Pharmacology Flashcards
In terms of errors, what’s the difference between a slip and a lapse?
A slip is an action that involves recognition or selection failure, whereas a lapse, is a failure of memory or attention
What factors can increase the rate of medication errors?
Increasing number of elderly patients with comorbidities, polypharmacy and increased risk of ADRs
Doctors with little experience
Vast number of new drugs
Clinical evidence for drugs is usually only for drug used in isolation in healthy patients
Many ADRs only come to light in post-marketing surveillance
On-call prescribing can mean that doctor doesn’t know the patient
Blind following of guidelines can lead to prescription where serious ADRs/DDIs exist
Doctors working shift work with reduced total hours - less experience/more tired
What are the two different approaches within Reason’s model of accident causation?
Person approach - Accidents occur due to aberrant mental processes so counter measures are centered on the person
System approach - Errors are seen as a consequence of the system that they occur within. Countermeasures are centered on barriers and safeguards
What do Black Triangle drugs indicate?
Drugs that are intensively monitored. Generally been newly released, or have changed indications, formulations or is a combination product. Any side effect, even if thought to be unrelated must be reported.
What is meant by a serious reaction to a drug?
Any reaction that results in or prolongs hospitalisation
What is pharmacogenetics?
How genetic variability affects the pharmacokinetics or pharmacodynamics of a drug in an individual
Why is understanding of pharmacokinetics important in everyday practice?
Knowledge of bioavailability impacts on formulation used
Knowledge of half lives impact on dosing regimen
Understanding of intra-subject variability allows for correct dosing within special groups
What are the main passive factors affecting the systemic entry of a drug?
pH
Lipophilicity
Molecular size
What are the main active factors affecting the systemic entry of a drug?
Active transport
Splanchnic blood flow
Destruction by gut and bacterial enzymes
What are the main factors affecting the peak plasma concentration of a drug and how long it spends in the body?
First pass metabolism
Rate of uptake
What is bioavailability?
The fraction of a drug that finds its way into a specific compartment
How is bioavailability calculated?
Amount of drug reaching systemic circulation/total amount of drug administered
What kind of graph can be used to express bioavailability?
Time (x) vs plasma concentration (y) graph
How can bioavailability be calculated clinically using AUCs?
= AUC oral/AUC IV - shows total exposure with oral route compared to total exposure in optimal IV route
What are the two main factors that affect the bioavailability of a drug?
Absorption and first pass metabolism
What factors can affect absorption and so affect bioavailability?
Formulation
Age
Food (if lipid/water soluble)
Vomiting
What are three possible sites of first pass metabolism?
In gut lumen by substances such as gastric acid, proteolytic enzymes, and grapefruit juice, or by drugs such as ciclosporin, insulin and benzopenicllin
At gut wall as p-glycoprotein efflux pumps can remove drugs from enterocytes, back into the gut lumen
In the liver (hepatic first pass)
What are the main factors affecting the distribution of a drug in the body?
Lipophilicity - if lipophilic, will exit plasma and enter other tissues
Plasma protein binding - if high, there’s less freely available
Tissue protein binding - if high, there’s less freely available
Mass of volume of target tissue and the density of binding sites within that tissue
When are protein binding drug interactions particularly important?
If there’s high protein binding, if there’s a low volume of distribution or if there’s a narrow therapeutic ratio
What factors affect protein binding of a drug?
Hypoalbuminaemia
Pregnancy
Renal failure
Displacement by other drugs
What factors affect tissue distribution of a drug?
Disease states Regional blood flow Active transport Lipophilicity Specific receptor sites in tissues Drug interactions
What is volume of distribution?
A measure of how widely a drug is distributed in tissues
How is volume of distribution calculated?
Total amount of drug in the body/Plasma concentration of a drug at time=0
Roughly, what will the volume of distribution be in a very lipophobic drug that doesn’t exit the plasma?
Roughly equal to plasma volume of 5 litres
Roughly, what will the Vd be in a drug that can exit the plasma and enter other fluid compartments?
Between volumes of ECF and ICF so between 10 and 40 litres
Roughly what will the Vd be in a drug that’s very lipophilic and enters various tissues?
Extremely high - in the hundreds
What is the main purpose of metabolism of drugs prior to excretion?
To increase their ionic charge so they’re excreted more easily. Eg in very lipophilic drugs, would otherwise diffuse back along their concentration gradient through renal cell membranes
What are the main reactions involved in phase 1 metabolism?
Oxidation and reduction, mainly carried out by cytochrome P450 system
What is the CYP450 system affected by?
