Selected Drugs Flashcards
What are examples of Drug Target sites?
Cell membrane receptor sites, nuclear receptors, transport mechanisms, ion channels, enzyme inhibitors
Where are opioid receptors found?
Brain, spinal cord, GI tract
What is an example of an opioid agonist?
Morphine
What are the opioid receptors?
mu, kappa, delta, sigma
What are opioid agonist effects?
Analgesia, miosis (constrict of pupil), cough suppression, sedation, constipation, nauseas & vomiting, rashes & itching, hypotension, respiratory depression, tolerance & dependence. WH
Where in the spinal cords are high in opioid receptors?
Thalamus & dorsal horn
What opioid receptor subtype has the most involvement with analgesia?
Mu
What are the main side effects of opioid agonists?
Respiratory depression, pupil constriction, reduced GI motility, euphoria, dysphoria, sedation, physical dependence
What causes opioid agonist adverse effects?
Unwanted effect are attributable to stimulation of the various sub groups and locations of opioid receptors: therefore difficult to eliminate side effects
What differences between opioid agonists?
All opioid agonists have the same mechanism of action (i.e. opioid receptor agonists) but differ in receptor selectivity, potency, duration of action, metabolism & this determines their clinical use
What are other uses of opioid agonists?
Diarrhoea (loperamide), cough suppression (pholcodine)
What are natural opioids?
Morphine and codeine are naturally occurring opioids
Morphine
Gold standard opioid analgesia, relatively short half-life, available immediate and sustained release
Codeine
Mild to moderate analgesia, anti-diarrhoea agent & cough suppressant. Isa pro-drug - it must be partially metabolised to morphine (active drug) in the liver to have an effect
Oxycodone
Twice as potent as morphine (care with dose conversation), immediate and sustained release
Pethidine
Fast acting, short duration, less respiratory depression. Has toxic metabolite norpethidine
Methadone
long half-life (24 hours) less frequent dosing required, but risk of accumulation. Main agent in opioid substitution therapy
Fentanyl
Fast onset of action, very potent
Buprenorphine
Partial agonist so has an analgesic ceiling as much h less risk of respiratory depression
What is the use of a competitive antagonist in opioid agnostic?
Reversal of opioid overdose. e.g. naloxone
How does tramadol work?
Is a weak agonist for opioid receptors it act principally by inhibition of noradrenaline rey-take and stimulation of serotonin release at nerve synapses in the CNS/spinal cord thus modifying pain impulses to the CNS
What are some side effects of tramadol?
Nausea, dozzine, increased risk of seizures and serotonin syndrome
What are the natural corticosteroids?
Adrenal context produces the natural corticosteroids hydrocortisone (cortisol) and aldosterone
What is hydrocortisone?
A glucocorticoid (it has metabolic, anti-inflammatory and immunosuppressant effects)
What is aldosterone?
A mineralocorticoid (helps maintain blood volumes, promotes retention of sodium & water, increases excretion of hydrogen & potassium)
What are hydrocortisone & aldosterone important?
In the maintenance of homeostasis, reaction to stress & tissue maintenance
What is hydrocortisone as a drug used for?
Anti-inflammatory agent e.g. dermatitis
How do synthetic hydrocortisone differ from natural?
Have a similar action to natural but are longer-acting (longer half-life) and more potent) e.g. prednisolone, methylprednisolone, beclomethasone, dexamethasone
What is the mechanism of action of glucocorticoids?
They enter the cell and bind to glucocorticoid receptors (GR) in the cytosol. The steroid-GR complex enters the cell nucleus. The complex undergoes binding with various tissue factors that allow it to attach to specific genes in the nuclear. This binding causes either induction or suppression of specific messenger RNS (mRNAs) involved in the production of inflammatory mediators (suppressed) or anti-inflammatory proteins (induced)
What are some examples of the use of glucocorticoids?
Prevention of transplant rejection, severe allergic reactions, autoimmune disease, inflammatory disorders, prevent preoperative nausea & vomiting, in haematological malignancies
What are some side effects of glucocorticoids?
Cushingoid effects (weight gain, fat redistribution, osteoporosis, hyperglycaemia, poo wound healing), HPA Axis suppression e.g. adrenal atrophy, decreased growth, decreased response to infection, mineralocorticoid effects (hypertension, oedema), CNS effects (euphoria, headache, restlessness, depression, anxiety), visual disturbances (cataract, glaucoma), GI effects (bleeding, ulcer)
What is an example of a pro-drug glucocorticoid?
