BP Theme 2 Flashcards
what is the peripheral nervous system made up of
sensory nervous system
autonomic nervous system
somatic nervous system
what is the autonomic nervous system made up of
sympathetic and parasympathetic ns
what occurs in the sympathetic (fight or flight) response
Pupils dilate (peripheral vision) Lens of eye adjust for far vision Airways in lungs dilate Respiratory rate increases Heart rate increases Blood vessels to limb muscles dilate Blood vessels to visceral organs constrict Salivary secretions reduced Brain activity general alertness
what occurs in the parasympathetic (fight or flight) response
Pupils constrict Lens of eye readjust for closer vision Airways in lungs constrict Respiratory rate decrease Heart rate decrease Blood vessels to limb muscles constrict Blood vessels to visceral organs more dilated Salivary secretions normalise Brain activity normalise
what are the pre and post ganglionic neurotransmitters for the sympathetic system
preganglionic- ACh
postganglionic- NA
what are the pre and post ganglionic neurotransmitters for the parasympathetic system
preganglionic ACh
post ganglionic ACh
what is the organisation like for the somatic efferent system
ACh released at neuromuscular junction
what are the exceptions for the sympathetic nervous system
sweat glands
-the pre and post ganglionic fibres contain ACh
adrenal glands
-adrenaline is released from the adrenal glands. ACh activates adrenal medulla which releases adrenaline into the blood stream
what is the pharmacology of ACh
Synthesis- choline/choline acetyl transferase
Storage- vesicles
Release- exocytotic
Receptor interaction- muscarinic/nicotinic
Termination- in synapse by acetylcholine esterase
what are the 2 classes of receptors that the actions of ACh are mediated by
muscarinic receptors - affinity for an extract fly agaric mushroom
nicotinic receptors- affinity for tobacco farm
what are the 3 main muscarinic receptor (mACh) subtypes and where are they located
M1,2,3
G-protein coupled receptor
Located at postganglionic parasympathetic synapses on target organs
what are the 2 main nicotinic (nACh) receptor subtypes
neuronal type- brain and autonomic ganglia (excitatory)
muscle-type- neuromuscular junction (NMJ) (excitatory)
what are the characteristics of cholinergic muscarinic receptors
g-protein coupled
slow response
mainly located on effector tissues
muscarine
what are the characteristics of cholinergic nicotinic receptors
ligand gated ion channels
fast response (milliseconds)
located in ganglia and on NMJ
nicotine
what effects to muscarinic receptors mainly mediate
parasympathetic effects
what are the effects of muscarinic agonists
parasympathetic activation
stimulate muscle receptors-increase in pupil constriction and decrease in focal length
bronchoconstriction- decrease in cardiac output, increase GI motility, increase exocrine gland secretion
what are muscarinic agonists known as
parasympathomimetics
what are the effects of muscarinic antagonist
pupil dilate
Increase in focal length of the lens
Bronchodilation
- Increase in cardiac output, (rate & force)
- Decrease GI motility
- Decrease exocrine gland secretion(dry mouth decreased sweating)
what are Muscarinic antagonists known as
parasympatholytic
what are the clinical uses of muscarinic agonists
Pilocarpine used to treat Glaucoma - build up of aqueous humour behind the lens
Treatment of xerostomia
Use Pilocarpine stimulates saliva secretions
what are the clinical uses of Muscarinic receptor antagonist
Tropocamide-
Pupil dilation in eye surgery
Atropia
Decrease oral/respiratory secretions before oral procedures and as an adjunct to anaesthesia
Atropine
Resuscitation in bradycardia (causes increase heart rate)
Ipratropium-
Asthma (causes bronchodilation)
Hyoscine
Motion sickness- Orally it decreases gastric motility
where are neuronal type nicotinic receptors receptors located
both ps and symp ganglia
what are the effects of agonists for neuronal type nicotinic receptors (nicotine)
sympathetic:
vasoconstriction, tachycardia, hypertension
parasympathetic:
bradycardia, hypotension, increase GIT motility, increase secretions
why are Ganglionic\neuronal nicotinic agonists not clinically useful.
The effect of agonists activating both systems is autonomic confusion
what are the effects of antagonists for neuronal type nicotinic receptors
loss of sympathetic & parasympathetic reflexes, especially cardiac
Ganglionic\neuronal nicotinic antagonists are not of great therapeutic value
where are muscle type nicotinic receptors receptors located
Located at the NMJ
what does stimulation of muscle type nicotinic receptors by ACh cause
depolarisation (in muscle fibre this is known as an end plate potential (EPP)) and contraction of the skeletal muscle fibre
what does agonist action on muscle type nicotinic receptors do
causes contraction of skeletal muscle and antagonist will block this.
what is a clinical example of the agonist for muscle type nicotinic receptors
Suxemethonium
what is a clinical example of the antagonist for muscle type nicotinic receptors
Tubocurarine
what is the clinical effect of nicotinic agonists at neuromuscular junction
Initial depolarisation/EPP and muscle fibre contraction (muscle twitch)
Paralysis / muscle relaxation (for surgery)
Depolarising block
what is the clinical effect of nicotinic antagonists at neuromuscular junction
Hyperpolarisation, inhibition of EPPs
Muscle fibre relaxation
Paralysis (for surgery)
Non-depolarising blocker
what is ACh release inhibited by
toxins: botulinum toxin, & bungarotoxin
what occurs in BOTOX
Botulinum toxin injected locally is used to treat muscle spasm, and in plastic surgery
neuromuscular block and paralysis/loss of wrinkles
what are the Therapeutic targets for drugs affecting cholinergic transmission
receptors
drug release
termination
how do anticholinesterases work
Acetylcholinesterase the enzyme responsible for the metabolism of ACh and termination of the action of ACh can be inhibited
This will increase ACh transmission
what are the Effects of anticholinesterase on the autonomic nervous system
Reflect increased transmission at parasympathetic postganglionic synapses- increase secretions, bradycardia, hypotension, pupil constriction
what are the Effects of anticholinesterase on the neuromuscular nervous system
Increased muscle tension and twitching, at large doses causes a depolarising block.
At lower doses Neostigmine used to treat myasthenia gravis (autoimmune disease, circulating antibodies against muscle nicotinic receptors)
what is the drug for anticholineresterases that induce paralysis for surgery
neostigmine
which drug is used to treat glaucoma and xerostomia and what class of drug is are they
pilocarpine
muscarinic agonists
which drugs are used to decrease secretion and cause pupil dilation in eye surgery and what class of drug is are they
atropine
tropicamide
muscarinic antagonist
which drug is used to treat asthma and what class of drug are they
ipratropium
muscarinic antagonist
which drug is used to decrease gastric motility and motion sickness and what class of drug are they
hyoscine
muscarinic antagonist
what drugs induce paralysis for surgery and what class of drug are they
suxamethonium- nicotinic AGONIST
tubocurare- nicotinic ANTAGONIST
neostigmine- anticholineresterase
what is the biochemistry/pharmacology of noradrenaline
Precursor of tyrosine
Converted to nor adrenaline in a number of steps
DOPA converted to dopamine
NA taken back up into the neurone after released into synapse, its not broken down like Ach
what are the potential sites for drug action when NA acts as a neurotransmitter
synthesis metabolism storage/release uptake receptor
what are the fundamentals of neurotransmission for NA
Synthesis
- tyrosine/tyrosine hydroxylase/DOPA
- decarboxylase, DA β-hydroxylase
Storage - vesicles
Release - exocytotic
Receptor interaction α, β, receptors
Termination - Uptake and recycled or metabolism by monoamine oxidase
what are the 2 main classes of NA receptors
alpha receptors
beta receptors
what are the types of alpha-na receptors
alpha1 and alpha 2
where a-noradrenic receptors located and what type of receptor are they
in effector tissues/targets of sympathetic system
g-protein coupled receptors(or metatropic receptors)
is the response fast or slow for a-NA receptors
Slow (seconds) responses
where in the PNS do NA act as neurotransmitter
on the sympathetic tissues
what are the types B- NA receptors and where are they located. what type of receptor are they
B1,2,2
Located in effector tissues/targets of sympathetic system
G-protein coupled receptors (metabotropic receptors)
is the response fast or slow for b-NA receptors
Slow (seconds) response
Which noradrenergic receptors mediate sympathetic effects?
