mechanism: COX-2 specific inhibitor
Uses:
- Rheumatoid and osteoarthritis treatment.
- For patients who cannot tolerate traditional NSAIDs due to GI issues.
Adverse effects:
- Increased cardiovascular risk (heart attack, stroke).
- GI bleeding risk (COX-2's role in healing gastric ulcers may be inhibited).
109
Why does Celecoxib cause cardiovascular effects?
COX-2 function: Produces prostacyclin (PGI2), an antithrombotic and vasodilator.
Inhibition of COX-2: Reduces PGI2, causing potential platelet aggregation and vasoconstriction.
Kidney effects: COX-2 also regulates renal blood flow, Na excretion, and renin release. Inhibition can lead to hypertension and edema.
110
What are the effects and adverse effects of Paracetamol (Acetaminophen)?
Mechanism: Believed to be COX-3 selective in the CNS.
Effects:
- Good analgesic and strong antipyretic.
- Weak anti-inflammatory effect.
- Well-tolerated and suitable for patients with GIT issues.
Adverse effects:
- Hepatotoxic in overdose due to liver metabolism.
- Chronic use may lead to nephrotoxicity.
- Toxicity can cause hepatic necrosis, fatal at 20-30g.
111
What is hepatotoxicity, and how is it related to Paracetamol overdose?
Cause: Due to formation of a toxic reactive intermediary during liver metabolism.
Signs: Appear 2-4 days post-overdose, with increased liver enzymes and bilirubin levels.
Outcome: Untreated patients have a risk of fatal liver failure, especially with high doses (10g or more).
112
Define nociception and pain.
Nociception: The physiological ability to sense pain, as encoded by nociceptor stimulation.
Pain: Combination of nociception and the subjective (emotional) experience, which can vary widely among individuals.
113
Describe the signaling involved in acute pain and inflammation.
To the spinal cord: Nociceptive input is transmitted to the spinal cord and brain via the spinothalamic pathway.
Modulation: The ascending transmission is modulated by descending inhibitory pathways from the brain to the spinal cord's dorsal horn, which are rich in opioid receptors and can be utilized medicinally.
114
Explain the descending pain control pathway regions rich in opioid receptors.
Pathway: Cortical brain regions project to the periaqueductal grey (PAG) in the midbrain, the rostral ventromedial medulla (RVM), and the dorsolateral funiculus in the spinal cord.
Function: This pathway is essential for endogenous pain management, utilizing serotonin (5-HT) and enkephalins, which block spinothalamic pain transmission.
115
What are the key points about opioids in pain transmission?
- Pain signals travel via the spinothalamic tract to brain regions rich in opioid receptors, which play a role in pain reduction.
- Opioid receptors are crucial in the body's pain management, decreasing pain signaling when activated.
- Pain perception varies among patients; opioids are reserved for severe pain requiring management.
116
What are opioid receptors, and how do they work?
Type: Family of GPCRs (Gi) that, when activated, decrease adenylyl cyclase function and neurotransmitter release.
Effect: May cause hyperpolarization and reduced neurotransmitter release, inhibiting synaptic function and often reducing glutamate release.
117
List the types of opioid receptors and their endogenous agonists.
Types:
- MOP (mu opioid receptor)
- DOP (delta opioid receptor)
- KOP (kappa opioid receptor)
- NOP (nociceptin/orphanin FQ peptide receptor)
Endogenous agonists: Endorphins, enkephalins, dynorphins, etc.
About 75% of opioid receptors are MOP and are presynaptic in the CNS.
118
How does opioid activity impact nociception transmission?
Opioid activity reduces afferent signaling pathway activity and enhances descending inhibitory pathways, resulting in reduced nociception and pain perception.
119
What are some key points about opioids and their mechanism?
Opioids include both natural (codeine, morphine) and synthetic compounds that interact with opioid receptors in pain pathways.
Opioid receptors are GPCRs that inhibit adenylyl cyclase or increase K+ flow, inhibiting pain transmission.
Activation of opioid receptors reduces pain signaling, providing relief.
