Pharmacology Flashcards
What is the difference between pharmacodynamics and pharmacokinetics?
Pharmacodynamics= the biochemical and physical effects of drugs on the body. Pharmacokinetics= how the drug reacts he's its target, how much will be absorbed, excreted and distributed. Pharmacokinetics= 'what the body does to the drug' Pharmacodynamics= 'what the drug does to the body'
What is pharmacology?
the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes.
What is clinical pharmacology?
the study of drug action in man providing scientific basis for rational, safe and effective prescribing. (Understanding why people have different reactions.)
What are therapeutics?
the application of the principle of clinical pharmacology to the use of drugs as medicines to treat human diseases.
What are agonists and antagonists?
Agonists= drugs that stimulate body systems 'a ligand that binds to a receptor and produces a conformational change that initiates in intracellular signal' Antagonists= drugs that inhibit pathways.'a ligand that binds to a receptor but does not produce a conformational change'
What is a ligand?
A small molecule which can bind to receptors eg drugs or hormones
What happens when a ligand bonds to a receptor?
It creates a change in the glycoprotein which releases a signal into the cell which cascades and turns into a biological response.
Usually reversible
What happens when the concentration of ligand increases?
A larger biological response occurs
How are channel linked receptors effected by ligands?
Changes the protein to allow ions to cross, leading to depolarisation or hyerpolarisation of membranes.
When a ligand stimulates it ,called ligand- gated channel
What are examples of ligands and receptor names of channel-linked receptors?
Ligand- acetylcholine
Names- cholinergic (nicotinic) and GABAergic
What is the mechanism of g-protein coupled receptors?
The receptor protein associates with a G protein to activate either an enzyme which produces a ‘secondary messenger’ or an ion channel
Ligand causes a conformational change which exchanges bound GDP for the more abundant GTP, which triggers dissociation of the g-protein form the receptor which goes on to interact with other proteins.
What are ligands that influence g-protein coupled receptors?
acetylcholine
adrenaline
opioids
What are examples of g-protein coupled receptors?
Cholinergic
Beta-adrenergic
Opioid
What are enzyme linked receptors?
They initiate enzymatic conversions. The proteins have 3 main parts; a ligand binding domain, a hydrophobic transmembrane domain and a linked cytosolic enzyme.
What do enzyme linked receptors usually control?
Responses are slow- couple of hours
- Have a role in growth and differentiation of cells
- mediates rapid effects on the cytoskeleton
What are examples of enzyme- linked receptors and their ligands?
Ligands=Insulin, Leptin
Examples= insulin receptor, leptin receptor
What is the mechanism of nuclear receptors?
Stimulate mRNA synthesis in the cell leading to protein synthesis.
Have direct influence on gene expression, cell growth, metabolism and homeostasis.
What is an example of an irreversible drug reaction?
Aspirin, it is so strong
How do drugs influence ion gated channels?
CHANNELS= drugs can effect the permeability of the channel by occupying the space in it. ENZYMES= Drugs can act a substrate and will bind to the active site or a different site- competition. TRANSPORTERS= can bind to it and cause a conformational change that prevents it from binding to its su
How do drugs influence enzymes?
ENZYMES= Drugs can act a substrate and will bind to the active site or a different site- competition. Competitive= binds to active site Allosteric= binds elsewhere which changes shape of active site.
What are the 3 ways drugs influence transporters?
- allosteric inhibition, binds to it and causes a conformational change
- may bond to the molecule site where the substances bind to be transported
- may act as a false substrate
How can the effects of a competitive antagonist be reduced?
increasing the concentration of agonists
What is a partial agonist?
A ligand that binds to a receptor and produces a conformational change that initiates an intracellular signal but one that is of a lesser magnitude than for the full agonist
What is an inverse agonist?
They are incapable of activating a receptors- biochemically equivalent to antagonists, but produce a pharmacological response opposite to those caused by agonists at the same receptor.
What is the effective dose range, max response (Emax) and ED50 of a drug?