Prednisone - turned into active drug prednisolone
What is the general mechanism of action of diuretics?
Diuretics promote the excretion of sodium ions by the kidney (known as naturesis) by blocking the sodium transporters at various parts of the nephron so that sodium is not reabsorbed and stays in the urine. As a consequence water is also excretion.
What diuretics cause vasodilation?
thiazides therefore reducing blood pressure
What are some potassium sparing diuretics?
Amiloride + Spironolactone. Act on Collecting duct
What are some Loop diuretics?
Frusemide + Bumetanide. Working on Loop of Henle
What is the use of diuretics?
Increase urine output in oedematous states e.g. congestive heart failure, renal failure, liver failure. Reduce high blood pressure. To correct electrolyte imbalances (amiloride)
What order of potency are diuretics?
Loop diuretics, thiazide diuretics, potassium sparing, aldosterone antagonist
What is an example of a thiazide diuretic?
Bendrofluazide, hydrochlorthiazide
What is an example of a potassium sparing diuretic?
Amiloride
What is an example of an aldosterone antagonist?
Spironolactone
What is an adverse effect of loop diuretics?
Very potentn, dehydration, major loss of potassium (hypokalaemia), usually require potassium supplementation, very high doses required in renal failure
What is an adverse effect of thiazides?
Hypokalaemia, increase glucose and uric acid (gout)
What is an adverse effect of potassium-sparing diuretic?
Hyperkalaemia - care with other drugs which promote hyperkalaemia
What is an adverse effect of aldosterone antagonists?
Hyperkalaemia, breast enlargements (gynaecomastia) in males
What is an example of an Ion Channel as a drug target?
Calcium channel blockers
Where are smooth muscle cells found?
Heart, blood vessel, other internal organs
What causes contraction in smooth muscle cells?
An influx of extra cellular calcium to stimulate release of internal calcium stores and cause smooth muscle contraction
How does calcium enter smooth muscle cells?
The calcium enters the smooth muscle cells through specialist voltage-dependent calcium channels (called L-channels).
What does partial blockage of calcium channel blockers cause?
Partial blockage causes smooth muscle relaxation in blood vessels, myocardial cells leading to vasodilation & reduced cardiac contractility. Principle use in angina and hypertension, sometimes cardiac arrhythmias and acute stroke
What are some examples of calcium channel blockers?
Nifedipine, diltiazem, verapamil, felodipine, amlodipine
What are some adverse effects of calcium channel blockers?
Flushing, hypotension, dizziness, headaches, reflex tachycardia
What is an example of an enzyme as a drug target?
COX Inhibitors
What is COX?
Cyco-oxygenase is an enzyme that catalyses the conversation of arachidonic acid in cell membranes which results in a cascade of reactions to produce prostaglandins and thromboxanes
What triggers the arachidonic acid cascade?
The arachidonic acid cascade is triggered by damage or injury to the cell membranes e.g. following mechanical injury or thermal injury
What physiological actions do prostaglandins cause?
Platelet inhibition, vasodilation, renal homeostasis, pain, inflammation, GI cytoprotection, fever
What physiological actions do thromboxanes cause?
Platelet aggregation, vasoconstriction
What is an example of a COX inhibitor?
Aspirin (acetylsalicyclic acid)
What is the main use of Aspirin?
Analgesic (1-2g/Day), anti-inflammatory (4-6g/day), antiplatelet agent (75-150mg/day)
At low doses how does Aspirin work?
Reduced production of thromboxanes esp. TXA2 which causes platelet aggregation and vasoconstriction, with little effect on prostaglandins at these doses.
What are some side effects of Aspirin?
GI tract (ulceration, bleeding), kidneys (renal impairment)
What are some examples of NSAIDs?
naproxen, diclofenac, ibuprofen, indomethacin, ketoprofen
What are some side effects of NSAIDs?
Gastric irritation & ulceration due to decrease in PG effects on stomach esp. in high doses, chronic use. Also affect renal blood flow (PG dependent() and increase sodium retention - overuse of NSAIDs ins a major contributor to acute renal failure & renal impairment
What are the two isoenzymes in the COX?
COX-1, COX-2
What is COX-1
Mediates ‘ctyoprotective’ prostaglandins
What is COX-2
mediates ‘inflammatory’ prostaglandins
What are COX-1 inhibitors?
Selectively inhibit the production of pro-inflammatory PGs (therefore, much reduced GI effects)
What is an example of a COX-2 Inhibitor?
