Drugs for pain, inflammation and OP Flashcards
Outline the neuronal pathway of pain perception.
The process of linking the stimulus to a response involves four stages
- Pain sensing - involves specific receptors known as nociceptors located in various tissues around the body.
- Signal transmission from the peripheral tissue to the dorsal horn of the spinal cord via afferent PNS neurons.
- Ascending transmission - involves transmission of the signals through the spinal cord to the brain via ascending tracts in the spinal cord - involves crossing of the second order neuron to the contralateral side (opposite side) - followed by the ascent of the spinothalamic tract through the medulla oblongata before synapsing with the third-order neurone in the thalamus
- Tranmission from thalamus to somatosensory cortex - this is where pain is consciously perceived
Note - thalamus is also connected to pre-frontal cortex - where cognitive and motor responses are coordinated -and to the limbic system - responsible for affective and emotional response.
Why is the dorsal horn a critical point in the pain pathway?
Important region because….
1. Pain signals transmitted that are being transmitted to the brain can be inhibited or amplified - Gate control theory
2. Site where reflexes are initiated to produce a protective motor responses.
Gate control theory
- Secondary neuron receives excitatory input from the PNS and a inhibitory signals from descending neurons from the brain - net level of excitation will influence the strength of transmission that ascends to the brain
Excitatory Neurotransmitters - The main excitatory neurotransmitters are the amino acid glutamate acting at AMPA and NMDA receptors and the neurokinin substance P acting at neurokinin A receptors. CGRP is another excitatory neurotransmitter that acts synergistically with substance P
Inhibitory Neurotransmitters - main inhibitory neurotransmitters are enkephalins and β-endorphin acting at G-protein-coupled (GPCRs) opioid receptors - block voltage gated Ca2+ channels, activation reduces cAMP and opens K+ channels - driving hyperpolarization. Other important inhibitors are GABA, glycine and cannabinoids.
What are the two main inputs at the dorsal horn according to the gate control theory?
The degree to which that gate is open may be influenced by…
(i) descending nerve impulses from the thalamus and cerebral cortex
(ii) other local afferent sensory inputs.
This helps to explain why factors such as mood, stress, tension and relaxation can significantly modify the perception of pain
Is pain sensing in our body regualted/controlled by different neurons to the sensing one’s?
Yes, pain sensing is separate and specific from other sensory modalities and not merely an augmentation of touch.
Nociceptors are found in somatic structures such as the skin, joints and muscles but are also present in the visceral lining of many of the internal organs.
Important difference!
- Pain pathway switches to the contralateral side of the spine/brain
- Afferent inputs that respond to fine touch and vibration ascend to the brain on the ipsilateral side (same side) as the input
Explain the biological underpinning behind the acute and more chronic/longer lasting pain associated with a injury?
Injury - sharp intial acute pain, followd by duller, less well-localised but more long lasting pain sensation.
Reason - 2 seperate afferent populations of neurons.
Acute pain - faster myelinated A𝛿
fibres convey the rapid, sharp pain that allows for a more immediate response to the threat
Longer lasting pain - Most of the nociceptive afferents are slower unmyelinated C fibres which account for the more sustained dull sensation.
Provide a brief outline of the different inputs that may drive the activation of nociceptive nerve endings.
Note - there is a final common pathway for all inputs - driving an action potential. Action potentials are facilitated by the increased availability of Ca2+ ions.
Examples include….
1. Cellular damage increasing availability of hydrogen ions, ATP and ROS - increased Na+ conductance
2. Inflammatory mediators - prostaglandins, prostacyclin and leukotrienes - GPCR agonists - upregulate Na+ influx
3. Inflammatory mediators - histamine, serotonin and bradykinin - GPCRs - increase IP3 production - increase Ca2+ levels
Note - Inhibitory mediators - endogenous opioids (enkephalins, B- endorphin, and dynorphins - downregulate Adenylate cyclase) and Nitric oxide (drives cGMP prodcution - reduces Ca2+ availability)
What are the different classifications of pain?
Dividing pain into three general groups based on pathways - nociceptive pain (somatic or visceral), neuropathic pain, and inflammatory pain.
- Nociceptive pain - can be located in somatic (skin, muscles and joints) - localized pain or visceral structures (internal organs) - diffuse pain
Note - Visceral pain is often associated with marked autonomic phenomena, including pallor (pale), sweating, nausea, gastrointestinal disturbances and body temperature change etc.