The effective dose range is where there is the most change in the drug response
Max response is when the curve levels off, no higher response can be brought about
ED50 is the drug dose that gives 50% of the max response
Where does the adverse curve need to be for a successful drug?
Far to the right
What is the therapeutic window?
the range of dosage of a drug or of its concentration in a bodily system that provides safe effective therapy
What happens to the ED50 when there is a competitive antagonist present?
If there is is an antagonist present, higher concentrations of agonist are required to preoduce the same response. Therefore, ED50 will be higher.
The curve will be shifted to the right
What happens to the the dose-response curve when there is a non-competitive antagonist?
What is the competing agonist and antagonist on beta-1-adrenceptor?
Antagonist= atenolol
Agonist= noradrenaline
What are the competing agonist and antagonist on muscarinic cholinergic recptors?
Agonist= acetylcholine
Antagonist= Atropine
What are the competing agonists and antagonists on mu-opioid?
Agonist= morphine
Antagonist= naloxone
What will the dose-resonse curve look like for partial agonists?
What is meant by drug efficacy?
Efficacy is the term used to describe the extent to which a drug can produce a response when all available receptor or binding sites are occupied. Corresponds to Emax.
A full agonist will have a higher efficacy than a partial; partial can only achieve sub-maximal responses even when all receptor sites are occupied.
What does therapeutic efficacy mean?
Used to describe the comparison of drugs that produce the same therapeutic effects on a biological system but do so via different pharmacological mechanisms.
What does drug potency mean?
Used to describe the amount of drug required to produce a given response. More potent drugs produce responses at lower doses, so have a lower E50.
Related to its affinity for the recptor, which indicates how readily the drug-receptor complex is formed.
What is receptor selectivity?
Where a ligand can bind with higher affinity to some receptors of a specific type compared with others.
Drugs that are considered to be ‘selective’ for one receptor can still produce significant effects at other subtypes. ‘it may be lost when the dosage is increased’
What does affinity mean?
the degree to which a substance tends to combine with another
Where is selectivity most likely to be achieved?
at the lowest effective dose.
How are receptors categorised into subtypes?
Selectivity of agonists and antagonists
Differential responses to agonists
How are agonist and antagonist selectivity for two receptor subtypes defined?
Agonist selectivity- the ratio of ED50 from the dose-response curves
Antagonist selectivity- the ratio between the ED50 change is plotted on a D-R curve with and without the antagonist.
What does desensitisation, tolerance and tachphylaxis mean?
Desensitisation=Refers to the common situation where the biological response of a drug diminishes when it is given repeatedly. May be restored by increasing the dose.
Tolerance= describes a gradual loss of response to a drug that occurs over days or weeks
Tachyphlaxis= describes desensitisation that occurs very rapidly.
What does desensitisation over a long and short time indicate?
Short- depletion of chemicals required for drug to work
Long- reduction of target receptors or physiological changes that offset the actions of the drug
What do reractoriness and cross-tolerance mean?
Refractoriness= a state in which there is a lack of response to a drug
Cross-tolerance= patient exhibits desensitisation to a drug due to developing a tolerance to a pharmacologically similar drug.
What are some mechanisms that effect pharmacodynamics?
- reduction in receptor numbers
- receptor inactivation
- exhaustion of mediators of drugs
- physiological adaptions, eg hormone response
What is the therapeutic index?
The ED50 ratio between the doeses causing adverse effects and those required to produce beneficial effects.
Each patient is unique and so has a different therapeutic index for certain drugs- this means there will always be patients who have adverse effects.
What effects absorption of a drug?
- The route that it was absorbed by- barriers to cross
- molecular size
- pH
- surface area of absorpsion route
- blood supply to absorpsion area
- rate of stomach emptying
*
What do drugs need to be in order to pass the phospholipid membrane?
Need to be lipid soluable- most drugs are slightly alkaline or acidic
What limits small, highly lipid soluable drugs passing into the tissue?
