Possible 2 mark questions (all topics, not including definitions) Flashcards
what four words does ADME stand for? (a useful term in pharmacokinetics)
Absorption
Distribution
Metabolism
Excretion
(things that the body does to the drug - pharmacokinetics)
describe the process of first pass metabolism
when a drug is administered orally, it is absorbed by the gastrointestinal tract and transported via the hepatic portal vein to the liver where it is metabolised. as a result, only a small portion of the drug is passed into systemic circulation.
list the four organs of the body where first pass metabolism takes place
liver and gut (stomach, small intestine, large intestine)
list the four main routes of drug administration
enteral (via the gut): can include orally or rectally
parenteral (not via the gut): can include injections or topical administration
what are the pros and cons of oral drug administration?
pros:
- low infection risk
- self administration is possible
cons:
- comes up against issues of first pass metabolism
- stomach is a harsh environment so drugs need to be formulated appropriately for this.
what are the pros and cons of topical drug administration?
pros:
- local effect
- low infection risk
- bypass first pass metabolism
- low systemic effects/side effects
cons:
- long period of administration
- must be lipid soluble in order to permeate skin. must also be a drug with small molecules so they can be transported by carrier proteins
- often the carrier molecule used in drug formulation is a mild irritant in order to better permeate skin
what are the pros and cons of injection as a method of drug administration?
pros:
- rapid bioavailability
- can be targeted
- bypasses first pass metabolism
cons:
- infection risk is high
- targeting risk if the needle misses.
what is the difference between enteral and parenteral drug administration?
enteral is administration of a drug via the gut (orally or rectally) and so the drug is subject to first pass metabolism, meaning bioavailability is likely to be lower. parenteral methods bypass the gut and therefore bypass first pass metabolism.
what are the processes that affect drug absorption?
- route of administration
- permeation (the ability of the drug to cross cell membranes)
list the properties in Ficks law that determine how fast a drug is able to be absorbed.
- surface area
- distance
- concentration gradient
what are the three main processes that affect drug distribution in the body?
- protein binding (only free, unbound drug can pass through cell membranes or bind to receptors. those bound to plasma proteins cannot)
- blood flow (higher blood flow = more drug in that area of the body)
- membrane permeability (a more permeable membrane will allow more drug into or out of a cell)
describe phase I metabolism
phase I metabolism is the first stage of breaking down a drug, it often involves creating toxic metabolites. the product of phase I metabolism is called the derivative. Phase I metabolism usually involves enzymes such as cytochrome P450 in the liver. phase I changes the chemical structure of the drug through processes such as oxidation or deamination.
describe phase II metabolism
phase II metabolism is the second stage of drug metabolism. (although can happen without phase I preceding it.) it involves the conjugation of the phase I metabolite with an endogenous substance, via covalent bonding, this makes the drug water soluble and biologically inactive. following phase II metabolism, the conjugate can be excreted from the body safely.
name the four main protein targets for drugs
receptors
ion channels
carrier molecules
enzymes
describe the process of pro-drug conversion using codeine as an example
codeine is a mild opioid in its original form, some other pro-drugs have no physiological effect in their original form. however, when codeine is metabolised in the liver, a portion of it becomes morphine, which is a much stronger opioid. it is this morphine that then passes into systemic circulation. pro-drugs can be activated by metabolism in the liver through interaction with enzymes. genetic differences determine how fast codeine is metabolised in the liver, and it can be dangerous for fast metabolisers as they end up with high doses of morphine in their blood.
describe the difference between an ion channel blocker and an allosteric modulator
an ion channel blocker is a drug that sits in the pore of an ion channel, physically blocking it by being there. alternatively, an allosteric modulator binds to the ion channel at another site and changes the shape or function of the ion channel by doing so (so the channel is left open, but the molecule may change function or structure to change what comes into/out of the cell)
describe the different ways that drugs can interact with enzymes
- enzyme inhibitors: normal action of an enzyme is blocked by the drug sitting in the binding site of the enzyme as they are substrate analogues (same shape as the intended substrate)
- false substrate: the drug binds to the enzyme and is broken down by it, this creates abnormal metabolites
- pro-drug: the drug binds to the enzyme and when it is broken down by the enzyme, it becomes a biologically active drug
what is the difference between an orthosteric antagonist and a allosteric antagonist
both drugs block the action of a receptor. orthosteric antagonists bind to the intended ligand binding site and block the intended ligand from binding. allosteric antagonists bind to somewhere else on the receptor and change the shape or charge of the intended ligand binding site, deactivating it.
describe the difference between an agonist and an antagonist
an agonist is a molecule which activates a receptor. an antagonist either blocks a receptor or reduces a response caused by an agonist. they oppose each other.
what is the difference between a drug and a medicine
a drug is a chemical substance of known structure that has a biological effect. a medicine is one or more drugs combined (usually with excipients such as bulking agents or coatings) and administered for desired therapeutic effect. most medicines will contain at least one drug but a drug can exist without being a medicine.
what are the three different names that can be given to a drug?