- Neuropathic pain - injury to neurones in the peripheral or central nervous system - described as being ‘burning’, ‘shooting’ or ‘stabbing’.
- Inflammatory pain - features of inflammation - heat and redness due to increased blood flow, pain due to both activation and sensitisation of nociceptors and swelling due to a local increase in vascular permeability
Prominent part of the amplification of the inflammatory response is the release of free arachidonic acid from membrane phospholipids by the action of phospholipase A2, which are then converted into prostaglandins via the cyclo- oxygenase pathways
Note - overlap between inflammatory and nociceptive pain - interested in seeing what is the main driver.
What is the definition of an analgesic?
Drugs that releive pain by modfying pain transmission pathways without blocking nerve impulse conduction, reducing consciousness or markedly altering sensory function
Note - there are many other drugs - anti-inflammatory, anti-epileptic, vaso-contrictors/dilators that may all reduce pain - but not primary mode of action
Note - aneasthetics reduce pain - but they do this by driving loss of consciousness
What are the different categories of analgesics?
Classification of analgesic drugs in to…
- Simple analgesics, of which paracetamol is the most important
- Opioid analgesics, which can be subdivided into weak opioids (e.g. codeine) and strong opioids
Opioid analgesics are the main category of analgesic drugs and are reserved for treating moderate-to-severe pain that has failed to respond to paracetamol - only common non-opiod analgesic
What drug is the first line treatment for pain?
Paracetamol Whoop Whoop
Effective with a good safety profile
What is the mechanism of action behind paracetamol
Paracetamol is an aniline analgesic
Structurally similar to aspirin - but have different pharamcological effects
Paracetamol is only a weak inhibitor of cyclo-oxygenase + no evidence for anti-inflammatory effect
Surprisingly, in spite of the availability of modern investigational techniques, the exact mechanism of action of this ubiquitously used analgesic is still uncertain.
Possibilities
- Appreas that the brain is the primary site of its analgesic and antipyretic actions.
- Some studies suggest that it reduces production of local prostaglandins - indicating the presence of a further isoform of cyclo-oxygenase in the brain
- Interferes with cyclo-oxygenase in the brain by a redox mechanism
- Enhances the descending inhibitory serotoninergic pathways by increasing the bioavailability of serotonin.
Outline the pharmacokinetics of paracetamol.
- Oral administration - rapidly absorbed from the gastrointestinal tract - its systemic bioavailability being dose- dependent and ranging from 70 to 90%.
- Peak plasma concentration is reached after around 1 to 2 hours.
- Plasma half-life of paracetamol in healthy subjects is around 2 hours
- Undergoes extensively Phase II metabolism in the liver to form sulfate and glucuronide conjugates, which are subsequently excreted in the urine
- Therapeutic dose - low amounts are converted to highly reactive alkylating metabolite - rapidly inactivated with reduced glutathione and excreted
Paracetamol - What are the clinical effects, indications, contra-indications and people you use caution perscribing to?
Clinical effects - pain relief and reduction of fever
Caution should be applied when treating…
- Adult patients with low body mass
- Those who have established liver disease, or risk factors for it
How are the paracetamol dosages and formulations typically perscribed?
Formulation
- Tablets or capsules (500 mg), oral suspension (24 mg/mL)
- Intravenous injection
- Suppositories
Dosage
- 500 mg–1 g (1–2 tablets) by mouth (PO) every 4–6 hours
- Maximum dose: 4 g/day
- Dose reductions: adults weighing < 50 kg, established liver disease, children less than 16 years old
Compound analgesics
- co-codamol 30/500 tablets = codeine 30 mg/paracetamol 500 mg
- co-dydramol 30/500 tablets = dihydrocodeine 30 mg/paracetamol 500 mg
What are some adverse reactions and drug interactions associated with paracetamol?
Paracetamol is a relatively safe drug with a low risk of adverse effects when used appropriately - Most important advise - limit to 4g per day
Hypersensitivity reactions such as thrombocytopenia, leukopenia and skin rashes are rare
Be aware of is hepatotoxicity which is most commonly seen following a deliberate overdose - why –> Phase II metbaolism overwhelmed resulting in increased Phase I reaction in the cytochrome P-450 enzyme system to a toxic intermediate (NAPQI) - depletes liver’s glutathione stores (required for reduction) - radical accumulates causing toxicity & necrosis.