What limits low lipid soluable drugs?
The perfusion (passage of fluid through the circulatory system) of the tissue, so the concentration gradient does not become balanced
the rate of membrane penetration
What are the 4 ways in which a low lipid-soluable drug can pass through the membrane?
Passive diffusion, carrier mediated transport, pore mediated transport and pinocytosis
How do steriods cross the membrane?
Passive diffusion
What is pinocytosis?
Uncommon- the cell membrane folds back in on its self to form an endosome containing a small amount of extracellular fluid containing a drug.
What are the different administration pathways?
- Orally, into stomach then bowls
- Buccal, dissolved between upper lip and gum
- sublingual, dissolved under tongue
- rectal
- inhaled
- intravenous
- intramuscular
- topical and subcutaneous for skin
What is the bioavailability of a drug?
the fraction of the initial dose of a drug that successfully reaches the site of action
Why may drugs administered orally not be absorped?
Some molecules destroyed by gasric acid
some destroyed by ‘first pass’ enzymes in intestinal wall
Some returned to the intestine through membrane transporters such as P-glycoprotein
Can bind to food
How do the graphs of time- plasma conc vary for the intravenous and oral route?
What are factors affecting distribution of drugs?
Molecular size, lipid solubility, ionisation, binding to plasma proteins, rate of blood flow and special barriers (e.g. the blood-brain barrier). Additionally some drugs have particular affinity for specific tissues.
How do drugs move around the body (bulk, filtration and diffusion)?
What proteins are acids, bases and steriods bound to in plasma?
Why and when are they bound?
Weak acids- albumin
Weak bases- alpha1-acid glycoprotein
Steriods- globulin
Bound as soon as drug enters plasma. Bound drug molecules cannot leave the plasma because the protein they are bound to is too large- also cannot be excreted or metabolised. As the concentration of unbound drugs falls, the bound drugs dissociate themselves to keep a steady concentration.
What are the different types of endothelium?
Normal- any drugs crossing must cross two membranes and cytosol of cells or through the small gaps between the cells
Specialised organs- discontinuous allowing free passage of drugs in water.
Central nervous system- tight junctions and impermeable layer of peri endothelial cells (pericytes)
Vast majoirty of aqueous drugs cross by diffusion
What is the volume of distribution defined by?
the volume of fluid required to contain the total amount of drug in the body (A) at the same concentration as that present in the plasma (CP).
Volume of distributon (L) = amount of drug (mg)/plasma concentration (mg/L)
Cannot be measured however, only inferred
What is the relevence of volume of distribution?
it provides an indication of the extent of the drug’s distribution and its tissue binding. A small volume of distribution suggests that a drug is largely retained in the vascular compartment while large volumes suggest significant uptake and binding in most tissues.
What is metabolism?
the conversion of a substance from one form to another by the actions of enzymes or organisms.
Where is the main site for drug metabolism?
The liver- contains a high concentration of the metabolising enzymes in the smooth endoplasmic reticulum- the P450 system
Any absorbed chemicals must be able to survive the conditions of the liver to be passed into the circulatory system.
Metabolism also occurs in the skin, lungs, small bowl mucosa and kidneys.
What is the aim of the liver when metabolising drugs?
turns the drug molecule into an inactive metabolite that poses no danger to the body, converts that metabolite into a chemical form that can be excreted from the body, otherwise the drugs would be reabsorbed in the rectal area.
How are the cytochrome enzymes organised and how do they metabolise drugs?
Each cytochrome enzyme contains a haem-bound iron at the active site, responsible for binding with oxygen and the drug substrate, enabling the transfer of one atom of oxygen to the substrate in the presence of NADPH, which provides the reducing equivalents to facilitate the reaction.
What occurs in phase II of drug metabolism in the liver?
Phase II reactions involve conjugation of the metabolite formed in a Phase I reaction with natural endogenous constituents to form glucuronide, sulphate, acetyl and methyl conjugates. These products are water-soluble and therefore suitable for excretion either in urine or bile
What factors affect metabolism?
