Pharmacology Flashcards
What are the main ion for 1) axonal transmission 2) pre-synaptic terminal
1) Na+ and K+
2) Ca2+
Ca release is triggered by Na+ and K+ wave of depolarisation
What are three ways of inactivating neurotransmitter
neuronal uptake (main), metabolism by glial cells and extraneuronal uptake
What is the function of cocaine
blocks neuronal uptake of NA, DA, 5HT
What is the different dose response of cocaine (high&low dose)
low dose: slow absorption, relief from fatigue, hunger, altitude sickness, some psychological dependence
high dose: rapid absorption, intense euphoria, severe psychological and physical dependence
What is the main cause of death from using cocaine
cardiac collapse
What is the main effect of amphetamine
it displaces NA from storage vesicle, so more NA can diffuse to synaptic cleft via non-exocytotic release. It can work under low concentration of NA
What is NA associated with in the brain?
stimulant effects, mood, appetite, cardiovascular control
Tyrosine is converted to L-DOPA via?
tyrosine hydroxylase
L-DOPA is converted to dopamine by?
dopa decarboxylase
dopamine is converted to NA by?
dopamine B-hydroxylase
NA is converted to adrenaline by?
PNMT
Dopamine rich area in the brain is associated with which function?
motor
What is the drug treatment of Parkinson’s disease?
L-DOPA + peripheral DDC inhibitor (block peripheral dopamine conversion)
What is Huntington’s disease? What is the drug treatment of Hungtinton’s disease?
GABA deficiency, lack of neuronal inibition
Treatment: Baclofen, GABA agonist, or Chlorpromazine, dopamine antagonist
T/F Neurotransmitters can be excitatory or inhibitory, and it determines whether a synapse is excitatory or inhibitory
False, first statement is correct, but the nature of the synapse also depends on the neurotransmitter receptor
What are the targets of analgesic drugs
pain and sensory pathways at all levels including periphery, spinal and the brain
What is the main difference in target between local and general anaesthetic
local: regionalised inhibition of pain and sensory pathways
General: depresses cortical processing of pain signals, with loss of consciousness
Describe the neural pathway of pain
peripheral nerve picks up the signal. Signal is relayed to spinal cord to secondary neuron. Secondary neuron carries information for processing in the thalamus, then finally to tertiary neuron that relays to the cortex
What is the significance of adding lime to cocaine
drug formation affects pharmacokinetics. A basic environment deprotonates the drug, making it more lipid soluble
Cocaine is not only a CNS stimulant, it is also a _________
local anaesthetic (first)
Define “local anaesthetic agents”
drugs that reversibly block conduction of nerve impulses at the axonal membrane
local anaesthetics are often ______ with different onset, duration and _______. They serve to block _______ Channels
weak bases
toxicity
Na+
Give an example of an aminoester
why is it short acting (45mins)?
procaine, it is short acting because it can be rapidly hydrolysed by esterases (like AchE)
Lignocaine is a _________ , which is a stabilised form of _________ and is no longer affected by _________ . However, it requires ________ of the liver, so the effect of drug varies between individuals
aminoamide
aminoester
esterases
conjugation
What are some examples of lethal toxins that lie on the same pathway as local anaesthetics?
tetrodotoxins
saxitoxin
immobilise preys or serve a protective function
Give three properties of local anaesthetic that make it a clinically useful drug
1) selective binding to Na channels (except for cocaine)
2) reversible binding without damaging nerves
3) will affect all nerves and excitable tissues, so local application is crucial for limiting systemic distribution
What are some other excitable tissues affected by local anaesthetics?
1) peripheral motor neurons (paralysis)
2) ANS nerves (hypotension, CNS convulsion, coma)
3) heart (anti-dysrhythmic to cardiac arrest)
With an epidural injection, we can block 100% and only lose ________% of motor neuron function
less than 50
if injected correctly
Which part of the Na channel does the local anaesthetic bind to? How is that different to toxins?
intracellular domain (S6, to be specific) toxins bind extracellular domains, so the effect does not dependent on channels being active
Why does benzocaine belong to a different class of anaesthetic
it is hydrophobic and therefore fast acting and not use-dependent (does not dependent on Na channel being open and active)
Why does lignocaine act slower than benzocaine
it is hydrophilic, so gets across the membrane slower than benzocaine.
Note that lignocaine is 65% protonated at pH 7.4, so does not diffuse well
There are two gates on a Na channel, what are they?
M gate extracellularly which opens during depolarisation
N gate intracellularly, which closes during hyperpolarisation
What is the effect of local anaesthetics blocking Na channels?
the neuron is unable to reach threshold potential, and action potential is therefore prevented
Does local anaesthetic affect resting membrane potentials?
No, the drugs can also stabilise axonal membrane
why are small fibres more sensitive to local anaesthetic
thinner membrane, quicker drug diffusion
Why does lignocaine cause cardiovascular symptoms like myocardial depression, vasomotor centre in brainstem, and hypotension?