What is the difference between the term opiate and opiod?
Opioid - refers to all natural, semi-synthetic, and synthetic agents that are capable of activating opioid receptors
Opiate - refers strictly to those opioids such as morphine and codeine that occur naturally
What are the different classifications of opiods?
Opioids are, by definition, molecules that are capable of being agonists at endogenous opioid receptors - three main sub-types - mu, kappa and delta -
Example of action Mu-recepotrs linked to adenylate cyclase, inhibiting Ca2+ entry pre-synaptically and facilitates K+ exit into outisde the cell post-synaptically
Three main categories…
1. Natural agonists - produced endogenously β-endorphin, the enkephalins and the dynorphins
2. Strong opiods - e.g. morphine, which are full agonists at opioid receptors
3. Weaker opioids - e.g. Codeine, less efficacious as opioid receptor agonists
What is mechanism of action of opiods?
The main sites of analgesic action are in the brain, the dorsal horn of the spinal cord and nociceptive neurones.
Opioids act on G-protein-coupled receptors that are located both pre-synaptically and post-synaptically.
Pre-synaptically, opioids block calcium channels on nociceptive afferent nerves to inhibit the release of neurotransmitters such as substance P and glutamate, which contribute to nociception.
Post-synaptically, opioids open inwardly rectifying potassium channels, which hyperpolarise cell membranes (efflux of K+), increasing the required action potential to generate nociceptive transmission.
Other mechanisms include potentiation of serotoninergic neurotransmission and antagonism of the binding of glutamate at the N-methyl-D-aspartate (NMDA) receptor
Outline the impact of opiods on the pain pathway.
Actions of opioids at pre- and post-synaptic neurones have an important influence on both the ascending and inhibitory descending pain pathways.
Ascending pathway - Dorsal horn - spinal cord contains opioid interneurones that release endogenous opioid neurotransmitters targeted at both pre-synaptic and post- synaptic opioid receptors - inhibits first and second order neurons
Descending inhibitory pathway is itself under inhibitory control by GABAergic neurones (GABA inhibits descending pathway) - endogenous opioid neurones in the central nervous system can reduce the inhibition of the inhibitory pathway by preventing the release of gamma-aminobutyric acid - net effect of this action is to enhance the descending inhibitory signals
Outline the pharmacokinetics of opiods - morphine?
Morphine undergoes extensive Phase II metabolism in the liver to form glucuronide conjugates at the 3- and 6- positions, which are subsequently excreted in the urine
Most other opioids (including oxycodone, fentanyl and tramadol) undergo Phase I metabolism in the liver cytochrome P450 system, principally through the CYP3A4 and CYP2D6 isoforms
Codeine - cytochrome P450 isoform CYP2D6 - gentic variation means that 10% of people won’t convert to morphine.
What are the clinical effects, indications, contra-indications and cautions for opiates?
The main indication for opioid analgesics is the treatment of moderate-to-severe pain - myocardial infarction, bowel perforation and fractured bones, and chronic pain
Two other less common indications for opioids are for pulmonary oedema (venodilatory effects reduce venous return to the heart) and for suppressing an intractable cough.
Several important contra-indications - acute respiratory depression and reduced consciousness
Caution in the elderly and those with pre-existing respiratory disease who are vulnerable to adverse effects
What are the different dosages and formulations for morphine?
Note - The dose of morphine, as well as most other opioids, should be reduced in the elderly or those with hepatic and renal disease that make them more vulnerable to the adverse effects
What are the adverse effects associated with opiods?
In the respiratory system, the most important effects of opioids is suppression of respiratory drive due to a central effect in the brainstem and this is the cause of many deaths amongst addicts. Can be reversed by administration of the mu- opioid receptor antagonist, naloxone.
Overacrhing adverse effect - dependency/addiction
Provide an overview of the pharmcodynamic drug interactions of opiods.
Pharmacodynamic interactions occur with drugs that have a similar or opposite effect on body tissues and organ systems.
Important interaction - with other drugs that also inhibit the activity of the central nervous system
e.g. Alcohol and benzodiazepines also interact to depress respiration and are often contributory factors in opioid- related deaths
Provide an overview of the pharmcokinetic drug interactions of opiods.