a1 –receptors
where is the a2 receptor
its a Presynaptic receptor
what does a2 receptor do
Inhibits neurotransmitter release (both NA and ACh)
Can be on terminals of other neurones and inhibit the release of nt
how does NA act on presynaptic receptors
NA is released and feedbacks onto the receptors on the terminal, it turns off further activity of the neurone thus decreasing further release of neurotransmitter
what are the types of presynaptic (a2) receptors and where are they located
autoreceptor- receptor on its own neurone
heteroreceptor- receptor on a different neurotransmitters neurone
what are the Sympathetic effects mediated by B1, B2 and B3 receptors
Pupils dilate
Lens of eye adjust for far vision
Airways in lungs dilate
Heart rate increases
Blood vessels to limb muscles dilate
Blood vessels to visceral organs & skin constrict
Brain activity general alertness
what are the effects mediated by a1 – receptors
smooth muscle & vaso-constriction
what are the effects mediated by a2 – receptors
inhibition of neurotransmitter release
what are the effects mediated by B1 – receptors
increase cardiac rate and force
what are the effects mediated by B2 – receptors
bronchodilation, ciliary muscle relaxation
what are the effects mediated by B3 – receptors
lipolysis/increased metabolism
what are the Noradrenergic agonist drugs acting on NA receptors
Adrenaline Clonidine dobutamine Salbutamol Clenbuterol
what are the uses of adrenaline and what is the effect of the a1
Given subcutaneously (locally) adrenaline can prolong & isolate local anaesthesia
-a1 – mediated vasoconstriction- around the areas of the local anaesthetic prolongs the duration of it as it isolated it
how is adrenaline used to treat an anaphylactic shock and how is this mediated by a1, B1 and B2 receptors
intramuscular adrenaline given
a1 - mediated smooth muscle contraction (vasoconstriction, )
b1 – mediated cardiac stimulation
b2 - mediated bronchiol smooth muscle relaxation:
what is clonidine and what does it do
an a2 agonist
Presynaptic autoreceptors regulate release, agonist inhibits NA release
what is clonidine used for
hypertension (can result decrease sympathetic outflow)
can treat withdrawal symptoms in morphine withdrawal (inhibits central NA release)
what is dobutamine and how are the receptors involved, what does it treat
selective b 1 agonist
b1 – receptors: increased cardiac rate and force
Used to treat heart failure.
b 1 – mediated cardiac stimulation (increased firing rate and increased contractile force)
what is Salbutamol and how are the receptors involved, what does it treat
selective b 2 agonist
b2 – receptors: bronchodilation
Used to treat asthma.
b2 – mediated bronchiol smooth muscle relaxation
what is Clenbuterol and how are the receptors involved, what does it treat
b2 – receptors: bronchodilation
b3 – receptors: lipolysis/increased metabolism
- Weight loss
- Muscle gain
Used to treat asthma (b2 )
Increases muscle bulk in athletes/body builders/livestock (b3)
what are the Noradrenergic antagonist drugs
Prazosin Tamsulson Propranolol Atenolol Timolol
what is Prazosin and how are the receptors involved, what does it treat, what are the side effects
selective a1 -antagonist
blocks a1 – mediated smooth muscle & x
Used to treat hypertension
a1 – antagonism: vasodilation and decreased vascular resistance
Side effects: orthostatic or postural hypotension due to some loss in sympathetic reflex
what is Tamsulson and how are the receptors involved, what does it treat, what are the side effects
selective a1 -antagonist
blocks a1 – mediated smooth muscle & vaso-constriction
Used to Urination problems in prostate hyperplasia
a1 – antagonism: relaxation of smooth muscle in bladder neck, ease of urinary flow
Side effects: orthostatic or postural hypotension due to some loss in sympathetic reflex
what is Propranolol and how are the receptors involved, what does it treat, what are the side effects
b1 b2 antagonist (non selective to b1/b2)
b1– receptors mediate increased cardiac rate and force
b2– receptors mediate bronchodilation
Used to treat hypertension and angina
Blocking b1 receptors decreases cardiac output and also decreases oxygen demand.
However blocking b2 receptors causes bronchoconstriction. Therefore contra-indicative in asthmatics .
what is Atenolol and how are the receptors involved, what does it treat, what are the side effects
selective b1 antagonist
b1– receptors mediate increased cardiac rate and force
Used to treat hypertension and angina
Blocking b1 decreases cardiac output and also decreases oxygen demand.
Side effect: can cause rebound hypertension/ angina on abrupt withdrawal probably due to b1 receptor supersensitivity
what is Timolol and how are the receptors involved, what does it treat
selective b2 antagonist
b2– receptors mediate ciliary muscle/lens of eye relaxation
Used to treat glaucoma, antagonism of b2– receptors cause ciliary contraction, and decreased intraocular pressure
what does Timolol, b2– receptor antagonist cause
ciliary muscle contraction and decreased intraocular pressure
outline the Noradrenergic regulation of salivary glands
Direct sympathetic innervation a1, b1, b2
Indirect via innervation of vascular adrenergic innervation.
b1 stimulates protein secretion
a1 stimulates water electrolyte secretions
Clonidine: inhibits NA release, common side effect xerostomia, particular problem given chronic use of clonidine.
what drug affects NA synthesis and how, when is it used
Methyldopa acts as false substrate for DOPA decarboxylase
Decreases overall noradrenergic neurotransmission
Used in the treatment of hypertension
what Drugs affecting NA storage, when is it used
NA stored in synaptic vesicles
Reserpine disrupts storage of NA in synaptic vesicles
Overall decrease in NA neurotransmission
Used to treat hypertension
what Drugs affecting NA release, when is it used
NA release is subject to autoinhibitory control via presynaptic a2 -autoreceptor
clonidine (a2-agonist) causes inhibition of NA release
Overall decrease in NA neurotransmission
Used to treat hypertension
what Drugs affecting NA reuptake, when is it used
NA reuptake inhibitors prolong the action of NA in the synapse
desipramine tricyclic antidepressants
reboxetine selective noradrenaline reuptake inhibitors
what Drugs affecting NA metabolism and how
monoamine oxidase (MAO), and catecholamine transferase (COMT) metabolise NA after reuptake
By blocking these enzymes the amount of NA available for release is increased.
tranylcypramine blocks MAO and allows more NA to be recycled so increases NA neurotransmission.