Genetic variations of the P450 enzymes, age (older patients= reduced capacity), sex, nutritional status, disease status, interacting drugs, dose of drug and route of administration.
What are enzyme in inducers and inhibitors?
An enzyme inducer is a type of drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme. It is the opposite of an enzyme inhibitor.
What is first pass metabolism?
The loss of a proportion of an orally administered drug dose by metabolism in the small bowel mucosa and liver is known as first-pass metabolism and can significantly reduce the bioavailability of some drugs.
How are drugs excreted?
At kidney, drugs are excreted into urine, largeb molecules excreted into the bile and subsquently, the faeces.
The lungs allow some volatile anaesthetic gases to leave
Other routes include tears, sweat, saliva, hair and breast milk.
Why must molcules be water soluble to be excreted?
If the drugs were not water soluable, they would be rapidly reabsorped down a concentration gradient.
Water soluable molecules are trapped in the kidney tubes.
What are the 3 processes that affect urinary excretion?
Glomerular filtration-carries water, ions and most molecules of low molecular mass across the fenestrated glomerular membrane into the renal tubule. The extent that drugs or their metabolites are filtered depends on renal blood flow and the degree of binding to plasma proteins.
Tubular secretion- The tubular cells contain specialised transporter molecules that enable the active transport of acidic and basic drugs into the tubular lumen.
Passive tubular reabsorption- lipid soluable drugs flow down a conc gradient back into the body. Strong acids and bases are not reaborbed.
How are drugs excreted into the bile?
Conjugation, particularly with glucuronic acid, facilitates biliary excretion. Most drugs excreted into the bile require active transport- ATP-dependent transport protein such as P-glycoprotein.
What is the rate of elimination and clearance?
The rate of elimination is the amount of drug that is eliminated in a unit of time (min).
Clearance is the rate of elimination of the drug from the body divided by the plasma drug concentration.
What is the half-life of a drug?
HALF LIFE= describes the time period over which the plasma concentration halves. If a drug is doubled, the drug concentration will also double (does not mean effects will double).
What are the two ways the time-drug concentration relationship can arise?
First order kinetics- a constant fraction of drug is cleared in a unit of time
Zero-order kinetics- a constant amount of drug is cleared in a unit of time
Different drugs follow these two relationships
What are the different elimination rate vs dose and plasma concentration vs dose for first and zero order kinetics?
When will a drug that follows first order kinetics be in the therapeutic range?
What does the dosage regime involve?
individual dose, the frequency of dose administration and the duration of treatment.
What is the ‘steady state’ of a drug?
‘Steady state’ is reached when the concentration of drug in the body is sufficient to mean that the rate of elimination
There will be peaks and troughs however these will be in the therapeutic range
achieved based on half life rather than dose interval
What will the time vs plasma concentration graph look like for drugs with long and short half life?
What will the graphs of time vs plasma concentratio look like for continuous intravenous injection at the start and after the needle has been removed?
The rate of rise and fall is dependant on the half life, reaching 50% of the steady state after one half-life
How are patients treated in life threatening circumstances with drugs that have a long half life?
an initial ‘loading’ dose that is much larger than the regular maintenance dose, and equivalent to the amount of drug required in the body at steady state, is given
What are the somatic and autonomic nervous systems?
Somatic= controls organs under voluntary control
Autonomic= Regulates organ function and homeostasis. Can be further divided into sympathetic (danger and stress) and parasympathetic (background housekeeping)
What are the differences between sympathetic preganglionic and postganglionic fibres?
Sympathetic preganglionic fibres
• myelinated
• cell bodies in lateral horns of the spinal segments
• synapse in ganglia with a postganglionic fibre
Sympathetic postganglionic fibres
• unmyelinated
• much longer than preganglionic fibres
• run all the way to the effector organ
What is the ganglion?
A ganglion is a collection of neuronal bodies found in the voluntary and autonomic branches of the peripheral nervous system (PNS).