Pharmacokinetic interactions occur with drugs that alter the handling of opioid analgesics in the body
Main interactions - drugs co-administered which either inhibit or enhance the the Phase I metabolism of opioids in the liver cytochrome P450 system
Commonly prescribed drugs that are also metabolised through the same cytochrome isoforms, and therefore potentiate the effect of opioids by inhibiting their metabolism, include…
- anti-arrhythmic drug amiodarone
- selective serotonin re-uptake inhibitors (SSRIs)
- antibiotics (e.g. ciprofloxacin, clarithromycin)
A small number of drugs induce the production of more metabolising enzymes and can increase the rate of elimination of opioids, includes..
- anti-epileptics (e.g. carbamazepine)
- antibiotic rifampicin
- corticosteroid dexamethasone.
Provide an overview of the pharmcokinetic drug interactions of opiods.
Pharmacokinetic interactions occur with drugs that alter the handling of opioid analgesics in the body
Main interactions - drugs co-administered which either inhibit or enhance the the Phase I metabolism of opioids in the liver cytochrome P450 system
Commonly prescribed drugs that are also metabolised through the same cytochrome isoforms, and therefore potentiate the effect of opioids by inhibiting their metabolism, include…
- anti-arrhythmic drug amiodarone
- selective serotonin re-uptake inhibitors (SSRIs)
- antibiotics (e.g. ciprofloxacin, clarithromycin)
A small number of drugs induce the production of more metabolising enzymes and can increase the rate of elimination of opioids, includes..
- anti-epileptics (e.g. carbamazepine)
- antibiotic rifampicin
- corticosteroid dexamethasone.
What advise do we give to patients when perscribing opiods?
How to take the medicine - depends on the formulation - immediate or modified release + what is meant by ‘as required’ perscriptions
Taking medicine as prescribed and clarifying the point at which review will be necessary
Impact it may have on driving and other skilled tasks
What do we look for when monitoring the effects of opiods - acutely and chronically?
Acute - cardiorespiratory signs of toxicity such as reduced respiratory rate, a fall in arterial O2 saturation or low blood pressure.
Chronic - impact of treatment on pain control, adverse effects and dependency.
Outline the use of local anaesthetic drugs for pain releif, include example, general mechanism, methods of administration and adverse effects,
What are some other drugs used to treat neuropathic pain, migranes, MI and gout.
What is the definition of inflammation? How can you divide the causes of inflammation in a simple manner?
Inflammation can be defined as….
“A defensive response to tissue damage that is designed to eradicate the causative agent and initiate a repair process”.
The causes of inflammation might be conveniently divided into those that arise from…
- Outside the body (e.g. trauma, infection, chemical irritation and radiation)
- Pathophysiological processes arising within the body that cause inflammation as a secondary manifestation (e.g. autoimmunity, ischaemia and metabolic causes like gout).
How is inflammation categorized from a temporal persepctive?
Inflammation can be further divided in to acute and chronic, based on its duration.
Other causes of chronic inflammation are chronic infections, exposure to environmental factors (e.g. smoking, alcohol) and the low grade vascular inflammation associated with cardiovascular risk factors such as hypertension, hyperlipidaemia and diabetes
What are the four cardinal features of inflammation?
- Heat (or calor) arises because of the significant increase in blood flow related to vasodilatation in inflamed tissues, which is mediated primarily by nitric oxide (NO) and vasodilatory prostaglandins
- Redness (or rubor) also arises because of vasodilatation of superficial vessels
- Swelling (or tumor) arises because the local vessels become leaky - in response to histamine, bradykinin, leukotrienes, complement components, substance P and platelet-activating factor (PAF).
- Pain (or dolor) arises because of the release of inflammatory mediators such as bradykinin, histamine and prostaglandins in the vicinity of nociceptive neurones.
What are the two main categories of anti-inflammatory drugs?
-
Non-steroidal anti-inflammatory drugs (NSAIDs) - all inhibit the action of the enzyme cyclo-oxygenase (COX) and thereby reduce the production of prostanoids from arachidonic acid.
- NSAIDs can be divided into those that are not selective for COX-1 or -2 (e.g. ibuprofen, indometacin, diclofenac, naproxen), and those that are selective (e.g. celecoxib).