what do Tranylcypramine and other MAOIs do
they block the metabolism of NA but also block the metabolism of dietary amines
this can have sympathomimetic effect and result in hypertension
which drug inhibits NA synthesis
methyldopa
which drug inhibits NA storage
reserpine
which drug inhibits NA uptake
reboxetine
which drug inhibits NA metabolism
tranylcypromine
which drug inhibits NA release
clonidine
what are medical analgesics
Non-steroidal anti-inflammatories Opioid analgesics General anaesthetics Local anaesthetics Anxiolytics
what are non-medical analgesics
Alcohol
nicotine/caffeine
cocaine
LSD
what is nociception
the process whereby noxious peripheral stimuli are transmitted to the CNS
what receptors sense noxious stimuli
peripheral receptors (nociceptors)
what is the difference between nociception and pain
pain is personal and subjective- depends on many factors other than the stimulus itself
in most cases, what is the origin for the stimulation of nociceptive endings in the periphery
chemical
how is chronic pain caused
as a result of chemical mediators
how can you measure nociception
Apply electrodes within the periphery and measure how external stimuli increase the excitation of neurons
what are the main afferent fibres that sense different levels of pain
- C fibers
- Alpha delta fibers
- Alpha beta fibers
what are c-fibres, are they myelinated or unmyelinated
Non-myelinated -transmission is slow and unprotected
Low conduction velocity (achy pain)
Nociceptor/ thermoreceptor/ mechanoreceptor
Dull achy pain
what are a-delta fibres, are they myelinated or unmyelinated
Myelinated - speed of nociception is greater
Rapid conduction velocity (sharp pain)
Nociceptor/ mechanoreceptor
Terminate in deeper layers in the dorsal horn
what are a-beta fibres, when are they stimulated
Mechanoreceptor (pressure)
Only stimulated when there is physical interaction
where does the neural pathways of nociception start and end
primary afferent neurones (PANs) to the superficial lamina in the dorsal horn of the spinal cord
secondary neurones go through the brainstem to the mid-brain and to the thalamus in the brain
the fibres get passed over to one of the 3 cortices
what are some chemical mediators (substances which stimulate pain endings in the skin)
5-HT
Kinins
Metabolites of intermediary metabolism e.g. lactic acid
capsaicin
what is 5-HT
serotonin released from damaged cells can stimulate nociception
what is an ex of a kinins
bradykinin
most potent pain mediator
Initiate most nociceptive processes
what is an ex of Metabolites of intermediary metabolism
lactic acid
protons from lactic acid can interact with peripheral afferent neurone to cause pains
what is Capsaicin and what does it interact with
chemical product in food
vinalloid receptor-associated with burning
what do eicosanoids do
enhance the pain producing effects of other agents- they do not stimulate nociceptive endings e.g prostoglandings, prostocyclins
They reduce the sensitivity to other chemical mediators
the process of neural excitation produces NO, how does this affect pain
stimulate afferents to signal more to each other and increase the pain further
what stimulates nociceptive modulatory pathways
chemical mediatory
what are the effects of non-steroidal anti-inflammatory drugs (NSAIDs)
ANALGESIC
relieves pain
ANTI-INFLAMMATORY
reduces inflammation
ANTIPYRETIC
decreases elevated body temperature
ANTIPLATELET
reduces platelet aggregation
useful in patients with blood clotting problems etc.
what is the mechanism of action of NSAIDs
inhibition of prostaglandin (eicosanoid) production by irreversibly inhibiting cyclooxygenase (COX) function- this inhibits the inflammatory response
what is COX1
enzyme expressed in most tissue (predominantly in GI tract)- produce prostaglandins that helps form the mucus layer that coats the gut
what is COX2
induced in activated inflammatory cells (throughout the body)
therapeutic effects relate to the inhibition of COX2, however NSAIDs often inhibit COX1 which can cause side effects such as gut bleeding, why is this
NSAIDs are non-specific therefore cannot be selective between COX1 and COX2
how does aspirin act as an analgesic and anti-inflammatory mediator
decreased prostanoid synthesis leads to less sensitisation of nociceptors to effects of mediators e.g. 5-HT, kinins etc
how does aspirin act as an antipyretic
aspirin decreases PGE2 synthesis, PGE2 raises temp
what is aspirin hydrolysed by and whats its half life, how is it given
esterases to salicylate
Half-life (4-15 hours) - dose dependent (higher dose higher effect)
orally
what are the unwanted effects of aspirin
Low doses; GI irritation, hypersensitivity
Salicylism (high doses); tinnitus, vertigo, decreased hearing
Reye’s syndrome; rare childhood disorder- inflammation of meninges in the brain.
It interacts with warfarin
when does aspirin interact with warfarin and why
during phase 1 metabolism so the aspirin can become more therapeutically active
how does ibuprofen act as an analgesic and anti-inflammatory mediators
decreased prostanoid synthesis leads to less sensitisation of nociceptors to effects of mediators e.g. 5-HT, kinins etc
how does ibuprofen act as an analgesic an antipyretic
in fever temp raised due to synthesis of PGE2 due to pyrogens
ibuprofen decreases PGE2 synthesis
what drug is usually the first choice for inflammatory joint disease and why
ibuprofen
effective and better tolerated than most NSAIDs
how is ibuprofen administered and how rapidly is it absorbed
oral, topical, rectal
Rapid absorption (1-2 hours)
what are the unwanted side effects of ibuprofen and why
Relatively uncommon and mild.
Local sensitivity reactions.
Less gastric irritation than aspirin
Can’t tell the difference between COX1 and 2, binds to both.
how is paracetamol an analgesic
decreased prostanoid synthesis leads to less sensitisation of nociceptors to effects of mediators e.g. 5-HT, kinins etc
is paracetamol anti-inflammatory
no, it will help the pain not the cause
how is paracetamol antipyretic
in fever temp raised due to synthesis of PGE2 due to pyrogens
paracetamol decreases PGE2 synthesis
do paracetamol have anti-platelet properties
no
why may paracetamol exhibit less analgesic activity in inflammatory conditions
Suggest that it selects COX3 over 2 and 1
how is paracetamol administered, when does it achieve its peak plasma conc and whats its half life
Oral, rectal, IV.
Peak plasma concentrations within 30-60 minutes.
Half-life = 2-4 hours
what is paracetamol mainly conjugated to
glucuronic acid or sulphates
what are the unwanted effects of paracetamol
Hepatotoxicity in overdose or chronic usage
Allergic skin reactions
what are morphine analogues
looks like morphine e.g.
diamorphine (heroin)
codeine
what are synthetic derivatives of opioids
pethidine
Dextropropoxyphene
what are opioid neurotransmitters
enkephalins
endorphins
dynorphins
what are opioid receptors
three types - µ, δ and κ
All opioid receptors are linked through G-proteins to inhibition of adenylate cyclase
which opioid receptor i responsible for most of the analgesic effects of opioids
µ
what are the therapeutic effects of opioid analgesics
Analgesia
Euphoria and sedation- reducing the excitability of the nociception but also making someone feel good.
what is the ADME of opioid analgesics
oral, rectal, i.v., i.m.
erratic absorption from gut
extensive first pass metabolism- dangerous for alternate effects
when are opioids given and which ones
moderate to severe pain - strong opioids e.g. morphine, pethidine
mild to moderate pain/cough suppressive/antidiarrhoeal - weak opioids e.g. codeine
what are the adverse effects of opioid analgesics to the CNS
drowsiness and sedation
respiratory depression
tolerance and dependence
cough suppression
nausea/vomiting
what are the adverse effects of opioid analgesics to the PNS
Constipation- affect the intraneural plexus in the gut
histamine release
pinhole pupils
what are strong opioids and when are they given
morphine
- most valuable for severe pain relief
- terminal care
Pethidine
- more lipid soluble than morphine
- rapid onset/short duration
- less constipation than morphine
- prescribed by dentists
what are weak opioids and when are they given
dextropropoxyphene
- very mild analgesic
- used in combination with
dihydrocodeine
- Pharmacologically very similar to codeine
- Nausea and constipation limit dose and duration of use
what is the tolerance for opioids
Detected in 12-24 hours
Sensitivity will return on withdrawal
Extends to all pharmacological actions
what is the dependance for opioids
Following abrupt withdrawal after chronic treatment
Abstinence syndrome after acute treatment
What are anaesthetics
drugs which are used to PREVENT/BLOCK pain for a limited period of time for surgical or other procedures
what is the difference between anaesthetics and analgesics
anaesthetics prevent/blocks pain while analgesics CONTROL pain
what are the 2 broad classes of general anaesthetics
inhalation anaesthetics
intravenous anaesthetics
what are some inhalation anaesthetics
Halothane
Nitrous oxide
Enflurane
Isoflurane
what are some intravenous anaesthetics
Thiopental
Etomidate
Propofol
what are the two main theories for the mechanism of general anaesthetics
lipid theory: meyer overton theory
ion channel theory
what is the lipid theory: meyer overton theory
Strong relationship between anaesthetic potency and lipid solubility
agents interacted with lipid bilayer of plasma membrane, causing membrane expansion and consequent inability of membrane to facilitate changes in protein configuration and signalling
Lipid solubility related to anaesthetic potency
what is the ion channel theory
Anaesthetics target a number of ligand gated ion channels, including, GABAA, Glycine NMDA,
Ion channels in the membrane that control the excitability of neurones
Drugs interfere with the signalling of these ion channels
which one of the theories for anaesthetics is more valid
ion channel theory
what is Correlation of anaesthetic potency and lipid solubility
greater the lipid solubility the greater the potency
Low alveolar concentration then its very potent
what is the depth of anaesthesia determined by
concentration in the brain and spinal cord
what is the blood/gas partition coefficient in inhalation anaesthetics
measure of blood solubility and determines potency
lower blood gas coefficient the faster the induction and recovery
how is the speed of induction and recovery related to solubility in inhalation anaesthetics
the lower the solubility the faster the induction and recovery
e.g. Low (nitrous oxide)-rapid induction and recovery
High (halothane)- slow induction and recovery
what is the oil:gas partition coefficient
measure of lipid solubility
main factor that determines potency
what is the relationship between the oil:gas partition coefficient and potency
lower the oil:gas partition coefficient the lower the potency
what are the pharmacokinetics important in inhalation anaesthetics
Vascularisation of tissue will determine tissue levels of anaesthetic
- Brain good blood flow: high levels
- Body fat has poor blood flow so anaesthetic doesn’t accumulate in body fat
Ventilation rate:
-These drugs are not metabolised to a great degree so are removed by ventilation rate.