120
What classes of opioids exist?
Full agonists: Heroin, morphine, oxycodone, meperidine, fentanyl
Partial mu-receptor agonist: Buprenorphine
Mu-receptor antagonist: Naloxone
Blood-brain barrier (BBB) penetration is generally not an issue for these drugs.
121
How do opioids cause respiratory depression?
Opioids inhibit respiratory centers in the medulla and pons, reducing respiratory rate and tidal volume.
With overdose, breathing rate can fall to 3-4 breaths per minute.
This effect is reversible with opioid antagonists like naloxone, primarily targeting µ receptors.
122
What is the miosis effect seen in opioid overdose?
Miosis: Constriction of the pupils, a key diagnostic sign of opioid overdose, unchanging with repeated use.
Cause: Opioids stimulate the Edinger-Westphal nucleus of cranial nerve III, increasing parasympathetic tone and causing iris constriction.
123
How do opioids lead to constipation?
Opioids increase intestinal circular contractions, reduce coordinated peristalsis, and decrease secretion of fluids, leading to dry, hard stools.
Constipation tolerance does not develop with repeated opioid use.
124
Why do opioids cause nausea and vomiting?
The chemoreceptor trigger zone (CTZ) may detect opioids, signaling the vomiting center.
Opioids may stimulate the vestibular system, causing nausea.
Nausea occurs in ~45% of patients, but tolerance develops over time.
125
Describe the ADME properties of Codeine and Morphine.
Codeine: Greater bioavailability due to less first-pass metabolism than morphine; converted to morphine by CYP2D6.
Morphine: Well-absorbed in the gut, extensive first-pass metabolism in the liver; dosing may need adjustment in hepatic disease.
126
Which enzymes are involved in opioid metabolism?
CYP2D6 and CYP3A4, along with glucuronidation, play major roles in opioid metabolism.
127
Explain the difference between full and partial opioid agonists.
Full agonists: High affinity for MOP, generally well-tolerated at doses for severe pain.
Partial agonists: Cause intolerable side effects at doses needed for severe pain relief; often combined with NSAIDs for moderate pain.
128
What are examples of strong, mild, and mixed-action opioids?
Strong agonists: Morphine, fentanyl, methadone
Mild agonists: Hydrocodone, pethidine
Mixed actions: Buprenorphine
129
Why is morphine considered the "gold standard" opioid?
Used for severe pain management, with tolerance developing over time.
Tolerance varies across effects, with less tolerance to constipation than to analgesia or respiratory depression.
130
How is methadone used in opioid addiction treatment?
Long-acting synthetic agonist used to reduce heroin use and associated risks.
Given once daily to control withdrawal, commonly used in methadone maintenance programs.
131
What is hydrocodone (Vicodin)?
A semi-synthetic, moderate opioid agonist often combined with NSAIDs for pain management.
132
What are the properties of pethidine?
A synthetic, moderate opioid causing euphoria and restlessness, preferred during labor as it does not impact uterine function.
Slow elimination may affect neonates with respiratory depression.
133
Describe the use of buprenorphine in opioid addiction treatment.
Partial agonist with a ceiling effect on respiratory depression, reducing overdose risk.
Often combined with naloxone (Suboxone) to prevent misuse via injection.
134
What are naloxone and naltrexone, and how are they used?
Naloxone: Short-acting opioid antagonist used to reverse respiratory depression in overdose.
Naltrexone: Long-acting, orally bioavailable, useful in narcotic treatment due to its extended effects.
135
Summarize key points about opioid effects beyond pain relief.
Effects like hypotension and constipation are common, with tolerance varying by effect.
Respiratory depression, pin-point pupils, and death may occur with high doses.
Antagonists (e.g., naloxone) can reverse life-threatening effects.
136
Outline the general pain management plan.
Step 1 (mild pain, 1-3): Non-opioid (NSAID) + non-pharmacological options ± adjuvants.
Step 2 (moderate pain, 4-6): Non-opioid and weak opioid combination + non-pharmacological options ± adjuvants.