- Some NSAIDs that have intermediate properties (e.g. meloxicam, etodolac). - Corticosteroids - considered as a type of immunosuppressant drug as their primary mechanism of anti-inflammatory action is suppression of the immune response
Note - other immunosuppressant drug include disease-modifying anti-rheumatic drugs (DMARDs), cytokine modulators and a variety of other small molecules
How are NSAIDs categorized?
NSAIDs can be defined as a class of drugs that have in common the ability to act as reversible inhibitors of the conversion of arachidonic acid to prostanoids by the enzyme cyclo-oxygenase (COX) - basically a COX antagonist
Exception is aspirin which produces inhibition that is effectively irreversible - require new COX to be produced
Image shows classification based on chemical origin - but it is more useful to think to categorize based on selectivity for COX isoforms.
What is the arachidonic pathway?
- Arachidonic acid is released from membrane phospholipids by the actions of the enzyme phospholipase A2 (upregulated during inflammation)
- Arachidonic acid is converted into a range of active molecules - most known is the enzyme cyclo-oxygenase (COX) - rate-limiting enzyme involved in the conversion of arachidonic acid to prostaglandin H2, the precursor of all of the prostanoid mediators
Outline the pharmcokinetics of ibuprofen.
The pharmacokinetic handling of other commonly-used NSAIDs (e.g. naproxen, diclofenac, celecoxib) is broadly similar.
Outline the clinical effects, indications, contra-indications and cautions for NSAIDs.
NSAIDs have an anti-inflammatory action and so are indicated for a range of painful inflammatory conditions
Aspirin is a unique NSAID that inhibits cyclo- oxygenase irreversibly to prevent platelet aggregation at doses that are much lower than necessary for its anti-inflammatory effects - used for acute cardiovascular events (e.g. myocardial infarction, stroke) and also in the secondary prevention of cardiovascular disease
Contra-indications
- GI bleeding - interfers with muscus secretion
- Increases fluid retention
- Avoided during pregnancy
What formulations are available and what dosage is typically used for NSAIDs?
NSAIDs are usually administered by mouth as either immediate- release or modified-release preparations
Gels are available when trying to avoid systemic effects
What are the adverse effects associated with NSAIDs?
-
Gastrointestinal adverse effects are related to inhibition of COX-1 which normally generates PGE2 that contributes to gastric mucosal protection against gastric acid
- Gastrotoxicity is reduced amongst patients taking the COX-2
- Perscribed with proton pump inhibitor - Renal function - NSAIDs can lead to decreased glomerular filtration rate, salt and water retention, and acute kidney injury - watch out with elderly
- Asthma - increase in production of leukotrienes, which act as bronchoconstrictors
- Cardiovascular - increase blood pressure (due to impaired kidney function), oedema and cardiovascular risk
- Increase bleeding time - reduction in thromboxane A2, which is responsible for increasing platelet adhesiveness and vasoconstriction
What are some pharmacodynamic interactions we need to keep in mind when perscribing NSAIDs?
- Gastrointestinal adverse effects - combining with other NSAIDS or corticosteroids and with other drugs that favour bleeding if the gastric mucosa is damaged including anticoagulants (warfarin, apixaban, heparins and Aspirin - big one)
- Renal impairment - other drugs that might adverse affect renal function because they block the renin-angiotensin system (e.g. ACE inhibitors) or cause dehydration (e.g. diuretics)
- Water retention - NSAIDS will counteract the activity of antihypertensive drugs
What are some pharmacokinetic interactions we need to keep in mind when perscribing NSAIDs?
Pharmacokinetic interactions - NSAIDs impairing the excretion of other drugs
NSAIDs may interfere with the elimination of the disease-modifying anti-rheumatic drug methotrexate and the mood-stabilising drug lithium
Why is the term corticosteroid not very precise?
Ther are several kinds of steroid hormone secreted by the adrenal cortex that are derived from the structure of cholesterol.
Include…
- Mineralocorticoids (e.g. aldosterone)
- Glucocorticoids
- Sex steroids
When used in medical practice without further qualification, the term ‘corticosteroid’ (or even simply ‘steroid’), usually implies ‘glucocorticoid’,
How are corticosteroids/glucocorticoid categorised?
Glucocorticoids can be divided into those that occur….