- chemical name (describes the drugs chemical structure)
- generic name (class of drug to which the molecule belongs)
- proprietary name/manufacturers name (what the drug is sold as)
describe the mechanism of action of NSAIDs
NSAIDs inhibit COX enzymes, which convert arachidonic acid into intermediaries which then become prostanoids such as prostoglandin. by blocking COX enzymes, no prostoglandin is created so free nerve endings are not activated.
briefly outline the desired effects of NSAIDs
- anti-inflammatory agent (prostoglandin is a vasodilator, but also no prostoglandin means less substance P so less neurogenic inflammation and less vasodilation = less swelling and oedema)
- analgesic agent (blocking COX 1 leads to no prostoglandin so less peripheral sensitisation. blocking COX 2 in the spine also stops central sensitisation)
- antipyretic effect (pyrogens stimulate prostoglandin E2 in the hypothalamus, this sends signals to regulate temperature. NSAIDs block COX 2 so no prostoglandin i made and so nothing interferes with pyrogens in the hypothalamus)
- platelet aggregation (platelets produces thromboxane A2 which alters surface proteins on platelets and allows them to bind together. COX 1 inhibition reduces thromboxane A2 and reduces blood clotting)
explain how NSAIDs work as anti-inflammatory agents
prostoglandins derived from COX 2 enzymes are powerful vasodilators. inhibition of COX 2 removes these prostoglandins so no vasodilation occurs. lack of prostoglandin also prevents peripheral sensitisation and the production of substance P, which causes vasodilation and neurogenic inflammation. so the use of NSAIDs reduces swelling, oedema and redness.
explain how NSAIDs work as analgesic agents
NSAIDs block COX enzymes, which create prostoglandins. prostoglandins are early activators of free nerve endings and so lack of prostoglandin means that free nerve endings are not stimulated, preventing peripheral sensitisation also. NSAIDs also inhibit COX 2 in the dorsal horn of the spine, which prevents central sensitisation.
explain how NSAIDs work as antipyretic agents
pyrogens stimulate prostoglandin E2 in the hypothalamus, PGE2 inhibits temperature sensitive neurons, which means that the body can keep heating up with no signal of this reaching the hypothalamus. when the production of prostoglandin is stopped by NSAIDs blocking COX enzymes, temperature sensitive neurons can once again communicate with the hyppothalamus and homeostatic temperature control is restored.
explain how NSAIDs work in preventing platelet aggregation (blood clotting)
thromboxane A2 is produced by COX enzymes and changes surface proteins on platelets to allow them to bind to one another and create blood clots. when COX 1 is inhibited, thromboxane A2 production is stopped, which means platelets do not bind to one another and blood clots do not form. Aspirin has strong COX 1 selectivity and binds irreversibly to COX 1 in platelets so they never recover the ability to clot so new platelets must be produced in their place
when and where are COX 1 and COX 2 enzymes found?
COX 1: present in most tissues, primary roles are within gastrointestinal system and blood clotting
COX 2: usually undetected in tissues but is produced at the site of injury in response to inflammatory cytokines. also present in the CNS (spine).
list the potential unwanted side effects of NSAIDs
- gastrointestinal (COX 1 selective NSAIDs such as aspirin)
- respiratory (both, but common with COX 1 selective NSAIDs such as aspirin)
- Renal side effects (both COX1 and COX2 selective NSAIDS)
- liver damage (both, less common side effect but more severe)
list the intentional and unintentional side effects of aspirin
intended effects:
COX 1 inhibition leads to reduction in blood clotting/platelet aggregation. even though aspirin is COX 1 selective, it will still bind to some COX 2 so will also have analgesic, antipyretic and anti-inflammatory effects
unintended side effects:
COX 1 inhibition leads to potential for gastrointestinal issues, through the removal of protective mucous, and respiratory side effects such as aspirin induced asthma.
however through the inhibition of COX enzymes more generally could also have renal and hepatic side effects.
how can aspirin lead to gastrointestinal problems?