how are inhalation anaesthetics mainly eliminated- outline pathway
via lungs
enter through lungs into arterial blood majority into brain and some into tissues small component metabolised (toxic) excreted out through lungs
outline the Toxicity of anaesthetics that are metabolised
Methoxyflurane: extensive (60%) hepatic metabolism resulting in nephrotoxic fluoride ion (no longer used)
Halothane 15 % (hepatotoxic)
Isoflurane 0.5 %
Desflurane 0.5 %
Sevoflurane 3 %
what are side effects common to inhaled anaesthetics
Malignant hyperthermia Cardiovascular Respiration hepatic toxicity (mainly halothane) Kidney
what is malignant hyperthermia
Rare but most common with halothane and isoflurane
hypermetabolism, muscle rigidity, muscle injury and increased sympathetic nervous system activity, hyperthermia.
what are the Cardiovascular side effects of inhaled anaesthetics
Can cause hypotension (except nitrous oxide)
Decreased output and decreased vascular resistance- exacerbates hypertension
what are the side Respiration effects of inhaled anaesthetics
Depressed respiration (> with the fluranes, iso>des>sevo)
what are the side hepatic effects of inhaled anaesthetics
Hepatic toxicity (mainly halothane) Anaesthetic is metabolised by liver
what are the side renal effects of inhaled anaesthetics
Depressed glomerular filtration and urine output: not really a problem because of decreased cardiac output and vasodilation (and infact usually give fluids)
what are some intravenous anaesthetics
THIOPENTAL SODIUM
ETOMIDATE
KETAMINE
PROPOFOL
Short onset of action (20 seconds
where do Thiopental & Etomidate both act on
GABAa receptor (on a1/b3 subunit interface)
what does etomidate do
causes an influx of Cl-, hyperpolarisation, and inhibition of the neurone.
why is etomidate safer than propofol
wider therapeutic window between anaesthesia and respiratory depression- less risk of overdose
(etomidate TI= 26)
(Thiopental TI =2.5)
where does propofol act
GABAA receptor on b3 /b3 or a1/b3 subunit interface
how does propofol have a very rapid metabolism and why is this good
Extrahepatic, elimination via plasma (esterases) and lungs
Rapid recovery
No hangover
Day case surgery
what is ketamine
NMDA receptor antagonist- influx and Na and Ca, depolarisation and excitation
Less hypotension than the etomidate/propofol
why is ketamine rarely used
Hallucinations, psychosis
what is the difference between local anaesthetic and general
prevent localised pain or nociception and also prevent tactile sensation
General anaesthetics also induce loss of consciousness
what do local anaesthetics do
block electrical signalling in neurones by blocking voltage gated Na+ channels
what are the types of neuronal signalling
Electrical signalling - the action potential
Chemical signalling – neurotransmission
what occurs during an action potential
Na+ goes into the cell (concn gradient) via voltage gate Na channels
Membrane potential rises and polarity changes
Na channels close and Na+/K+ATPase moves Na+ out
K+ pours out of the cell (concn gradient) via voltage gate K channels
Membrane potential falls again
what subunits is Voltage Gated Ion Channels made up of
three subunits a, b1 and b2.
what does the alpha subunit of voltage gated ion channel contain
single polypeptide. It contains extracellular domains, 4 transmembrane domains each comprising 6 a-helical regions
The α subunit contains, in the hydrophobic domains, voltage sensors that change their orientation when voltage varies
what are the beta subunits liked to the alpha subunits of voltage gated ion channel contain
b subunits flank the a-subunit.
The b2-subunit is linked covalently to the a-subunit, the b1-subunit is not linked.
The two b-units anchor the a-subunit into the lipid membrane.
what is the effect of local anaesthetics on voltage gated ion channels
Local anaesthetics are thought to interact with the a- subunit and physically ‘plug’ the transmembrane pore
Local anaesthetics binds in the ionised (hydrophilic) form – binding area is on the intracellular side of the channel
whats are the chemical/structural aspects of local anaesthetics
Unionised form gains access through nerve sheath and axon membrane
Ionised form binds in channel
Most anaesthetics are weak bases- the pH outside (pH7.4) of the cell is higher than inside the cell (pH7)
what is the general chemical structure of local anaesthetics
molecules consists of aromatic group , ester or amide group and amine group
basic side chain ensuring that the molecules are ionised at physiological pH
what does the aromatic domain of local anaesthetics ensure
lipid solubility
why is the duration of action of local anaesthetics limited
by the hydrolysis of the ester/amide bond and by the lipid solubility of the agent.
what is the difference between esters and amides
Esters are metabolised in plasma by esterases (except cocaine) Shorter T1/2
Amides metabolised in liver by CYP3A4,1A2 longer T1/2
how does local anaesthetic get into the cell
anaesthetic, a weak base, is injected as hydrochloride salt in an acid solution (i.e. dissolves in solution).
pH increases due to the higher pH of the tissues and free base released
Lipid soluble free base enters the axon. Inside the axon the pH is lower (the environment is more acidic, pH7), and re-ionization takes place.
The re-ionized portion enters the Na+ channels and blocks them, preventing depolarization
How can we manipulate local anaesthesics
Restrict site of action and prolong durations of action
Accelerate the speed of onset of the anaesthetic (Use slightly alkaline solution)
Do all nerves show similar susceptibility to local anaesthetics?
Different types of axons show different sensitivity to local anaesthetics
when is block conduction more effective for local anaesthetics
Block conduction in small diameter fibres more effectively than in large diameter fibres
how does myelination impact the nerves susceptibility to local anaesthetics
small myelinated axons* > non-myelinated axons > large myelinated axons
*Nosciceptive (pain) fibres are small diameter and particularly sensitive
are Motor axons more or less sensitive to local anaesthetics?
Motor axons have a large diameter and are less sensitive
what is use dependant block
the depth of block increases with an increase in action potential frequency
why does use dependant block occur
because the anaesthetic gains access to, and has higher affinity for the channels more readily when it is open and/or inactive
what are Unwanted side effects of local anaesthetics
CNS, confusion and agitation
Cardiovascular, hypotension
–Inhibition of sympathetic activity
–Inhibition of sodium conductance in cardiac tissue
why are anaesthetic not very effective in infected or inflamed tissue
Infective tissue is more acidic outside the neurones. Anaesthetic cannot cross the membrane and get into the neurone
what does chemotherapy eliminate
invading cells/microorganisms/organisms
what are the properties of effective chemotherapeutic agents
toxic to invading species/abnormal cell
relatively non-toxic to the host/normal cells
what is selective toxicity
refers to the exploitable differences between invading species and host which depend upon evolutionary distance, the extent of these differences has implications for toxicity
Why do dentists need to know about selective toxicity?
Chemotherapeutic agents form a major group of drugs in the Dental Practitioners’ Formulary i.e. dentists use them a lot!