Inducing and inhibiting drugs Alcohol/smoking Age Liver disease Hepatic blood flow
What are the main reactions of phase 2 metabolism?
Conjugation with glucuronide, sulphates, glutathione, N-acetylw
What are the main inducers of the CYP 450 system?
Phenytoin Carbamazepine Barbiturates Rifampicin Alcohol Sulphonylureas St Johns Wort
What are the main inhibitors of the CYP 450 system?
Omeprazole Disulfiram Erythromycin Valproate Isoniazid Cimetidine/Ciprofloxacin Ethanol intoxication Sulphonamides \+grapefruit juice
What is clearance?
The volume of plasma that is completely cleared of a drug per unit time
How is half life calculated using Vd and clearance?
= (0.693 x Vd)/Clearance
What are the main factors affecting renal elimination of a drug?
Glomerular filtration
Active tubular secretion (eg of penicillin)
Passive tubular absorption
What is passive tubular absorption of a drug affected by?
pH
Urine flow rate
What channels are important in renal elimination?
Organic Anion Transporters
Organic Cation Transporters
When is drug monitoring necessary?
In drugs with zero order kinetics
In drug with long half lives
In drugs with known toxic effects
In drugs with a narrow therapeutic window
To monitor the therapeutic effects of a drug
When there’s a high risk of DDIs
What is meant by first order/linear kinetics?
That the rate of elimination of a drug is proportional to the drug level so a constant fraction is eliminated. (straight line on a log graph)
What is meant by zero order/non-linear kinetics?
That the rate of elimination of a drug is constant (curved line on a log graph)
What are some drugs with zero order kinetics?
Phenytoin
Fluoxetine
Verapamil
High dose aspirin
How is a loading dose calculated?
= Vd x desired therapeutic concentration
What are the main, usual sites of action for drugs?
Receptors
Enzymes
Ion Channels
Substance transport
What are some unconventional modes of action for drugs?
Acting as an enzyme Chemically reactive with small molecules Covalently linking to macromolecules Disruption of structural proteins Binding of free molecules of atoms
What is meant by affinity?
The tendency of a drug to bind to a specific receptor type
How can affinity be expressed?
Kd or Ki
Concentration at which half of receptors are bound
What is meant by efficacy?
Maximal effect of a drug when bound to a receptor, so when no increase in drug concentration will cause a further increase in response
What is meant by potency?
The dose required to produce the desired biological response?
How is potency expressed?
In agonists, as concentration at which there’s 50% of the maximal response = EC50
In antagonists, is the concentration that reduces the maximal response by 50%
Give some examples of drugs with narrow therapeutic ranges
Warfarin
Digoxin
Aminoglycoside antibiotics
Aminophylline
How can drugs have pharmacokinetic reactions in terms of absorption?
If drugs affect gut motility, can affect time available for absorption. eg metoclopramide increases rate of gastric emptying
How can drugs have pharmacokinetic reactions in terms of distribution?
If drugs compete for binding sites eg on plasma/tissue proteins, can affect free plasma concentrations
How can drugs have pharmacokinetic reactions in terms of metabolism?
Many drugs can alter their own metabolism or that of other drugs, by interacting with the CYP450 system
What are some common drug classes that commonly lead to DDIs?
Anticonvulsants Anticoagulants Antidepressants Antibiotics Antarrhythmics
How can drugs have pharmacokinetic reactions in terms of elimination?
If a drug affects protein binding, tubular secretion, urine flow or pH, it can affect a drug’s elimination
How can cardiac diseases alter a drug’s pharmacodynamics?
If there’s reduced cardiac output, there’s reduced organ perfusion so reduced hepatic and renal clearance. This can increase risk of toxicity.
Will also mean there will be an excessive response to hypotensive agents
How can renal diseases alter a drug’s pharmacodynamics?
If there’s a reduced GFR, there’s reduced clearance so increased risk of toxicity. Any electrolyte disturbances also increase risk of toxicity.
How can hepatic diseases alter a drug’s pharmacodynamics?
If there’s disease, there will be reduced hepatic clearance and reduced CYP450 activity so increased drug levels in the body so risk of toxicity.
Also, if there’s hypoalbuminaemia there will be increased free plasma concentrations
What are Type A ADRs?
Those that are on target so either due to an exaggerated immune response or an effect on the same receptor or non-target tissue
What are Type B ADRs?
Those that are off target so due to interaction with different receptor sub-types or because of metabolites causing toxicity. May be due to an individual’s disposition or an inappropriate immune response.