Step 3 (severe pain, 7-10): Strong opioid ± adjuvants + non-pharmacological options.
137
What is physical dependence?
Occurs when pharmacological adaptation leads to tolerance, requiring more drug to achieve the same effect. If the drug is stopped, withdrawal symptoms emerge due to these adaptations, indicating physical dependence.
138
What is psychological dependence?
Involves emotional-motivational withdrawal symptoms. Many daily drug users show both physical and psychological dependence.
139
Define addiction.
Addiction is a condition in which a small minority of drug users develop compulsive and out-of-control drug use as a component of physical dependence.
140
What are the origins of substance dependence?
Substance dependence can be influenced by variables categorized into three areas: the agent (drug), the host (user), and the environment of use. Reinforcement, or the drug's ability to produce reuse-desirable effects, also increases the likelihood of dependence.
141
Explain drug dependence in terms of brain mechanisms.
The brain’s reward mechanisms, involving D2 receptors in the nucleus accumbens, play a role in the reward dimension of addiction. Genetics may also influence susceptibility to addiction.
142
What is innate tolerance?
Innate tolerance is a genetic lack of sensitivity to a drug observed even in first-time use.
143
Define acquired tolerance.
Acquired tolerance develops due to prolonged exposure, either through pharmacokinetic changes (distribution and metabolism) or pharmacodynamic changes (receptor regulation).
144
What is acute tolerance?
Acute tolerance is a process where the brain and CNS immediately mitigate a substance's effects, resulting in a decreasing drug effect relative to drug-plasma levels over minutes to hours.
145
Describe reverse tolerance.
Reverse tolerance occurs when the body’s response to the same dose of a drug increases over time rather than decreases.
146
What is cross-tolerance?
Cross-tolerance is when repeated use of one drug affects tolerance to other drug classes.
147
How are animal models used in drug research?
Animals, like rats, are often used to model drug self-administration, with dopamine released in the nucleus accumbens when a rat self-administers reinforcing stimuli.
148
Describe the reward pathways in the brain for rats and humans.
The reward pathways include dopamine release from the mesolimbic system, with the nucleus accumbens, VTA, and prefrontal cortex playing key roles. Collateral communication also involves the amygdala and hippocampus, impacting affective and memory systems.
149
What common physiological effect is shared by many abused substances?
Many abused substances increase dopamine (DA) release in the nucleus accumbens. Blocking DA receptors in this area can lead to dysphoria.
150
What role does the dopamine D2 receptor play in addiction?
D2 receptors in the nucleus accumbens are involved in the reward aspects of addiction, though not in withdrawal, as shown in studies with transgenic mice.
151
How does the brain cope with change in response to drugs?
The CNS has "plasticity," allowing it to adapt by altering receptor numbers in response to drugs, depending on concentration and duration of exposure.
152
Explain how ligand-receptor interactions can lead to long-term changes in the CNS.
Drugs can alter endogenous ligand release or act as ligands, initiating signaling cascades that may lead to changes in protein expression, potentially causing irreversible neuroplastic changes.
153
What factors affect a drug's abuse liability?
Factors include rapidity of onset, availability, cost, purity/potency, and mode of administration (chewing, GI, intranasal, subcutaneous, IV, inhalation).
154
Describe opioid dependence mechanisms.
Opioids like heroin act on µ and D2 receptors, reducing GABA's inhibitory effect on DA neurons, increasing DA release and leading to tolerance through decreased adenyl cyclase activity and receptor uncoupling.
155
Explain the mechanism of cocaine dependence.
Cocaine blocks DA reuptake transporters, increasing dopamine concentration in the synaptic cleft and producing euphoria.
156
What is a "speedball"?
A combination of opioid and cocaine, which synergistically increases dopamine in reward pathways due to differing mechanisms of action.
157
What are the pharmacological effects of cannabis?
Cannabis is lipophilic and stored in body fat, with effects including CNS depression, relaxation, heightened senses, analgesia, antiemesis, and slight bronchodilation. CB1 and CB2 receptors mediate these effects.