What do the adrenal glands do?
The adrenal glands located on superior aspect of each kidney. It responds to nervous impulses in the sympathetic cholinergic preganglionic fibres by transforming the neural impulses into hormonal secretion into the circulation
What is the receptor and neurotransmitter in preganglionic sympathetic nerves?
- acetylcholine (ACh) is the neurotransmitter
- acts at nicotinic receptor at the preganglionic synapse
What is the transmitter for postganglionic sympathetic nerves?
Noradrenaline
(sweat glands are an exception postganglionic sympathetic fibres release ACh at muscarinic
receptors)
What are the receptors at postganglionic sympathetic nerves?
alpha1, alpha-2, beta-1and beta-2 receptors. These receptors classify as G-protein coupled receptors and are adrenoreceptors
What actions does the sympathetic nervous system do?
increases in circulation of blood carrying oxygen and nutrients to exercising muscle
Releases energy stores (e.g. glucose, free fatty acids) for exercising muscle
Diverts blood flow from less important circula7ons (e.g. skin, splanchnic) to make it available for muscles
Dilates bronchi allowing improved ventilation of the lungs
Dilates pupils allowing more light into the eye
Constricts sphincters
What are the agonist drugs that act on the sympathetic nervous system?
Alpha agonists- noadrenaline
Alpha and beta agonists- adrenaline
Beta-2 agonists- salbutamol
What are the antagonist drugs that effect the sympathetic nervous system?
Beta-1 selective antagonist- atenolol
Beta antagonist- propranolol
Alpha antagonist- doxazosin
What are the preganglionic and postganglionic fibres ike in the parasympathetic nervous system?
Parasympathetic preganglionic fibres=myelinated, leave the brainstem (midbrain, pons, medulla) and sacral segments (S2–S4) of the spinal cord, preganglionic fibres travel long distances to synapse with postsynaptic fibre in ganglia (clusters of synapses) located in effector organs
Parasympathetic postganglionic fibres =unmyelinated, much shorter than preganglionic fibres, most located near to or within effector organs
What neurotransmitter and receptor are present in the parasympethetic system?
Neurotransmitter- acetylcholine (aCh)
What are Muscarinic and nicotinic receptors?
Nicotinic- directly coupled to increased permeability of cation channels (Na+, K+), which depolarises the post-synaptic membrane. Nicotinic receptors are found in autonomic ganglia.
Muscarinic- G-protein-coupled receptors coupled to phospholipase C, which activates K+ channels or inhibits Ca2+.
What is the difference in length of preganglionic and postganglionic cells in sympathetic and parasympathetic systems?
Sympathetic- pre is short, post is long
Parasympathetic- pre is long, post is short
What are the functions of alpha and beta receptors in the sympathetic system?
Alpha-1 vasoconstriction
Alpha-2- located in the presynaptic membrane
Beta-1- heart rate increased
Beta-2- vasodilation, bronchial smooth muscle relaxion
What are the agonists and antagonists of the parasympathetic nervous system?
Cholinergic agonists- acetylcholine, pilocarpine
Cholinergic antagonists- atropine, ipratopium
What is a nociceptor?
A nociceptor (“pain receptor”) is a sensory neuron that responds to damaging or potentially damaging stimuli by sending “possible threat” signals to the spinal cord and the brain.
How does the body perceive pain?
Nociceptors detect pain and transmit signals to the dorsal horn.
These are then transmitted through the spinal cord to the brain via ascending tracts, to the thalamus.
This signal is then transmitted to the somatosensory cortext where pain is consciously perceived
What are the main excitatory and inhibitory neurotransmitters at the dorsal horn synapse?
Excitation- amino acid glutamate acting at AMPA
Inhibition- enkephalins acting at g-protein coupled opioid receptors.
Why is the dorsal horn synapse important in pain pathways?
Signals can be inhibited or amplified to be sent to the brain
What is the gate control theory?