- Naturally and are secreted by the adrenal gland (e.g. hydrocortisone, also known as cortisol)
- Synthetic group - which can be divided into…
a) Those that resemble hydrocortisone
b) Those that resemble betamethasone and acetonides
All glucocorticoids have powerful anti-inflammatory and also immunosuppressant effects but differ in their potency and their associated mineralocorticoid actions.
What is the mechanism of action behind corticosteroids?
Corticosteroids elicit their actions through their binding to cytosolic glucocorticoid receptors (GRs)
- Circulating free cortisol, being lipophilic, passes directly across the cell membrane into the cytoplasm
- Displace HSP that is bound to GR and translocates into the nucleus, dimerises (homo) and binds to sequences of target genes
- Up-/down-regulate gene expression.
Also non-genomic mechanisms - interfere with the transcription factors activated protein-1 (AP-1) and nuclear factor-κB (NF-κB) - both involved in inflammatory signalling
Further complexity and diversity is introduced through multiple glucocorticoid receptor isotypes - GRa (main) and GRb
Outline the different steps of the hypothalamic-pituitary-adrenal (HPA) axis?
Hypothalamic-pituitary-adrenal axis.
- Hypothalamus produces corticotropin releasing hormone (CRH) in response to many distinct circadian, neurosensory, blood-borne and limbic signals.
- CRH, in turn, acts on the anterior pituitary gland, resulting in the secretion of adrenocorticotrophic hormone (ACTH) into circulation
- ACTH acts on zona fasciculata of the adrenal gland, resulting in the synthesis and release of cortisol
- Circulation - cortisol is primarily bound to corticosteroid binding protein (CBG), with only a small fraction (~10%) existing as free, biologically active, cortisol
- Circulating cortisol negatively regulates both CRH and ACTH release at the hypothalamus and pituitary - negative feedback
Note - there are many stressors that increase CRH release - surgery, illness, etc.
Cortisol has a plethora of effects across the body as shown in the image.
Outline the pharmocokinetics of corticosteroids.
Prednisolone, the most commonly used oral corticosteroid
The plasma half-life of prednisolone in healthy subjects is around 2–3 hours although the intracellular effects are of a much longer duration
The pharmacokinetic handling of other commonly-used corticosteroids (e.g. hydrocortisone, dexamethasone) is broadly similar.
Outline the clinical effects, indications, contra-indications and cautions for corticosteroids.
Indicated for the treatment of a wide range of conditions where inflammation and overactivity of the immune system are involved
Include…. Bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis and other inflammatory arthropathies, polymyalgia rheumatica and giant cell arteritis, various autoimmune diseases (e.g. myasthenia gravis) and vasculitis)
Also used in allergic emergencies - e.g. penecillin
Replement therapy - for those with a non-functional adrenal cortex
Many circumstances for caution - care should be taken when prescribing corticosteroids for patients with…
1. Heart failure or hypertension (risk of salt and fluid retention)
2. Diabetes mellitus (worsening glucose control)
3. Peptic ulcer (negative impact on gastro-protection)
4. Untreated infection or a past history of tuberculosis
5. Osteoporosis or risk factors for it
6. Psychiatric disorders (known impact on mood and psychosis)
7. Recent surgery that necessitates healing of anastomoses
What are the formulations and dosages used for corticosteroids?
What are the adverse effects associated with corticosteroids?
When treatment is prolonged - there is a significant increased risk of unwanted adverse effects
- Immunosuppression
- Diabetes - increased glucose secretion
- Muscle function - weakening and wasting
- Bone - OP - direct effect on OB, OC and osteocytes, decrease calcium levels, increase PTH (stimulates OCs)
- Inhibit wound healing
- Psychosis
- Cause peptic ulceration or aggravate pre-existing ulcers.
- Renal - increase in renal stones and increase blood pressure
- Downregulates normal HPA axis - dependency
What pharmacodynamic drug interactions should we consider with corticosteroids?
Pharmacodynamic Interactions
Drugs that exacerbate the effects of corticosteroids - include other drugs that….
1. Exhibit gastrotoxicity such as other NSAIDS,
2. Precipitate hypokalaemia (Low potassium)
3. Precipitate arrhythmias when it occurs
4. Vaccinations with live viruses where there is a risk of more generalised infection occurring.
What pharmacokinetic drug interaction should we consider with corticosteroids?