What are some causes of variability in response to drugs?
Can be related to biological system, so due to age, weight, sex, pharmacogenetics, a person’s condition of health or due to a placebo effect
Can also be related to drug adminisration so because of the dose, formulation or route of administration, due to DDIs or in repeat administration, leading to tolerance, resistance or allergy
What are the actions of oestrogens?
Mildly anabolic Reduces LDL levels and increases HDL levels Increases sodium and water retention Reduces glucose tolerance Reduces bone resorption Increases blood coagulability Improves mood and concentration
What are some unwanted effects of oestrogens?
Breast tenderness Nausea and vomiting Water retention Impaired glucose tolerance Hypercoagulability and thromboembolism Endometrial hyperplasia and malignancy
What are some indications of oestrogen therapy?
In primary hypogonadism to stimulate development of secondary sexual characteristics
In primary amenorrhoea, with progesterone, to stimulate an artificial cycle
At sexual maturity for contraception
At or after menopause to reduce menopausal symptoms and to reduce bone loss
What’s the effect on congenital adrenal hyperplasia on sex steroid production?
Involves a deficiency in 21-hydroxylase enzyme which is normally responsible for conversion of progesterone into aldosterone and 17 alpha-OH progesterone into cortisol.
As it’s deficient, there’s a build up of progesterone and 17 alpha-OH progesterone pathway moves in direction of testosterone and oestrogen production so there’s precocious puberty
What are the actions of progesterone?
Anabolic Secretory endothelium Mood changes Increased bone mineral density Water retention
What are some unwanted effects of progesterone therapy?
Weight gain Fluid retention Acne Irritability Depression and PMS Nausea and vomiting Lack of concentration
What are the actions of testosterone?
Anabolic Acne Voice changes Aggression Adverse metabolic effects on lipids Male secondary sexual characteristics
How can oestrogen therapy be administered?
Can be given orally but is rapidly metabolised by the liver. Can instead be given as pessary or intravaginal cream for local effect as it’s well absorbed by skin and mucous membranes. This way, it enters the blood stream directly, avoiding the first pass effect
How can progesterone therapy be administered?
Can be given orally but is extensively metabolised by the liver. Can instead be given by IM depot injection, as a subcutaneous implant or as a vaginal ring
How can testosterone therapy be administered?
Can be given orally but is rapidly metabolised by the liver. Can instead be given as a subcutaneous implant, as an IM depot injection or as a transdermal patch.
What is hormone replacement therapy?
The continuous or cyclical administration of at least one oestrogen, with or without a progesterone. It aims to improve menopausal symptoms and helps prevent and treat post-menopausal osteoporosis.
How can HRT be administered?
Orally Transvaginally Nasally Subcutaneously Transdermally
What are some risks of HRT?
Cyclical withdrawal bleeding
Increased risk of endometrial, breast and ovarian cancers
Increased risk of thromboembolism
Increased risk of ischaemic heart disease and stroke
What are some examples of anti-oestrogens?
Clomiphene
Tamoxifen
What kind of drug is clomiphene?
Is an antioestrogen
What’s the mechanism of action of Clomiphene (antioestrogen)
It prevents oestrogen binding at the anterior pituitary so reduces negative feedback, increasing secretion of GnRH, LH and FSH. This causes ovary enlargement and increased oestrogen secretion
What is the general action of anti-oestrogens?
Weak oestrogens that compete with natural oestrogens for receptor binding sites
What is clomiphene used for?
To treat infertility if the problem is lack of ovulation
What is tamoxifen used for?
To treat oestrogen sensitive breast cancer
What is an example of an anti-progestogen?
Mifepristone
What kind of agent in mifepristone?
An anti-progestogen
How does mifepristone work?
Is a partial agonist at progesterone receptors to reduce progesterone action
It makes the uterus more sensitive to prostaglandins and when given with prostoglandins, can be used for medical termination of pregnancy or can be used to induce labour
What is an example of an antiandrogen?
Cyproterone
What kind of agent is cyproterone?
An antiandrogen
How do antiandrogens work?
Progesterone derivatives that exert a weak progestogenic effect. They’re partial agonists at progesterone receptors and can be used in COCPs
What is an example of a selective oestrogen receptor modulator?
Raloxifene?
What kind of agent is raloxifene?
A selective oestrogen receptor modulator
How do selective oestrogen receptor modulators work?
These have antioestrogenic effects on the breast and endometrium to prevent proliferation, but have oestrogenic effects on blood coagulation, lipid metabolism and bone
What can raloxifene (selective oestrogen receptor modulator) be used to treat?