prostoglandins promote the production of strong alkali mucous which lines the stomach so that stomach acid doesn’t start destroying the stomach itself. when COX 1 is inhibited by a COX 1 selective NSAID such as aspirin, prostoglandin production decreases and so less alkali mucous is produced. this may lead to aspirin induced gastritis and stomach ulceration.
how can aspirin use lead to respiratory side effects
arachidonic acid is also converted into leukotrienes which are bronchoconstrictors. when COX 1 is not inhibited, only some arachidonic acid is converted into leukotrienes, however when COX 1 is inhibited by NSAIDs such as aspirin, this leaves a large amount of arachidonic acid in the tissues of the lungs as none is being converted into other substances such as prostanoids, therefore, more arachidonic acid is converted into leukotrienes, so more bronchoconstriction takes place. this is an issue if the person already suffers with a respiratory condition such as asthma as it can induce symptoms of an asthma attack.
how can use of NSAIDs lead to renal damage?
prostoglandins promote vasodilation and glomerular filtration. when prostoglandins are not present, reduced renal filtration occurs, which leads to increased sodium retention. this in turn reduces the efficacy of the kidney and leads to damage.
how can NSAIDs use lead to liver damage?
the mechanism of this is not particularly well understood.
- retention of bile as a result of NSAID use could lead to liver damage
- mitochondrial damage which eventually leads to programmed cell death
- inhibition of prostoglandin E2 which is cytoprotective (stops programmed cell death)
- reactive metabolites - some of the metabolites of NSAIDs may cause an autoimmune response which eventually leads to the immune system destroying healthy liver cells.
outline the mechanism of action for opioids
at the dorsal horn in the spine, a nociceptive neuron meets a second order neuron. here, neurotransmitter is released to signal an action potential in the second order neuron and the nociceptive signal can then travel up the spine. however, endogenous opiates can reduce the transmission of neurotransmitter by binding to the synapse on the first order neuron. Opioids are drugs which artificially bind to the site of endogenous opiates and prevent the transmission of nociceptive stimuli to the second order neuron.
Opioids also have central effects within the brain but these are more complex and less well understood. overall opioids seem to depress the activity of neurons.
what are the potential side effects of opioids?
- constipation (activity of nerve cells in gut is downregulated)
- depression of cough reflex
- depression of respiration (neurons in brain stem responsible for inspiration, breathing in, are depressed)
- nausea/vomiting
- tolerance effects
- physical dependence and addiction
- euphoria
what are the potential long term effects of opioid use?
- immune suppression
- decreased sex hormone production
- opiate induced hyperalgesia (hypersensitivity to pain rather than pain suppression)
outline the mechanism of action of paracetamol
the mechanism of action of paracetamol is poorly understood. it is almost an nSAID but not technically. it may inhibit COX 2 within the CNS or even act on COX 3 which is very poorly understood in humans. alternatively it may activate descending inhibitory pathways or activate cannabinoid receptors.
- either way it is an analgesic and antipyretic
outline the process of metabolising paracetamol
phase I: this involves the breaking down of paracetamol into the toxic metabolite, NAPQI
phase II: glutathione breaks NAPQI down into the biologically inactive glutathione conjugate which can then be excreted from the body.
- unfortunately there is only enough glutathione in the body to cope with 4g worth of paracetamol per day, hence this is the maximum dose.
what are the potential side effects of paracetamol?
- overdose is very harmful and cause liver and kidney damage. it can also cause low blood cell count including low white blood cell count and low platelet count
- allergic reactions
- low blood pressure as the metabolites of paracetamol are vasodilators
what is the WHO analgesic ladder?
a treatment strategy for the management of pain. low levels of pain should be treated with no opioids, as pain increases the strength of opioid prescribed should increase.
- issues with this include the potential for over-reliance on opioids (addiction and possibility that they stop working) and lack of biopsychosocial approach (better ways of managing long term pain)
describe the difference between A delta and C fibres
both fibres are nociceptive fibres. but they have different properties. A delta fibres are large and myelinated and therefore transmit information much quicker (this is why you feel a sharp pain first). whereas C fibres are much thinner and non-myelinated, meaning they transmit much slower (why the dull, aching pain comes after the sharp pain). there are more C fibres in the body, making up about 70% of all nociceptive fibres.
describe the pathway of nociceptive information from the site of damage to the brain
A delta and C fibres both collect nociceptive information and carry information to the spine.
once in the spine, both fibres travel up the spinothalamic tract, which decussates in the spine, although carry slightly different information and target different areas of the brain.
- faster A delta fibres travel via the direct spinothalamic tract (lateral) to the cortical areas of the brain to allow for conscious awareness of pain. this allows for distinct spatial discrimination of the injury as well.