Forms part of clinical due care and responsible prescribing
what can Invading cells/microorganisms/organisms include
neoplastic cells
bacteria
•e.g. Streptococcus species
viruses
•e.g. herpes viruses
fungi
•e.g. candida albicans
parasites
e.g. protozoa, helminths
how are bacterial infections managed
Treatment of infections
General prophylaxis- prevent infection following surgery in susceptible individuals
Broad spectrum antibiotics can be given in the prophylactic matter
what are the modes of action of antibacterial drugs
Inhibition of cell wall synthesis
•e.g. β-lactam antibiotics (penicillins)
Inhibition of protein synthesis
•e.g. macrolides (erythromycin), tetracycline
Inhibition of bacterial nucleic acids
•e.g. quinolones
Inhibits bacterial DNA synthesis/degrades DNA
•e.g. metronidazole
what do β-lactam antibiotics do
prevent the cross-linking peptides from binding to the tetrapeptide side chains
they inhibit transpeptidases- which the enzyme which catalyses cross-linking
what are ex of β-lactam antibiotics
Penicillins, cephalosporins
what do Macrolide Antibiotics do
Inhibit ribosomal function- which help tRNA make new amino acid chain
Bacterial ribosomes differ structurally from mammalian ribosomes
what are ex of Macrolide antibiotics and how do they inhibit ribosomal function
Tetracycline - interacts with protein synthetic pathway at the level of elongation – stops tRNA from binding to the 30 S ribosomal unit
Erythromycin- tops translocation- works at the large subunit to stop formation of peptide chain
what do Fluoroquinolones do
Inhibit DNA replication or nucleic acid synthesis
Inhibit topoisomerase II (bacterial specific DNA gyrase) preventing normal DNA supercoiling process
what are other ways to target bacterial nucleic acid synthesis
Inhibit the synthesis of the nucleotides
Altering the base pairing properties of the DNA template
Inhibiting either DNA or RNA polymerase
Directly inhibiting DNA itself
what are Antifolates
Class of drugs not commonly prescribed in terms of antibiotic function due to side effects
• e.g. sulfonamides, trimethoprim
how do antifolates work
Different mechanism of action- Targeted inhibition of the bacterial specific folate synthetic pathway.
what steps do antimicrobials inhibit in folate biosynthesis, and what are the names of the enzymes that do this
dihydropteroate synthetase prevents the conversion of pABA to Folate
dihydrofolate reductase prevents the conversion of folate to tetrahydrofolate
what forms does herpes virus exist in
Simplex = cold sores
Varicella zoster = chicken pox
Epstein Barr (EBV) = glandular fever
what are the symptoms of herpes virus
‘flu-like’ symptoms (fever, headache, aches and pains)
blister/ulcer stage.
how does the herpes virus occur
its due to external stimuli that reactivate the dormant virus, for example it is usually dormant in sensory ganglia in particular on the front of the face, so stimulation of ganglia can cause cold sores in that area
how does Aciclovir work to treat herpes and what are the benefits of it
it is a synthetic guanosine analogue- nucleotide based sequence with similar structural shape to nucleotides of herpes
Only toxic to an infected the cell
high therapeutic index
which herpes virus is Aciclovir specific to
simplex
Varicella-zoster:- less susceptible
Cytomegalovirus (CMV):- small and reproducible
EBV:- slightly sensitive
aciclovir requires intracellular phosphorylation- metabolic activation, how does it achieve this?
Utilises simplex virus specifically, thymidine kinase will phosphorylate the acicolvior into monophosphate form and then into di and tri form.
The triphosphate forms is therapeutically active- Antiviral action
outline the Antiviral action of Aciclovir
Aciclovir-TP -a DNA chain terminator
Inhibitor of viral DNA polymerase
Host significantly less susceptible
what are the superficial (common) fungal infections in dentistry
Candidiasis (oral cavity, tongue)
Dermatomycoses (mouth)
what are the systemic (rare) fungal infections in dentistry
Systemic candiasis
why has there been an increase in fungal infections in the last 20-30 years
widespread use of antibiotics and increase in immunocompromised individuals (immunospression in cancer treatment, transplant medicine, AIDS)
what do fungal cell membranes contain
sterol ergosterol
main sterol in mammalian cell membranes is cholesterol
what are the 3 key drug classes form antifungal agents
- Azoles - imidazoles and triazoles
- Polyenes- nyastin
- Mitotic inhibitors- griseofulvin
which drug classes are ergosterol inhibitors
azoles and polyenes
which drug classes are intracellular inhibitors
mitotic inhibitors
how do azoles work
Inhibit how ergestrol is made in the fungal cell
Affect membrane lipid synthesis
2 types
Imidazoles
Triazoles
how do polyenes work
Break apart the ergesterol
Form pores in membrane
Nystatin
how do mitotic inhibitors work
Interferes with fungal cytoskeleton
Griseofulvin- inhibits mitosis of fungal cells
how do azoles inhibit the biosynthesis of ergosterol and what does this lead to
Block 14-α demethylase cytochrome P450- mediated step in the biosynthesis of it. lack of rigidity and shape in fungal membrane
this causes increased cell wall permeability and inhibition of replication
when are azoles effective
in treatment of dermatomycoses, candidiasis and some systemic infections
what are the subclasses if azoles and what are ex of teh drugs given for eacg each, which one contains nitrogen
Imidazoles- does not contains nitrogen
- ketoconazole, miconazole, clotrimazole.
Triazoles- contains nitrogen
- fluconazole.
what does ketoconazole do, what are its drawbacks
given orally
Causes inhibition of reactions catalysed by cytochrome P450 involved in both steroid biosynthesis and drug metabolism
Has several drug interactions as it can inhibit the metabolism of other drugs- side effects
may cause hepatotoxicity
what does Miconazole do and how is it administered
Used topically, orally (for oral and intestinal infections) or intravenously (i.v.).
Less toxic than ketoconazole but may also inhibit drug metabolism
Other topical agents include clotrimazole.
what does fluconazole do and how is it administered
Can be given orally (i.v.)
Relatively non-toxic
Unlike imidazoles does not undergo metabolism and has long half-life (22h)
Not as many drug-drug interactions
Less inhibition of P450 but some drug interactions may occur
what do polyenes do and how are they administered
Bind to sterols in membrane forming an ion channel.
Binds to ergosterol creating a pore, loss of structural rigidity.
Can be given i.v. as detergent or lipid complex.
why are poles effective in fungal cell walls over mammalian cell walls
Higher affinity for binding to ergosterol compared with cholesterol.
how does griseofulvin work, when and how is it given
mitotic inhibitor
Inhibits cell division by interfering with spindle formation
Used orally in treatment of dermatomycoses (hair and nails).
Appears to be taken up selectively by cells which synthesise keratin
what are the effects of Anxiolytic-Sedative-Hypnotic Drugs
alleviate fear and anxiety
produce a degree of amnesia and analgesia
induce sleep (Hypnotics)
Why do dentists need to know about anxiolytic-sedative-hypnotic drugs?
administered to patients who are unable to handle the emotional stress caused by a visit to the dentist i.e. they experience severe anxiety
what is anxiety and what are the symptoms a patient may present
feelings of uneasiness, apprehension and tension
palpitations, headache, dizziness, flushing, sweating, tense muscles
some phobic states/panic attacks are not subjective
what does the GDC say about conscious sedation
can be an effective method of facilitating dental treatment…’
‘…produces a state of depression of the CNS…’
‘…verbal contact with the patient is maintained…’
‘…patient remains conscious, retains protective reflexes and is able to understand and respond to verbal commands…’
‘…deep sedation…must be regarded as general anaesthesia’
what are the types of sedation method in dentistry
Inhalation- nitrous oxide
Oral- benzodiazepines and H1 antagonists
Intravenous- Benzodiazepines
what is nitrous oxide
Light and rapid anaesthesia
50% NO in oxygen (Entonox)
Recovery in ~ 4 mins
Mild nausea and vomiting
what are the dose dependent effects of sedatives
relief of anxiety
sedation
hypnosis
general anaesthesia
what are barbiturates and what effect do they have on ion channels
Positive allosteric modulator of GABAa receptors
they change how long the Cl- channel is open
what do Barbiturates do
Increase effects of GABA, and inhibit glutamate neurotransmission
They have a separate binding site on the GABA receptor (unlike benzodiazepine)
why is the clinical use of Barbiturates limited
increased toxicity in overdose- Severe CNS depression, comas, death
this is due to their direct effect on the opening of ion channels,
why do benzodiazepines have less potential to completely suppress the CNS
they only work at the frequency of the opening/closing of the Cl- channels, which makes them safer
what are the anxiety disorders which benzodiazepines are used to treat
Panic disorder- discrete periods of intense fear
Generalised Anxiety Disorder- chronic worry
Simple Phobia- fear of object or situation
what is the chemical structure of benzodiazepines
Benzos are a 7-membered ring fused to an aromatic ring with 4 main substituent groups which can be modified.