Pharmacokinetic interactions occur theoretically with drugs that alter the rate of metabolism of corticosteroids
Exposure to system corticosteroids may be reduced by drugs that enhance CYP3A4 metabolism (e.g. carbamazepine)
Increased by those that inhibit CYP3A4 metabolism (e.g. ketoconazole, clarithromycin).
What advise do we give to patients when perscribing corticosteroids?
Patients on long-term corticosteroid treatment should be issued with a Steroid Treatment Card & Patient Information Leaflet.
Specific warnings
1. Immunosuppression, patients should be warned about the increased susceptibility to infection
2. Regarding adrenal suppression, patients should be warned that if corticosteroids are taken for longer than 3 weeks, treatment must not be stopped abruptly
3. Patients should be warned about mood and behavioural changes, especially when corticosteroid treatment is taken at high doses
When someone is perscribed corticosteroids, what should we monitor/keep an eye on?
When it comes to dealing with long term chronic infection, what other types of categories of drugs are used instead of NSAIDs and corticosteroids?
Examples
- Chronic rheumatic conditions - Disease-modifying anti-rheumatic drugs (DMARDs) - methotrexate
- Biological immunosuppressant drugs - are based on recombinant antibody technology
- Some of these drugs prevent metabolic causes of inflammation such as the effects of acid on the gastric mucosa or the effect of uric acid
- Cardiovascular disease is the commonest cause of death in the developed world and chronic inflammation of the vascular wall is an important part of the pathology - antihypertensives, cholesterol- lowering drugs and drugs for diabetes all indirectly improve vascular health by reducing the inflammatory response
What are the differences between cortical and trabecular bone?
Outline the changes that occur in bone as we age (young, midlife and old age).
What is osteoporosis? Who does it mainly effect? What are the two main types (think causes)?
Note - Trabecular bone is more metabolically active, and osteoporotic fractures tend to occur at sites composed of more than 50% trabecular bone.
Primary osteoporosis describes the development of osteoporosis as a result of predictable physiological changes with ageing.
Secondary osteoporosis arises when other important driving factors - include immobilisation, malnutrition and malabsorption syndromes, endocrine diseases (e.g. thyrotoxicosis, Cushing’s disease) and drugs (especially corticosteroids).
What are the primary and secondary preventions used for osteoporosis?
Primary prevention aims to prevent or slow the progression of osteoporosis and thereby prevent future occurrence of fragility fractures
- maintenance of a normal BMI level - not included in image
Secondary prevention - treatment of people that have osteoporosis - most common bisphosphonates
What are the pharmacokinetics of bisphosphonates?
Low absorption - Bisphosphonates are never given at meal times or with dairy products
Long bone half life - explains why single or short courses of intravenous bisphosphonate injections can be effective
What are the clinical effects, indications, contra-indications and cautions for bisphosphonates?
Indications - OP, Paget’s disease of the bone and bone pain or hypercalcaemia associated with cancer.
Contra-indications - pre-existing abnormalities of oesophagus (e.g. oesophagitis), any factors that delay oesophageal emptying and increase the risk of bisphosphonate-induced oesophageal irritation
What are the different formulations and dosages used for bisphosponate perscriptions?
Intravenous zoledronic acid is used for the once-yearly treatment of osteoporosis, as a single dose for the treatment of Paget’s disease of bone or tumour-induced hypercalcaemia or every 3 to 4 weeks to reduce bone damage in advanced cancer cases involving bone
What are the adverse effects associated with bisphosphonate use?
Note - atypical fractures - occur after minimal or no trauma, and some patients experience thigh pain weeks to months before presenting with a completed femoral fracture - frequently bilateral
What pharmacodynamic & -kinetic drugs interactions should we be aware for bisphosphonates?
PD interactions - The most important interactions bisphosphonates are with other drugs that can potentially cause irritation to the lower oesophageal mucosa, notably non-steroidal anti-inflammatory drugs (NSAIDs), aspirin and ibuprofen
PK interactions - occur with drugs that reduce the absorption of oral bisphosphonates - Calcium or iron supplements, vitamins, antacids, coffee, tea, soda, mineral water, calcium- enriched juices, and food can decrease the absorption of alendronate.
What advise should we give to patients when prescribing bisphosphonates?
What are some other durgs used for the treatment of OP?