- slower C fibres travel via the indirect spinothalamic tract and target areas of the brain that are involved with the unconscious processing of pain including the hypothalamus, limbic system and reticular formation. this pathway has far worse spatial discrimination (a general ache in your foot rather than a pinprick pain)
describe the direct spinothalamic tract
the direct spinothalamic tract is an afferent sensory spinal pathway that carries information regarding pain/nociception to the conscious areas of the brain (cortical areas). the pathway decussates in the spinal cord. it travels through the lateral branch of the spinothalamic tract (which carries pain sensation). this branch of the spinothalamic tract primarily contains A delta fibres which carry fast, sharp pain and allow for clear spatial discrimination of the location of the injury.
describe the indirect spinothalamic tract
the indirect spinothalamic tract is an afferent sensory spinal pathway that carries information regarding pain/nociception to the unconscious areas of the brain such as the hypothalamus, limbic system and reticular formation. this pathway decussates in the spine. this pathway primarily contains slower C fibres which carry slow, aching pain with poor spatial discrimination for the site of injury.
briefly describe the pain gate theory
this is a theory proposed by Melzack and Wall whereby there is a ‘gate’ in the spinal cord that can be open (more experience of pain) or closed (less experience of pain). this gate can be closed by ascending physiological input such as the mechanoreceptor fibre, interneuron and nociceptor interaction that underlies the ‘rub it better’ principle (to summarise this, the activation of a mechanoreceptor allows an inhibitory interneuron to inhibit nociceptive signals reaching a second order neuron in the spine). however the gate can also be controlled by descending modulation from the cortical areas of the brain. for example if someone is happy and relaxed, descending signals from the brain can close the pain gate to reduce nociceptive signals. A biopsychosocial model of pain perception.
describe the process of peripheral sensitisation
When there is damage to an area of the body, early activators of free nerve endings include histamines, bradykinins, H+, K+ etc can trigger action potentials and lead to pain sensations.
when injury is persisting, free nerve endings release substance P. substance P activates mast cells to release more histamine, which in turn leads to greater activation of the free nerve ending. this creates a kind of feedback loop. substance P is also a powerful vasodilator and causes neurogenic inflammation at the site of injury.
describe the process of central sensitisation
central sensitisation, also known as spinal hyperexcitability, follows the principles of a process called long term potentiation, whereby a one time maximal stimulation of a second order neuron in the spine can lead to increasing sensitivity to lower levels of stimuli.
normal stimuli level = activation of AMPA receptors which causes a depolarisation/action potential as normal
maximal/large stimuli level = unblocking of NMDA receptors which allow for the entry of Ca2+ ions into the neuron, this starts an intracellular cascade whereby more AMPA receptors are made and AMPA receptors are made more sensitive. this means that the neuron itself becomes more sensitive to lower levels of stimulation.
list/describe some real world application of the pain gate theory
- ‘rub it better’ (also i think sometimes when someone is experiencing dermal injection into the skin, the clinician may rub the skin to reduce the sensation of the needle)
- psychological coping techniques (relaxation and meditation exercises, healthy coping strategies, distraction can all close the pain gate)
- social techniques (social support and lack of social isolation can close the pain gate)
biopsychosocial viewpoint is more important for individuals dealing with chronic pain as they will need long term self-management techniques outside of the use of drugs.
list some of the psychosocial factors which open or close the pain gate
closing the pain gate:
- social support
- healthy coping strategies
- distraction
- happiness
opening the pain gate:
- unhealthy coping strategies or pain catastrophising
- boredom
- anxiety
- lack of social support/social isolation
describe the descending modulatory pain pathways
descending modulatory pain pathways stem from the periaqueductal gray. they are a top down control mechanism of pain. broadly they act on endogenous opioid receptors and stop first order neurons from releasing neurotransmitter in the dorsal horn. there are two descending pathways. the serotonergic pathway releases serotonin and the noradrenergic pathway which releases noradrenaline.
why is pain a useful sensory modality?
pain warns us of an actual or potential risk to the body. it provides an alert of actual or potential damage so that the body can react (either consciously or unconsciously in the case of spinal reflex arcs) to remove itself from danger or away from noxious stimuli. pain largely prevents damage or further damage to the body.
briefly describe the different types of pain
acute = less than 3 months
chronic = longer than 3 months
neuropathic = no longer/no biological cause
superficial = skin level, localised
somatic = within the body, deeper, longer lasting
visceral = within organs or organ systems, dull, long lasting ache.