what is the pharmacological effects of benzodiazepines
Reduction of anxiety and aggression
Sedation and induction of sleep
Muscle relaxation
Anticonvulsant effects
Amnesia
how do benzodiazepines cause a reduction of anxiety and aggression
Less aggression due to the reduction in CNS function
how do benzodiazepines cause sedation and induce sleep
Decrease time taken to get to sleep
Increase total duration of sleep
Decrease REM sleep (dreaming)
Decrease SW sleep (deep sleep)
how do benzodiazepines cause muscle relaxation
Increased muscle tone in a common feature of anxiety
May result in aches and pains e.g. headache
Relaxant effect clinically useful
Anticonvulsant effects
what is the mode of action of benzodiazepines
they bind to a specific regulatory site on the GABAA receptor
BDZ binding enhances neuronal inhibitory effect of GABA
GABA and BDZ bind to independent sites of the same receptor-Cl-ion channel complex
BDZ do not open the Cl- ion channel by themselves, they increase the affinity of the receptor for GABA
Benzodiazepines change frequency of Cl- channel opening
what are the pharmacokinetics of benzodiazepines
Well absorbed when given orally
Bind strongly to plasma proteins
High lipid solubility leads to accumulation in body fat- patients will describe a ‘hangover’
Short Acting
Long Acting
what are short acting benzodiazepines, how are they metabolised
Metabolised to inactive compounds straight away
Short half life e.g. temazepam
Arguably better for minor issues e.g. so no hangover issues
what are long acting benzodiazepines, how are they metabolised
Metabolised to pharmacologically active metabolites with long half-lives
Diazapam is metabolised to nordiazepam which has a half life of ~60h
what are the unwanted effects of benzodiazepines
Interaction with alcohol- increases the CNS depression
hangover effects’ e.g. drowsiness, confusion
Development of dependence (not the same as addiction)
Sexual fantasies
Amnesia- effects memory recall
how are benzodiazepines used in dentistry
Sedation as adjunct to local anaesthesia (amnesia)
Pre-anaesthetic medication (anxiolytic effects)
what is propranolol
β-adrenoceptor antagonists –
how does propranolol work
Anxiolytic but not sedative
-Reduce physical symptoms (tremor, palpitations etc) of anxiety
Inhibition of somatic or autonomic responses
-Decreased noradrenergic transmission
what are the Unwanted side effects of propranolol
Cardiac depression, bradycardia
Non-selective β-adrenoceptor inhibition (β1/ β 2)
what buspirone
5-HT1A agonist
how does buspirone work
Anxiolytic but not sedative
-Partial agonist of inhibitory autoreceptors (5-HT1A)
Long anxiolytic development time
-> 2 Weeks
Fewer withdrawal effects
-Generally mild nausea or dizziness
what are the monoamine neurotransmitters and what do they treat
5-Hydoxytryptamine (5-HT, serotonin)
-Depression, anxiety
Dopamine (DA)
-Schizophrenia
Noradrenaline (NA)
-Depression, anxiety
what is involved in 5-HT biosynthesis & neurotransmission
Tryptophan gets taken up into the neurone and its converted to 5-HTP
Needs to be stored in vesicles
15/16 types of receptor subtypes
Like NA a specific transporter takes the neurotransmitter back up into the neurone
what is involved in DA biosynthesis and neurotransmission
Similar to NA biosynthesis
In dopamine no extra enzyme in the vesicle
Released into the synapse and acts on receptors
Taken back up and recycled
why is DA targeted in schizophrenia
Dopamine theory of schizophrenia states that schizophrenia is associated with increased DA function
what are the Three main dopamine pathways in the brain
Nigrostriatal pathway
mesolimbic pathway
tuberoinfundibular pathway
what is involved in the Nigrostriatal pathway
projects from the substantia nigra into the dorsal striatum
this mediates fine movement.
This is dysfunctional in Parkinson’s disease.
what is involved in the mesocortical/mesolimbic pathway
dopamine from ventral tegmental area to frontal cortex/ventral striatum
Dopamine associated with mood and cognition.
Reward/addiction (ventral striatum)
In schizophrenia this is thought to be the pathway overactive
what is involved in the tuberoinfundibular pathway
Dopamine from hypothalamus feeds onto the pituitary stalk
controls endocrine function- tonic inhibition of prolactin secretion.
what is the Role of dopamine in regulation of prolactin secretion
the secretion of prolactin is inhibited due a prolactin releasing inhibiting factor (PRIF)
what is the link between DA receptor antagonists and schizophrenia
Dopamine theory of schizophrenia states that schizophrenia is associated with increased DA function
Use D2 receptor antagonists to counteract this increase in DA function
D2 antagonists are effective antipsychotics
what is the Dopamine theory of schizophrenia
Drugs with a high affinity for the receptor are required at a low dosage
D2 receptor antagonism underlies pharmacological mechanism
what can happen when D2 receptors are blocked
we block D2 in the extrapyramidal area which can induce Parkinson’s.
what are the symptoms of Parkinson’s syndrome
Tremor
Muscle rigidity
Loss of facial expression
what are the symptoms of • Tardive dyskinesia
Repetitive rhythmical involuntary movements,
lip smacking, chewing,
rocking, rotation of the ankles or legs,
marching in place, and
repetitive sounds such as humming or grunting
what are the extrapyramidal side effects (EPS) of D2 antagonism in the nigrostriatal DA pathway
Parkinson’s syndrome
Tardive dyskinesia-video
what are the side effects of D2 antagonism in the tuberoinfundibular DA pathway
hyperprolactinaemia
- Galactorrhoea,
- Gynaecomastea
this is due to primary pharmacology of the drug
what receptors do Antipsychotics also have affinity for, and what is this associated with
Histamine receptors
- H1 mediated
- Sedation, weight gain
Muscarinic
- M1 mediated
- Dry mouth, blurred vision, constipation, urinary retention
Adrenergic
- α1 mediated
- Postural hypotension
Side effects associated with the secondary pharmacology of the drug
what is the Antipsychotic Classification of the drugs based on their side effects for Phenothiazines (outline their side effects)
Group I
- Sedation (affinity for H1)
Group II
- Anticholinergic (affinity for M1)
Group III
-EPS (predomantly D2)
what phenothiazine drugs are group I, II and III
Chlorpromazine (group I)
Thioridazine (group II)
Fluphenazine (50X more potent)
(group III)
what are Thioxanthenes
Flupenthixol
Similar profile to phenothiazines
what are Butyrophenones
Haloperidol
Selective to D2
Lack muscarinic and antihistamine activity (no sedation) but EPS a problem
what are Limitations Of Classical Antipsychotics
Approximately one-third of patients with schizophrenia fail to respond
Limited efficacy against negative symptoms
High proportion of patients relapse
Side effects and compliance issues
what are the +ve symptoms of Schizophrenia
Disorders of thought/disorganised behavior
Hallucinations (aural and visual)
Paranoia
what are the -ve symptoms of Schizophrenia
Blunted emotions/anhedonia
Social withdrawal
Apathy/loss of energy
what are atypical antipsychotics
Clozapine, Olanzapine, risperidone, amisulpiride, quetiapine
what are the benefits of atypical antipyschotics
Better EPS side effect profile (without loss of antipsychotic efficacy)
Better at treating negative symptoms
- Lower affinity for D2 receptor!