To help prevent and treat post-menopausal osteoporosis.
Slightly reduces risk of invasive breast cancer
How do the effects of more recent preparations of the COCP compare to earlier preparations?
New generation (3/4) exert less androgenic effects and have less of an affect on lipoprotein metabolism, however they carry a higher risk of thromboembolism
How does the COCP work?
Oestrogen acts to reduce FSH secretion and so prevent follicular development. Progesterone acts to reduce LH secretion and so prevent ovulation. It also thickens cervical mucus
Both act to alter the endometrium to discourage implantation and can interfere with coordinated contraction of fallopian tubes, uterus and cervix that normally aid fertilisation and implantation.
What are some benefits of the COCP?
Reduces menstrual symptoms Reduces iron deficiency Reduces PMT Reduces risk of benign breast disease Reduces risk of fibroids Reduces risk of functional ovarian cysts
What are some ADRs of the COCP?
Venous thromboembolism Myocardial infarction Reduced glucose tolerance Hypertension Increased risk of stroke, especially if focal migraines are present Headaches Mood swings Cholestatic jaundice Increased gallstone risk Precipitates porphyria Weight gain Nausea, flushing, dizziness, irritability and depression Amenorrhoea on cessation of variable length
How does the POP work?
Thickens cervical mucus, impairing sperm transport
Alters endometrium
Affects motility and secretions of the fallopian tubes
What are some disadvantages of the POP?
Less reliable contraceptive effect compared to the COCP
Causes disturbances to menstruation
What are some benefits of the POP?
Suitable alternative is oestrogen therapy is contraindicated
Suitable if marked increase in BP is found with COCP
What are some important drug interactions with the COCP?
Metabolised by CYP450 system. Oestrogen used at minimum effective dose so any induction of this system and so increased clearance can lead to contraceptive failure.
Phenytoin, Carbamazepine, Barbiturates, Rifampicin, Alcohol, Sulphonylureas
COCP enters enterohepatic circulation so broad spectrum antibiotics that affect gut flora and so absorption could lead to contraceptive failure
What are three different methods of emergency contraception?
Levonorgestrel used up to 3 days after intercourse
Copper bearing intrauterine device used up to 5 days after sex
Ullipristal diacetate used up to 5 days after sex
How can levonorgestrel be used as emergency contraception?
Is a high dose progestogen. Alters cervical mucus and delays ovulation
How do copper IUDs work as emergency contraception?
Prevent fertilisation by damaging the sperm and egg before they meet
How is ullipristal diacetate used as an emergency contraceptive?
In a selective progesterone receptor modulator
What is atherosclerosis?
A thickening of arterial walls due to the invasion and accumulation of white blood cells
How do atheromas form?
Endothelial dysfunction and endothelial injury lead to the attraction of monocytes. LDLs adhere to the vessel wall and are oxidised by monocytes. When oxidised, they’re taken up by monocytes to form foam cells, which then join with T cells to form fatty streaks. Platelets, macrophages and endothelial cells release cytokines and growth factors that cause smooth muscle cell proliferation and fibrous cap formation, which leads to atheromatous plaque forming.
What effect does the oxidisation of LDLs by monocytes have, leading to propagation of atheroma formation?
Oxidised LDLs act to reduce motility of macrophages and stimulate the activation of T cells. Also stimulate the division and differentiation of vascular smooth muscle cells.
The LDLs are toxic to endothelial cells and promote aggregation of platelets
What effect do statins have on lipid profiles?
Reduce LDLs by 5-15%
Slightly increase HDLs by 5%
Reduce triglycerides by 10-35%
Reduce vLDLs
How do statins work?
Inhibits the HMG CoA Reductase enzyme which is involved in cholesterol synthesis. Also increase uptake of LDLs hepatically by increasing receptor number so there’s an increase in their clearance from the plasma
What are some side effects of statins?
Myopathy Increased transaminase levels but no evidence on liver disease GI disturbances Arthralgia Headaches
What are some secondary benefits of statin use?
Anti-inflammatory
Plaque reduction
Increase function of endothelial cells
Reduce thrombotic risk
What are some important drug reactions of statins?
Risk of rhabomyolysis with combination therapy with fibrates or niacin
Metabolised by CYP enzymes
What are some examples of fibrates?
Bezafibrate
Ciprofibrate
What kind of agent is bezafibrate?
Fibrate - Lipid lowering drug
What effects do fibrates have?