Because it blocks Na channels on all excitable tissues, so there is direct blocking of myocardial fibres and vasomotor centres, and there is hypotension because of SNS block
Why does cocaine cause hypertension instead of hypotension?
it does block the sympathetic nerves, but it also blocks the reuptake of NA, hence increase cardiac output
The CNS and CV side effects of lignocaine are proportional to blood drug concentration. Which side-effect is not proportional?
hypersensitivity / allergic response
In a dental wound, why does a dentist need to clean it up as much as possible before using anaesthetic?
Inflamed areas tend to be acidic, and local anaesthetics are more in the charged, protonated form in acid. Cleaning up the wound lower the dose required
Describe the four stages of general anaesthesia
I) amnesia/euphoria, pre-excitement stage
II) excitement (last about 20 seconds)
III) surgical anaesthesia, unconsciousness but regular breathing
IV) medullary depression, one you want to avoid as there is CV/Resp arrest
All general anaesthetic increase likelihood of respiratory and CV side effects. What is often given in conjunction in order to prevent obstruction of airways
anti-muscarinics to block secretions, as secretions are retained
What should we consider if general anaesthetic is applied to a patient undergoing surgery sitting up?
must monitor CV function, as there is sometimes inadequate response to fall in BP and CO
What is Meyer-Overton Lipid Theory? What makes this theory plausible?
anaesthesia is caused by volume expansion of membrane lipids, impinging on the normal protein function. This is possible because drug effect can be reversed by pressure
What do anaesthetics do to the effects of neurotransmitters?
enhance inhibitory receptors (GABA) and inhibit excitatory (glutamate) receptors
What is propofol?
IV general anaesthetic
What is the problem with most CNS drugs?
the drugs are somewhat empirical. SSRI for example, the effect varies based on individual
On a biochemical level, what is the treatment for epilepsy
reduce excitation from glutamatergic neurons
increase inhibition from GABA neurons
What is an example of glutamatergic epileptic drug? How does it work?
Phenytoin - it inhibits Na channel on glutamatergic neurons to reduce action potential triggering glutamate release
Note that it only works when the channel is open
What is an example of GABAergic epileptic drug? How does it work?
Benzodiazepine, enhances GABA receptor activity by binding the allosteric site
T/F different neurotransmitter receptor in the CNS can have similar desirable effect
True, for example, serotonin, NA and NPY all have effect on anxiety
What is the use of benzodiazepine? Why is it used less in the market nowadays
it is use to treat epilepsy, anxiety, sleep disorders, sedative. It is used less because it affects coordination
What are some clinically recognised anxiety disorders?
generalised anxiety states
panic disorder
phobias
PTSD
How can beta-antagonist be used as an anxiolytic
it blocks the physical manifestation of anxiety like increased heart rate and resp rate
What class of drugs is barbituate
general depressant, very good anaesthetic
What is it becoming obsolete
it is exceeding toxic with low therapeutic index. It can induce liver enzyme and abrupt withdraw can cause death
Why can you overdose on barbituate but not benzodiazepine
Because of the way drugs open the GABA channels
with benzodiazepine, there is a ceiling effect on how frequent the channel can open.
Barbituate binds GABA receptors and keep them open, so there isn’t a ceiling effect
What pharmacological term can be used to describe barbituate and benzodiazepine? (the way they affect GABA channels)
they are both allosteric modulators that increase the effect of endogenous agonist effect at GABAa channels
What is efficacy in pharm term?
the strength of the receptor activation
T/F The current treatment for Parkinson’s is very new
False, the therapy hasn’t changed for 50 years
Where is dopamine produced in the motor system? What is its effect on the target site?
from the substantia nigra, and it tonically inhibits the corpus striatum
What effect does the corpus striatum exert on the cortex?
GABA, so inhibition
What are some motor signs of Parkinson’s related to muscles?
Tremor, rigidity of limbs
bradykinesia, impairment of postural reflexes
decreased manual dexterity
What are the facial signs of Parkinsons?
impassive and no blinking
what are the symptoms of Parkinsons associated with speech?
monotonous
hypophonic
There are non-motor signs in Parkinson’s - what is usually the first presenting symptom? Which symptom usually follows shortly after?
Olfactory deficiencies
bowel and bladder control
which protein mutation will predispose to Parkinson’s?
alpha synuclein
What do motor symptoms present at the later stage of Parkinsons
you need to lose up to 80% of motor neurons before symptoms occur
What does a MRI scan of a Parkinson’s patient look like
There is asymmetric degradation of DA neurons
What is the role of L-DOPA in terms of managing the patient?
the drug provides symptomatic relief, but it’s not curative
Why do we need to add cholinergic antagonist along with dopamine?
movement relies on the balance of DA and Ach
when there is less DA, there is less inhibition, so neurons are hyper-excitable
anti-cholinergics are added to reduce effect of Ach, hence restore normal movement
What happens if we ingest dopamine
vomit violently
What needs to be co-administered with levodopa to ensure its efficacy?