158
How does overdose vary between opioids and stimulants?
Opioid and alcohol overdoses suppress breathing, while stimulant overdoses cause indirect increases in norepinephrine, potentially leading to death.
159
What are the types of withdrawal?
Precipitated withdrawal: Occurs when an antagonist displaces the drug, causing rapid and intense effects.
Spontaneous withdrawal: When drug use ceases naturally, symptoms often oppose the drug’s effects.
160
How are substance addictions treated?
Heroin: Treated with methadone to stabilize.
Nicotine: Treated with bupropion (noncompetitive nicotine antagonist).
Alcohol: Treated with naltrexone (opioid receptor antagonist).
161
What is the mechanism of action of amphetamines?
Amphetamines competitively inhibit DA transport and interfere with VMAT, increasing dopamine concentration.
162
Describe nicotine's effects and tolerance development.
Low doses stimulate, while high doses relax. Nicotine temporarily stimulates all ganglia and the CNS, followed by depression and receptor desensitization, leading to reduced effects with the same dose.
163
How is ethanol absorbed and metabolized?
Rapidly absorbed in the GI tract with first-pass metabolism that quickly saturates. Chronic exposure alters GABA A receptor composition, reducing positive allosteric effects.
164
What are ethanol's effects on the CNS?
Ethanol enhances GABA A-mediated inhibition, inhibits NMDA receptors, and reduces voltage-dependent Ca2+ channel opening, causing overall depressant effects.
165
Explain cross-tolerance of alcohol.
Chronic ethanol use can produce tolerance to alcohol and cross-tolerance to benzodiazepines.
166
What is serotonin (5-HT) and how is it synthesized?
Serotonin (5-HT) is synthesized from the amino acid tryptophan, which is actively transported across the BBB by a carrier protein and then enzymatically converted to serotonin in serotonergic neurons.
167
What are dopamine and noradrenaline, and what is their precursor?
Tyrosine is the precursor, leading to the synthesis pathway: Tyrosine -> L-DOPA -> Dopamine -> Noradrenaline -> Adrenaline. Dopaminergic neurons lack DbH, so they cannot make noradrenaline.
168
Describe common features of monoamine synapses.
Monoamine synapses have presynaptic VMAT-2 for sequestering neurotransmitters into vesicles, presynaptic receptors, autoreceptors, and postsynaptic receptors. They use presynaptic reuptake transporters (DAT, NET, SERT), which share homology and are targeted by pharmacological agents.
169
How is serotonin (5-HT) metabolized?
Serotonin is broken down enzymatically by monoamine oxidase (MAO) to 5-hydroxyindole acetic acid (5-HIAA), which is transported out of the CNS and excreted in the urine.
170
Describe the synthesis and metabolism of catecholamines.
Tyrosine is converted through a series of steps to dopamine, noradrenaline, and adrenaline. Metabolism involves MAO and COMT enzymes, creating metabolites like HVA and VMA, which can indicate systemic monoamine levels when measured in urine.
171
Where are noradrenergic pathways located in the CNS?
Noradrenergic cell bodies are in the pons and medulla, with the locus coeruleus (LC) in the pons involved in arousal and descending pain control.
172
What are the roles of noradrenergic receptors in the CNS?
Alpha1 receptors may affect motor control and cognition, alpha2 receptors influence blood pressure and analgesia, beta1 receptors are in higher brain regions, and beta2 receptors are in the cerebellum.
173
How is serotonin (5-HT) processed in the CNS?
5-HT is sequestered into vesicles by VMAT2 and cleared by SERT. It has various GPCR and ionotropic receptors and autoreceptors for self-regulation.
174
What are 5-HT autoreceptors, and where are they located?
5-HT autoreceptors like 5-HT1A decrease neuronal firing, while 5-HT1D in humans and 5-HT1B in rodents modulate 5-HT release presynaptically.
175
How do 5-HT receptor subtypes signal?
5-HT receptors are categorized into seven families (5-HT1 to 5-HT7) and mostly use GPCR signaling, except for 5-HT3, which is ionotropic, forming a Na+ and Ca2+ pore.