Theory based on the idea that the dorsal horn synapse is a gate through which afferent pain signals have to pass in order for pain to be transmitted to the brain
What and where are nociceptors?
Found in skin, joints, muscles as well as the visceral lining of many of the internal organs
They are a network of free nerve endings
In skin, located in epidermal layer
Why is pain sharp at first, and then a dull ache afterwards?
Signals produced by nociceptors are carried by two types of fibres
- alpha fibres convey rapid sharp pain
- slower c fibres account for dull sensation
How does cellular damage and inflammation effect neurotransmitters?
Most of the mediators (increase in concentration after tissue damage) that are capable of initiating action potentials in nociceptors act by influencing the intracellular availability of Na+ and Ca+ ions. They act on ion channels or as ligands at G-protein-coupled receptors.
Cellular damage increases availability of H ions and ATP all which increase sodium conductance
Inflammation, three important products of the inflammatory process, prostaglandins, prostacyclin and leukotrienes are agonists at G protein-coupled receptors linked to the enzyme adenylate cyclase. The enzyme generates cyclic AMP which indirectly up-regulates Na+ influx.
What are important excitatory and inhibitory neurotransmitters at the dorsal synapse?
The synapse with the secondary neurone involves the excitatory neurotransmitters glutamate (NMDA) and substance P (neurokinin), but is also influenced by several important inhibitory neurotransmitters including endogenous opioids, γ-aminobutyric acid (GABA), cannabinoids and adenosine- act at opioid receptors such as mu, delta and kappa. These are g-protein receptors and are located on both the pre-synap1c and post-synap1c membrane
(in brackets= receptor they act at)
What important decending inhibuitory neurotransmitter systems effect the dorsal horn synapse?
Pathways from decending inhibitory neurotransmitter systems include serotonin (targets serotonin receptors) and noradrenaline (alpha-2 agonist- inhibits glutamate and substance P from being released from stores)
What does somatic and visceral mean? (in terms of nociceptors)
SOMATIC- sites close to or on the surface of the body, more defined and sharp
VISCERAL- internal organs, less defined pain and associated with sweating, nausea, changes in body temp
What is neuropathic pain, allodynia and hyperalgesia?
Neuropathic- injury from neurones in the peripheral/CNS.
Allodynia- sensory inputs that would not normally be painful become painful
Hyperalgesia- (increased in severity of pain in response to a s1mulus that would usually only provokes mild pain
What are the broad range of drug types?
Analgesic drugs- reduce pain by influencing pain pathways, eg paracetemol or morphine
Anti-inflammatory drugs- target the inflammatory process and divided into NSAIDS and corticosteroids. NSAIDs, eg ibuprofen are common. Corticosteroids are synthetic analogues of the glucocorticoids that are naturally produced by the adrenal cortex.
Neuropathic pain- affect transmission of signals in the CNS. Eg Gabapentoids
Anaesthetic drugs- reduce pain perception as part of their global inhibitory actions on consciousness and central nervous system function, nitrous oxide
What is inflammation?
A defensive response to tissue damage that is designed to eradicate the causative agent (eg e.g. trauma, infection, toxin) and initiate a repair process.
Further divided into acute and chronic. Acute is a response to an acute insult that is required as part of the healing process. Might be due to trauma, eg bruise, infection eg dental, toxin eg sting or an allergic reaction. Chronic is on ongoing response to a chronic auto-immune disease that causes damage to key structures and chronic pain. Eg autoimmune disease or chronic infection.
What are the features associated with inflammation?
- Heat, blood flow and vasodilation increases in inflamed tissues
- Redness arises due to the above
- Swelling arises because the local vessels become leaky in order to allow proteins, antibodies and cells to extravasate from plasma into the tissues as part of the repair process.
- Pain due to release of inflammatory mediators such as bradykinin, histamine and prostaglandins in the vicinity of nociceptive neurones.
What recognises initial damage of cells?