- High affinity for D3, D4 receptors (D2 family) and 5 HT2A receptor
what are the what are the drawbacks of atypical antipyschotics
High incidence of metabolic syndrome, weight gain, become diabetic (Risperidone, olanzapine)
clozapine associated with agranulocytosis
what is the Hypothesis for mechanism of action atypical antipsychotics
Atypicals do have affinity for D2 receptor, however they have a much faster dissociation rate from the D2 receptor (Koff) (loose binding)
These drugs can be displaced by physiological phasic bursts of DA transmission (important in DA striatal pathways)
Results in less distortion of physiological DA signalling in striatal pathways
Cannot exclude the role of 5-HT2
what is the Distinction between typical and atypical based antipsychotics based on
Incidence of extrapyramidal side effects
Efficacy in treating treatment resistant patients
Efficacy against negative symptoms
what are some Antidepressant drugs
Tricyclic antidepressants (TCA’s)
Selective serotonin reuptake inhibitor (SSRI’s)
Monoamine oxidase inhibitors
what are Tricyclic antidepressants (TCAs)
First developed antidepressant
Tricyclic structure
Inhibit reuptake of 5-HD and noradrenaline
e.g. amitriptyline, imipramine, lofepramine
what are the consequences of Tricyclic antidepressants (TCAs) and what effect on which receptors is this due to
Block M1 receptors
- Dry mouth, blurred vision, constipation, urinary retention
Block H1 receptors
-Sedation, weight gain
Block α1 receptors
-Postural hypotension
when is TCA not used
Elderly
Cardiac patients (increase chance of conduction abnormalities)
Hepatic insufficiency
Suicidal patients (overdose)
Drivers (sedation)
Workers (sedation)
when is TCA useful
Severe treatment resistant depression
Where sedation is also required
Where disease history indicates efficacy and tolerance
and TCA are cheap!
what are the 2nd generation antidepressants and what is their pharmacology
SSRI: selective serotonin reuptake inhibitor
SNRI: serotonin/ noradrenaline reuptake inhibitor (venlafaxine)
NARI noradrenaline reuptake inhibitor (reboxitine)
what are the 2nd generation antidepressants selective for
5-HT or NA transporter and do not have affinity for postsynaptic receptors (fewer side effects)
The target the transporter but they do not have affinity for post synaptic receptors so don’t exhibit the same side effects as above
what are the side effects of SSRIs
- Sexual dysfunction (impotence)
- Gastrointestinal
- Precipitate anxiety
- Do not cause sedation or anticholinergic side effects
what are other uses of SSRIs
panic disorder,
obsessive compulsive disorder,
eating disorders
SSRIs have a better adverse side effect profile than TCAs, why is this important
important for the a lag time for the onset of therapeutic effects
what are the 2 isoforms of Monoamine oxidase inhibitors (MAOIs)
MAOA breaks down 5-HT, NA, ( and a bit of DA)
MAOB breaks down DA
what did old MAOIs do
blocked both isoforms irreversibly
Stimulant effects,
Dangerous in overdose
what do new MAOIs do
selective for MAOA, reversible (reversible inhibitors of monoamine oxidase A (RIMA) (e.g. moclobemide)
Less stimulant and safer
what are the interactions of MAOI
MAOI & cheese effect - - hypertensive crisis, resulting from and excess of dietary tyramine
MAOI & SSRIs
- Serotonin syndrome,
- hyperthermia, confusion hypertensive crisis
Releasing agents e.g (MDMA) and MAOI
- Serotonin syndrome
Antiparkinson drugs
-Severe hypertension
what is a hormone
A chemical substance synthesised by specific tissues and secreted into the blood stream, whereby it is carried to non-adjacent sites in the body and exerts its actions.
what is a neurotransmitter
A chemical substance synthesised by neurone and secreted directly onto adjacent neurones or tissue, whereby it exerts its actions. Do not circulate the blood stream
how is the endocrine system organised
Endocrine glands/cells secrete the hormones into the blood stream
All tissues are exposed to the hormones and it circulated through the body but they will only respond if they have the receptors
how is cortisol synthesised
hypothalamic nuclei releases CRH which acts on the anterior pituitary. this causes it to secrete ATCH which acts on the adrenal cortex to synthesise cortisol
how is the cascade for the synthesis of cortisol turned off
strong negative feedback system
what is the function of cortisol
increase and maintain then normal glucose levels in the blood
increase gluconeogenesis
decrease glucose uptake in to muscle and adipose tissue
decrease in protein synthesis (amino acids are free for gluconeogenesis)
how is blood glucose regulated by insulin
insulin secreted by the pancreas acts on insulin receptors in liver in muscles
insulin involved in the uptake and storage of glucose
outline how cortisol regulates metabolism
increase and maintain normal glucose in blood
increase gluconeogenesis
decrease in protein synthesis
role in regulating brain function
immune response/inflammation
what are disorders of cortisol
cushings syndrome- cortisol hypersecretion (excess cortisol secretion)
what are the causes of cushings syndrome
adrenal or pituitary tumour
side effect of chronic glucocorticoid therapy
how is cushings syndrome treated
removal of tumour
inhibition of cortisol synthesis by metyrapone
what does the treatment of cushings with metyrapone involve
11ß-hydroxylating enzyme can be blocked by metyrapone so decreasing the amount of cortisol available for secretion
at high levels what can cortisol (cortisol-like compounds) do
can inhibit inflammation and the immune response
what is the process by which extracellular insulin is released from the B cells of the islets of langerhans
glucose is taken up by a glucose transporter into the cell and glycolysis occurs
this causes an increase in ATP, ATP blocks the K+ channels causing depolarisation
ca2+ channels open causing the release of insulin
what is involved in diabetes mellitus
insulin hyposecretion
insulin receptor hyposensitivity
what is involved in type 1 diabetes
Insulin hyposecretion due to a loss of -cell
Substitute with insulin
Background intermediate acting (e.g isophane insulin)
+ short term fast acting (soluble insulin) before meal
what is short acting insulin
soluble insulin
sc (routine) & iv administration (emergency)
rapid onset and short duration (important in emergencies)
what is intermediate acting insulin
insulin complexed with zinc salts or protamine as particles
insulin slowly released from particles
what is long acting insulin
insulin complexed with zinc salts as crystals (large particle size)
insulin even more slowly released
Insulin glargine/detemir
o Soluble insulin but released slowly & evenly due to precipitation in tissues
what is type II diabetes
- Metabolic demands of obesity
- Desensitization of insulin receptors
- Pancreatic insufficiency- some functioning beta cells
Attempt to increase the insulin secretion from the beta cell that are there
what do sulphonylureas do and what are they used to treat
type II diabetes
block the KATP channels so cause depolarisation and increase insulin secretion independently of glucose levels (need partially functioning Beta cells).
Oral contraceptives and regulation of the Hypothalamic-pituitary-ovarian axis
hypothalamus releases GRH which acts on the pituitary. this releases FSH and LH the ovaries which causes ovulation
what are the Physiological effects of estrogen on endometrium
sensitises LH releasing cells in pituitary
proliferation of endometrium- preps the development of the uterus
Inhibits FSH so regulates cycle- don’t want to have high FSH
what are the Physiological effects of Progestrone on endometrium
renders the endometrium suitable for implanting of a fertilized ovum-
Inhibits further release of GRH, FSH, and LH so regulates cycle and ovulation
what are the options after ovulation takes place
Fertilization
No fertilisation
what occurs if no fertilisation takes place
corpus luteum regresses, progestrone levels drop.