Dopa-decarboxylase inhibitor in order to prevent metabolism in the periphery
T/F You need functional neurons for levodopa to work
True, hence there is a debate on when to start the drug. When you start using the drug, you increases degeneration of DA neurons
T/F Levodopa has a long half life
False, the half life is only about 1-2 hours, so patients need to constantly medicate
What happens if you take too much levodopa?
experience tardive dyskinesia, which is involuntary, repetitive body movements
What kind of central side effects does levodopa cause?
visual and auditory hallucinations abnormal motor movements mood changes depression anxiety
What is the function of levodopa?
increase dopamine synthesis
What is the function of bromocriptine? Why is it preferred in younger individual?
dopamine agonist
the disease is more aggressive in younger people
T/F bromocriptine has more CNS side effects than levodopa
True, it floods the whole brain with dopamine
What is the function of the drug Entacapone?
inhibits COMT, therefore inhibit the breakdown of DA
What is the function of selegiline?
it’s a Mao-inhibitor, reduce metabolism of dopamine
What is the new therapy for Parkinson’s, said to be available within 10 years?
phototherapy, turn on receptors in response to light
How does levodopa accelerate DA neuron death?
levodopa stimulates DA production. For DA to be produced, you need iron. The increased iron level creates reactive oxygen species, and the increased oxidative stress on mitochondria ultimately kills the neuron
What is MPTP?
a by-product of a party drug, which accelerates the death of DA neurons and Parkinson’s
What are the key areas in the brain involved in addiction
nucleus accumbens
ventral pallidum
amygdala
hippocampus
T/F Only monoamines are involved in addiction/reward
False, GABA, glutamate, and opioids can be involved as well
How does overdose on amphetamine cause death?
In general, it’s not the CNS effect. Death is caused by CV related issues like tachycardia, increased BP, and eventually vascular collapse
What are the symptoms of withdrawal of amphetamine
lethargy, sleep, desire for food, depression
MDMA (Ecstasy) is both a _______ and a _________. Structurally, it is similar to ________, but it is considered safer. There is strong ________ dependence as well as CV side effects. __________ can also be disrupted, leading to chills and sweating. MDMA in linked to production of ROS, and may cause ________ of 5HT and DA neurons
stimulant hallucinogen amphetamine psychological Thermoregulation degeneration
What is the primary effect of LSD
visual, auditory and tactile hallucinations due to disruption of sensory processing
Is LSD addictive?
not usually, because the effect can be aversive
How does tolerance development differ between ethanol and LSD
the tolerance of LSD comes from cross tolerance with other drugs (pharmacodynamic), while ethanol tolerance comes from increased metabolism (pharmacokinetics)
What class of drug is caffeine?
adenosine antagonist and phosphodiesterase inhibitor
What adverse effect on the tissue level can ethanol cause?
liver damage, neurodegeneration, foetal impairment
T/F Ethanol is a CNS stimulant
False, it is a CNS depressant
What are the actions ethanol in the CNS
inhibit Ca channel opening = stop exocytosis of transmitters
enhance GABA action
inhibit NMDA
What class of drug is flumazenil
GABA receptor antagonist
What are the subjective effects of D9-THC
sharpened sensory awareness
relaxation, feeling of well being
What class of drug is D9-THC
cannabinoid receptors agonist, a GPCR that inhibit adenyllate cyclase
What is the endogenous substance activating cannabinoid receptors
anadamide
What are the central effects of D9-THC
binding to CB1 to cause impaired short term memory, impaired motor coordination, catalepsy, analgesia, anti-emetic, increased appetite
What are the peripheral effect of D9-THC
binding to CB2 to cause tachycardia, vasodilatation, reduced intraocular pressure, bronchodilatation
what’s the pharmacological action of tricyclic antidepressant
inhibit neuronal uptake of NA and 5HT
adrenoceptor, muscarinic receptor, histamine and serotonin receptor antagonist
very non-selective
What are the clinical effects of tricyclic antidepressant
takes a few weeks to take effect because there is long term anti-depressant activity
T/F tricyclic antidepressant has a high therapeutic window
False, it has a narrow window and must be prescribed with care
T/F tricyclic antidepressant has a long half life
True, so there may be late on-set side effects. Patients need to start first on a low dose and increase if it’s working
What’s cheese reaction
when taking MAO-inhibitor, the tyramine contained in cheese cannot be neutralised, which can lead to a hypertensive crisis
What’s the advantage using Moclobemide
It’s a selective MAO-A inhibitor, so patients are less likely to get cheese reaction
What are the side effects of SSRI
nausea, insomnia, agitation, weight change, loss of libido, suicidal tendencies in adolescent
What’s an example of SSRI
Fluoxetine