Celecoxib, parecoxib, etoricoxib
What is the Triple Whammy?
A specific combination of drugs commonly seen to induct kidney failure/renal impairment
What drugs cause the Triple Whammy?
Diuretics, ACE inhibitors (or ARBs), NSAIDs (including COX-2 inhibitors)
What is selective toxicity?
Drug groups that are deliberately designed to produce toxic effects in some cells (e.g. invading organisms or neoplastic cells) and no the host cells
What is the difference between host cells and target cells?
There are structural and functional differences between host cells and target cells. Pharm and selective toxicity exploits these differences and the aim is to be toxic to the target cells without being toxic to the host cells.
What are anti-microbials?
A broad-ranging encompassing a very large number of antibacterial, antiviral, antifungal and anti-parasitic drugs
What are the potential targets of antimicrobials?
Cell wall, cell membrane, bacterial DNA, RNA< specific metabolic pathways (sites that differ from mammalian cells)
What type of antibiotic is penicillin?
Cell Wall inhibitor
What is the purpose of a cell wall?
Cell walls are not found in mammalian cells. They provide rigidity, shape and protection to bacteria. They contain complex polymer callled peptidoglycan with cross links or bridges that confer rigidity
What are the two main types of cell wall structure?
Gram-positive and Gram-negative. They have slightly difference structures and properties and can be differentiated using a Gram-stain. This helps guide choice of antibiotic
What does cell wall inhibitors cause?
Injury to the cell wall disrupts the osmotic balance within the bacterium; influx of fluid causes the cell to distort & burst (bactericidal - they kill the bacterial cells)
What do B-lactam antibiotics do?
(I.e. agents that containing a B-lactam ring in their chemical structure including penicillin’s) prevent transpeptidation whereby peptidoglycan units are cross-linked into the cell wall matrix. I.e. prevent cell wall being constructed
What are some examples of B-lactam antibiotics?
Penicillins, cephalosporins, carbapenems, monobactams
What is hypersensitivity?
Not a toxic effect or side effect. Although some individuals do display hypersensitivity (i.e. the body mounts an immune response to the presence of a foreign molecule) this can range from minor skin rashes and breathing difficulties. Anaphylactic sock rare 0.05% of cases
What are some side effects of Penicillin?
Hypernatremia and hyperkalaemia esp. in patients with renal impairment. Encephalopathy due to cerebral irritation occurs rarely but is dangerous in high doses.
What causes diarrhoea in antibiotics?
Due to alteration of the normal bacterial flora in the colon leading to diarrhoea and possible overgrowth of C.diff leading to colitis
What enzymes do some bacteria have that contribute to antibiotic resistance?
B-lactamases (including penicillinase) which deactivate the drug by breaking the B-lactam ring in penicillin’s and cephalosporins
What are mechanisms of action of antibiotic resistance?
Inactivation of drug by enzymes, Activation of drug efflux pumps, Inhibition of drug uptake by modified cell wall protein, alteration of drug target
What are cytotoxic drugs?
They are toxic to cancer ells especially those that are rapidly reproducing. Also toxic to normal cells which are also rapidly growing (e.g. blood cells).
What is the aim of cytotoxic therapy?
Eliminate cancer cells with least possible toxicity to normal cells.
Where do most cytotoxic drugs act?
At specific points in the cell cycle whilst some are independent of the cycle.
What are some side effects of cytotoxic drugs?
Most are selectively toxic to rapidly dividing cells. Most cytotoxic have both generic (e.g. anaemia, alopecia, mucositis) and specific toxicities (cardiovascular neural)
Can resistance occur in cytotoxics?
Yes, mechanisms similar to bacterial resistance
What is cyclophosphamide?
Is a pro-drug and non-toxic but is converted to both active and toxic metabolites in the liver. One metabolite is phosphoramide mustard - which is an alkylating agent. Combines with DNA in cell nucleus (G1 and S phases) to cause intra-strand linking - prevents cell division & damages/kills cells.
One metabolite aceolein is highly toxic to normal cells in bladder (causing haemorrhagic cystitis)
What is the purpose of cycles/pulses in cytotoxic drugs?
Cytotoxic given in combination with other agents (protocols) to utilise different mechanisms of action and reduce toxicity. Allows normal cells to recover sufficiently before next dose
What are some side effects of cyclophosphamide?
Non-specific: alopecia, anaemia, bone marrow depression
Specific: haemorrhagic cystitis