176
Where are serotonergic pathways located in the CNS?
Serotonergic pathways mirror noradrenergic ones, with cell bodies in the pons and upper medulla (raphe nuclei) and projections throughout the CNS.
177
What functions are associated with 5-HT activity or depletion?
5-HT affects arousal, mood, aggression, appetite, and migraines. Depletion can lead to insomnia, impulsive behavior, and increased appetite.
178
What are some pharmacological uses of the 5-HT system?
Drugs targeting the 5-HT system include buspirone for anxiety, triptans for migraines, SSRIs for depression, and MDMA for mood alteration.
179
How are serotonin and noradrenaline involved in treating depression?
Antidepressants increase synaptic concentrations of serotonin and noradrenaline by inhibiting their reuptake or metabolism, addressing imbalances linked to Major Depressive Disorder.
180
What are the main dopaminergic pathways in the brain?
Dopaminergic pathways include the mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular tracts, each linked to different functions such as cognition, pleasure, movement, and prolactin inhibition.
181
Outline dopamine synthesis.
Dopamine is synthesized from L-tyrosine to L-DOPA and then to dopamine.
182
How is dopamine metabolized?
Dopamine is metabolized by enzymes like COMT and MAO, followed by aldehyde dehydrogenase to produce metabolites that are eventually excreted.
183
Describe dopamine reuptake by DATs.
Dopamine reuptake is energy-dependent, driven by Na+/K+-ATPase gradients, where Na+ and Cl- ions assist dopamine transport back into the presynaptic neuron.
184
How do D1 and D2 dopamine receptors differ in structure?
D2-like receptors have a shorter COOH-terminal tail and a larger third intracellular loop, indicating different second messenger actions compared to D1-like receptors.
185
Describe dopamine receptor signal transduction.
D1/D5 receptors link through Gs to activate PKA, affecting ion channels, while D2/D3/D4 receptors link through Gi/Go, inhibiting Ca channels and adenylyl cyclase, affecting neurotransmission.
186
Where are dopamine receptors located in synapses?
D1 receptors are mostly postsynaptic, while D2 and D3 receptors are pre- and postsynaptic. D2 receptors are primary autoreceptors, decreasing dopamine release when activated presynaptically.
187
What functions do dopaminergic tracts serve?
Nigrostriatal controls movement, mesolimbic is associated with pleasure, mesocortical affects cognition and mood, and tuberoinfundibular inhibits prolactin secretion.
188
What role does dopamine play in nausea and vomiting?
Dopamine in the CTZ can trigger vomiting, which is why D2 antagonists can serve as antiemetics.
189
What disorders are associated with dopaminergic function?
Parkinson’s Disease, substance abuse, schizophrenia, depression, and ADHD involve abnormalities in dopaminergic tracts.
190
How do cocaine and amphetamines affect monoamines?
Amphetamines increase dopamine and noradrenaline, causing euphoria and heightened concentration. Cocaine blocks reuptake, increasing dopamine and noradrenaline, leading to dependence.
191
How does cocaine work as a local anesthetic?
A: Cocaine has local anesthetic properties by blocking sodium channels at the cellular level.
Cocaine has local anesthetic properties by blocking sodium channels at the cellular level.
192
Describe the effects of systemic cocaine use.
Systemic cocaine blocks reuptake transporters, causing vasoconstriction, arrhythmias, and potential dependency due to increased dopamine.
193
How does amphetamine increase dopamine levels?
Amphetamine competes for DAT, enters the neuron, and disrupts vesicle loading, causing non-vesicular dopamine release and increased extracellular dopamine.
194
What differentiates methamphetamine from amphetamine?
Methamphetamine crosses the BBB at higher concentrations than amphetamine, causing more intense stimulation and longer-lasting effects.
195
What are the short- and long-term effects of methamphetamine?
Short-term: increased attention, euphoria, respiration, and wakefulness.
Long-term: addiction, psychosis, brain changes, cognitive deficits, and weight loss due to dopamine involvement in motivation and pleasure.