Cell surface receptors recognise the products associated with either cell damage or the presence of pathogens- binding of the receptors activates these cells, promoting the release of inflammatory mediators (eicosanoids, chemokines, enzymes, nitric oxide and cytokines)
What is cell degranulation?
Degranulation is the immediate response of tissue mast cells (resident immune cell of connective tissue) to wounding, releasing preformed mediators into the local connective tissue which results in the recruitment of cellular and soluble effectors
What mediators does mast cell degranulation release and what does this cause?
Mast cell degranulation releases several mediators causes vasodilation, increased vascular permeability (allows large molecules to pass through) and pain including (i) the monoamine histamine, (ii) the peptide bradykinin, (iii) prostaglandins and (iv) leukotrienes.
This allows molecules such as antibodies, platelets to pass through membrane
What is the role of macrophages in inflammation?
Macrophages are also an immune cell involved in an early response to injury. When exposed to products of tissue damage they release a range of cytokines that amplify the inflammation. Cytokines are involved in local cell signalling.
Tumour necrosis factor-alpha is released by macrophages and modulates a variety of immunological and metabolic events. Local- activates neutrophiles and mononuclear phagocytes, also serving as a growth factor for fibroblasts. It also induction of apoptosis (programmed cell death). Systemic- induces fever and stimulates production of protein secretion by the liver. Some of its effects can become life threatening- hypotension, myocardial suppression and hypoglycaemia.
What role do neutrophils and lymphocytes have in inflammation?
Neutrophils- white blood cells, promote stopping or slowing of blood allowing leukocytes to interact with the endothelium
Lymphocytes help with acute response and acquired immunity. Recruited similar way to neutrophils. Some eliminate triggering pathogens and others remain as memory cells that provide immunity in the future.
What is the arachidonic acid pathway?
The arachidonic acid pathway is responsible for genera&ng a variety of pro-inflammatory prostanoids via the enzyme cyclo-oxygenase and also leukotrienes via 5-lipoxygenase - these pathways are the target for commonly used an&-inflammatory drugs (e.g. NSAIDs, corticosteroids)
What are the other pathways that influence the inflammation process?
The coagulation system- The coagulation system is made up of blood cells and proteins and is responsible for creating blood clots
The coagulation cascade is important following trauma because the production of fibrin limits blood loss. It also generates a variety of pro-inflammatory mediators such as factor Xa, thrombin and the tissue factor VIIa complex.
The complement system- a series of proteins that are activated by microbes and serve to promote inflammation and microbial destruction.
What drugs are used to treat inflammation and how do they work?
NSAIDS
Corticosteroids
Disease-modifying an&-rheuma&c drugs (e.g. DMARDs) (e.g. methotrexate) are drugs that are commonly used to decrease the activity of immune cells in autoimmune rheuma&c diseases
Anti-inflammatory drugs reduce inflammation by targeting the activity of the immune cells involved or by inhibiting the effects of pro-inflammatory mediators
How do NSAIDs trreat inflammation?
Non-steroidal an&-inflammatory drugs (NSAIDs) (e.g. ibuprofen) inhibit the enzyme cyclo-oxygenase (COX) which is responsible for conver&ng arachidonic said into prostaglandins and thromboxanes - coxibs (e.g. celecoxib) are newer drugs that are more specific for the COX-2 isoform that is up-regulated at sites of inflamma&on
How are corticosteriods used to treat inflammation?
Corticosteroids (e.g. prednisolone) are synthetic derivatives of endogenous glucocorticoids and act via intracellular receptors to alter gene transcription in a way that decreases the activity of immune cells and reduces the production of mediators
What is paracetemol?
Is a non-opioid analgesic that can be bought over the counter.
The mechanisms of action are unclear but probably involves reduced prostagladin (COX isoform) formation in the brain- has no peripheral anti-inflammatory effect. May have a redox action that inhibits COX in the brain but not outside it.
Can be taken as tablets or intravenously.
What is the standard dose of paracetemol?