- endometrium can not be maintained, menstruation occurs
- Lack of progestrone also means the clamp on GRH, FSH and LH secretion is released. These hormones are secreted again-cycle starts again, follicle develop
- Hormones secreted and the cycle starts again
what occurs if you lose progesterone
you lose your releasing factors
If fertilized ovum is implanted
ovum secretes human chorionic gonadotrophin, this stimulates corpus luteum to continue secreting progestrone:
- maintains endometrium and pregnancy
- Inhibits further secretion of GRH, FSH, and LH, this prevents further follicles developing
what is the function of Hypothalamic-pituitary-ovarian axis
Maintains endometrium and pregnancy
-ve feedback
what do Oral contraceptives target
the negative feedback system clamping secretion of GRH FH and LH
what do sex hormones in contraception do
Oral contraceptives mimic the negative feedback and turn off the releasing factors
They mimic the pregnancy state
what do oral contraceptives do
Oral contraceptives mimic the negative feedback and turn off the releasing factors
They mimic the pregnancy state
what are the 2 main types of oral contraceptives
Combined oestrogen and progestrone (combined pill)
Progestrone alone (progestrone only pill/minipill)
how does the combined pill work
Estrogen inhibits secretion of FSH via –ve feedback, this prevent development of ovarian follicle
Progestrone inhibits secretion of LH, (-ve feedback) prevents ovulation and also makes the cervical mucus less suitable for passage of sperm
Taken for 21 days then a 7 pill free period causes withdrawal bleeding (false period- no ovulation has taken place)
how does the progesterone only pill
Mainly effective due to effect on cervical mucus.
Does not actually blocked ovulation
Taken continuously, can cause irregular periods
Less reliable than combined pill- ovulation does take place
what are drug interactions with contraceptives
Broad spectrum antibiotic (e.g. amoxicillin) Enzyme inducers (e.g Barbiturates, phenytoin, rifampicin)
what is involved Contraception Metabolism
Fraction (variable) of exogenous hormone is conjugated in the liver (glucuronidation), and excreted in bile into duodenum
Gut flora with glucuronidase activity cleave the conjugate allowing reabsorption of active hormone. (may represent significant reservoir)
Broad spectrum antibiotic (e.g. amoxicillin), kill gut flora and so remove this reservoir
what do exogenous estrogen and progestrone do
target negative feedback and inhibit ovulation
why do dentists need to know about drugs and blood clotting?
Thrombo-embolic diseases are a major cause of death in developed countries
The drugs used affect blood clotting either by modification of blood coagulation or platelet adhesion and activation
Haemorrhage and bleeding of the GIT, mucus membranes, gingiva and urinary tract are common side effects
Since patients taking anticoagulants are on the edge of a haemorrhagic state, appropriate precautions must be taken for dental surgical procedures to be performed safely
what is haemostasis
the spontaneous arrest of blood loss from damaged blood vessels- essential to life
what are the main phenomena involved in haemostasis
Vasoconstriction
platelet adhesion and aggregation (eicosanoids)
fibrin formation (coagulation system versus fibrinolytic system)
what is a thrombosis
the unwanted formation of a haemostatic plug or thrombus within a blood vessel or the heart. This is different from a clot
how might a thrombosis occur
vascular disease e.g.atherosclerosis
prosthetic heart valves
atrial fibrillation
what are the consequences of thrombosis
deep vein thrombosis
pulmonary embolism
myocardial infarction
what is the difference between a blood clot and a thrombus
blood clots have not structure to them whereas thrombus’ have a distinct structure (white head and red tail)
blood clot forms in vitro and thrombus forms in vivo
thrombus’ can be arterial or venous
what is the difference between a arterial and venous thrombus
arterial- atherosclerotic, large head (platelets)
venous- normal, large tail-small head, gives rise to emboli
what are the processes that occur in blood clotting
complex series of enzymatic activations
produces active clotting factors from precursors
cascade mechanism which results in fibrin production
controlled by enzyme inhibitors and fibrinolysis
what are the main anticoagulants
heparin and oral coagulants e.g. warfarin
what is involved in the blood clotting cascade
blood clots in 4-8 mins
extrinsic and intrinsic pathway
Factor III, VII will stimulate the clotting process
Thrombin- factor 2 converts fibrinogen to fibrin. This can also co-recruit factor 13 which helps to stabilise the clot
what is heparin
sulphated mucopolysaccharide
found in secretory cells
can be low molecular weight heparins (LMWH)
outline the pharmacodynamics of heparin , what does it require for activity
heparin can bind to thrombin and antithrombin to inactivate thrombin
requires antithrombin III (a2 globulin) for activity
what does antithrombin III do
it stops the conversion of a soluble clot into an insoluble clot through the inactivation of:
thrombin, IX, X, XI and XII
why do LMWH’s have more consistent activity
Only bind to antithrombin not the other precursors
outline the pharmacokinetics of heparin
inactive orally
administered IV or SC (LMWHs)
short half life <1h (low dose) and 2h (higher dose)
eliminated by renal excretion
side effects include hypersensitivity and bleeding
outline the pharmacodynamics of warfarin
inhibits hepatic synthesis of vit K1 dependant clotting factors II, VII, IX, X
1-2 days before patient can stop clotting process
genetically determined resistance, reduced binding to vitamin K reductases
side effects - bleeding, skin necrosis
how is an overdose of heparin treated
overdose treated by IV protamine (binds to heparin and stops it from having a further effect)
how is an overdose of warfarin treated
vitamin K1 (iv or oral), fresh frozen plasma (thawed!)
outline the pharmacokinetics of warfarin
Dose - highly variable (1-20 mg/day)
Absorption - rapid, almost total
Plasma protein binding - ~99%
Metabolism - oxidation and reduction just as the vitK can
-Warfarin and vitK looks chemically similar- has the ability to act with reductase enzyme
Excretion - urinary metabolites
Half-life - 15-80h
Warfarin will stay in the body for a longer period of time over heparin
how is the effect of heparin monitored
partial thromboplastin time (PTT)
how is the effect of oral anticoagulants measured (warfarin measured)
prothrombin test (expressed as INR)
how is anticoagulant therapy monitored
Fasting blood taken to establish PT ratios
Issue with thrombosplastin variability required standardisation
Assigned international sensitivity index (ISI)
Patients PT is expressed as an INR (International Normalised Ratio).
-Compare to international standard
Typical Warfarin INR values range 2-4.
what are New/Direct oral anticoagulants – N/DOAC’s
New drugs that have come out
Still interact with the clotting cascade however target it without antithrombin
(Heparin binds to antithrombin III and turns off thrombin)
how do some drugs (name them) potentate THE EFFECT OF ORAL ANTICOAGULANTS
drugs which decrease platelet aggregation e.g. aspirin
drugs which inhibit cytochrome P450 e.g. co-trimoxazole
drugs which inhibit the reduction of vitamin K e.g. cephalosporin antibiotics. Clotting cascade dependant on vitK. Aspirins, NSAID, metronidazole etc have a known ability to interfere with vitK
how do some drugs (name them) decrease THE EFFECT OF ORAL ANTICOAGULANTS
drugs which induce cytochromes P450 e.g. rifampicin, many anticonvulsants
drugs which reduce absorption e.g. sucralfate
what does aspirin do
Inhibits eicosanoid production to inhibit platelet aggregation
- platelet-derived TXA2 promotes aggregation
- endothelium-derived PGI2 inhibits aggregation
aspirin irreversibly inhibits COX enzyme-mediated synthesis of both
endothelium can synthesise new COX, platelets cannot
net effect is an increase in PGI2 and inhibition of platelet aggregation
largely beneficial in disorders of arterial thrombosis
what are the dental implications for a patient medicated with Antiplatelet therapies
NSAID interaction with antiplatelet function of aspirin – delay NSAID for 1-2 hours.
Patient at increased risk of bleeding if 2 therapies (NSAIDS and aspirin)
Increased risk of bleeding following minor dental surgery with low dose aspirin.
Increased risk of mucosal damage and bleeding with combined NSAIDs.
what are the dental implications for a patient medicated with Anticoagulants
Antibiotics enhance anticoagulant activity (esp metronidazole, tetracycline)
NSAIDs contraindicated in postoperative pain and inflammation management – high risk of ulcerative bleeding.