500mg- 1g by mouth 4-6 hours daily but daily dose must not exceed 4g
Lower doses required for children, malnorished or those with liver disease
What are the adverse effects of paracetemol?
Hepatotoxicity (liver damage) if overdosed, when the liver’s capacity to reduce its highly reactive intermediate metabolite is overwhelmed- can be prevented by administration of reducing equivalents in the form of N-acetylcysteine
What are opiod analgesics?
Can be divided into strong opioids (eg morphine) or weak (eg codeine)
They are agonists at G-protein coupled opioid receptors which are located in both the CNS and peripheral nervous system, but also in other tissues
Normally given via oral route but can be given intravenously to treat severe pain.
What is the pre and post synaptic action of opioids?
Presynaptic action =inhibit calcium channels on nociceptive afferent nerves to inhibit the release of neurotransmitters such as substance P and glutamate
Postsynaptic action= open inward potassium channels to hyperpolarise cell membranes, increasing the required action potential to generate nociceptive transmission
What are pharmokinetics of opioids?
They have a relatively short half life (2-3 hours) and they are eliminated by phase I and phase II reactions in the liver.
What are the adverse effects of opioid analgesics?
CNS system can be effected- confusion, drowsiness
Respiatory depression can occur
Gastrointestinal effects as well- nausea, constipation
Long term use can lead to addiction so needs to be monitered closely
Effects reaction times and therefore driving
What are NSAIDs?
A class of drugs that have the ability to act as reversible inhibitors of the conversion of arachidonic acid to prostanoids by the enzyme COX
Can be divided based on their selectivity for COX-1 or COX-2
Most show little selectivity such as aspirin and ibprofen, however drugs such as celecoxib is selective for COX-2
What is the pharmacokinetics of NSAIDs like?
Relatively short half life (1-2) hours
Is eliminated by phase I (becomes hydroxylated and carboxylated) and Phase II (to form glucuronide conjugate) reactions in the liver, and then is excreted in the urine
What are COX-1 and COX-2 enzymes?
COX enzymes are enzymes that are responsible for formation of prostanoids, including thromboxane and prostaglandins
COX-1 is contantly present and is responsible for maintaining the production of housekeeping prostagladins in several organs
COX-2 is synthesised by inflammatory cells eg mast cells to provide prostaglandins which promote inflammation by increasing vascular permeability, attracting leukocytes and causing pain
How are NSAIDs administered?
Administered by mouth but can also be done topically- low dose aspirin is widely used to prevent cardiovascular events
What are adverse interactions and adverse effects of NSAIDs?
Adverse effects are ulceration of the gastric mucosa, renal impairment and cardiovascular risk
Interactions include anticoagulants (increase risk of gastrointestinal bleeding) and ACE inhibitors (increase risk of renal impairment)
What are corticosteroid drugs?
Term usually refers to glucocorticoid- They can be divided into those that occur naturally and are secreted by the adrenal gland (e.g. hydrocortisone, also known as cortisol) and those that are synthetic (e.g. prednisolone)
They bind to intracellular receptors that enter the nucleus and alter DNA ranscription to influence cell behaviour
They hypothalamic-pituitary-adrenal axis secretes cortisol which has a range of activities in various body tissues including suppression of immune cells, altered glucose metabolism, catabolic actions on bone and muscle, sodium and water retention and increased gastric acid production
How are corticosteriods administered, and what do they treat?
They are used to treat a wide range of inflammatory conditions
They can be administered systemically by mouth or intravenous injection, or more locally to target specific conditions and reduce the chance of adverse effects (eg inhaled, topically or to the eye)
What are adverse effects and interactions of corticosteriods?
Adverse effects- infections, diabetes, hypertension, osteoporosis, fluid rentention, supressed growthand peptic ulcers
Patients on treatments > 3 weeks should be warned about abrupt stopping
Corticosteriods interact with drugs similar to themselves, such as NSAIDs.
What are two common corticosteriod drugs?
Hydrocortisone, known as cortisol is natural
Prednisolone is synthetic