Slightly reduce LDLs
Increase HDLs by 15-25%
Reduce triglycerides by 25-50%
How do fibrates act?
Act on the peroxisome proliferator activated receptor.
Increase hepatic LDL uptake and increase glucose tolerance and reduce smooth muscle proliferation
When are fibrates used?
First line in many triglyceridaemias
Used in conjunction with dietary changes and statins in high cholesterol
What are some ADRs of fibrates?
Myositis Pruritis and itching GI upset Cholelithiasis AKI in toxicity
When are fibrates contraindicated?
In renal and hepatic disease
In preexisting gallbladder disease
Give an example of a cholesterol absorption inhibitor?
Ezetimibe
What kind of agent is ezetimibe?
Cholesterol absorption inhibitor
How to cholesterol absorption inhibitors, eg ezetimibe work?
Selectively inhibit intestinal cholesterol absorption by blocking the transport protein for cholesterol at the brush border of enterocytes. This means that less dietary cholesterol reaches the liver so there’s an upregulation of LDL receptors at the liver, so increasing its clearance from the plasma
How is ezetimibe (cholesterol absorption inhibitor) targeted for its action?
Circulates enterohepatically so limits its systemic exposure and ensures that it reaches its target
When are cholesterol absorption inhibitors (ezetimibe) used?
Either as an adjunct alongside diet and statin therapy, or alone if statins aren’t tolerated
What are some side effects of cholesterol absorption inhibitors (ezetimibe)?
Headache Abdominal pain Diarrhoea Rash Angioedema
What dietary changes can be made to help improve lipid profile?
Increase intake of fish oils, fibre and vitamin C
What is niacin?
A nicotinic acid derivative used to improve lipid profile
How to nicotinic acid derivatives work?
Convert to nicotinamid which reduces the hepatic secretion of vLDLs there’s reduction in LDL and triglyceride levels. Also the best agents for increasing HDL levels and they inhibit lipoprotein synthesis
What are some side effects of nicotinic acid derivatives?
Headache Itching Flushing Precipitates gout Hepatotoxicity Activates peptic ulcer Impairs glucose tolerance
When are nicotinic acid derivatives contraindicated?
In those with active liver disease, unexplained raised LFTs or with peptic ulcer disease
What can happen if statins are used in conjunction with fibrates?
Normally fine but if used with gemfibrozil, it acts to reduce the glucuronidation of statins and inhibits the organic anion transporters in the kidney, thereby inhibiting its metabolism and its clearance so there’s increased risk of toxicity and rhabdomyolysis
How does the type of statin given affect dosing regime?
Some statins, eg simvastatin, have a short half life of 1-4 hours so are taken at night in order to coincide with peak cholesterol production in the morning
However, some statins, eg rosuvastatin, have a longer half life of around 20 hrs and so can be given at any time
What lifestyle changes should be made on diagnosis with diabetes?
Reduce fat intake and increase relative calorie intake from complex carbohydrates, combined will aid with weight loss
Stop smoking
Limit alcohol intake
Increase exercise
What kind of agent is metformin?
A biguanide
Give an example of a biguanide?
Metformin
What are the actions of metformin?
Reduces hepatic glucose production Increases glucose uptake and utilisation by skeletal muscle Increases fatty acid oxidation Reduces carbohydrate absorption Reduces frequency of cardiac events
What are some ADRs of metformin?
GI disturbances that are dose related
Lactic acidosis
When is metformin contraindicated?
Renal disease Liver disease Shock Hypoxic pulmonar disease Because of risk of lactic acidosis
Other than diabetes, when else can metformin be used?
In Polycystic Ovarian Syndrome
Non-alcoholic fatty liver disease
Some forms of precocious puberty
What are the main types of insulin release stimulants?
Sulphonylureas
Glitazones
Meglitidines
Give some examples of sulphonylureas?
Gliclazide
Tolbutamide
What kind of agent is tolbutamide?
A sulphonylurea used in diabetes
How do sulphonylureas work?
Antagonise K+/ATP channel on Beta cells in pancreas so that they depolarise, increasing intracellular calcium and so stimulating release of insulin containing vesicles.
How do the half lives and so dosages of sulphonylureas differ?
Some eg tolbutamide have short half life of 4 hours so offers good coverage of meals and is given 2/3 times a day
Glibencamide has a half life of 10 hours so in given once a day
What are some ADRs of sulphonylureas?
Weight gain Hypoglycaemia, especially in the elderly and renal impairment Skin rashes GI disturbances Bone marrow toxicity
What are some important drug reactions of sulphonylureas?
Agents such as NSAIDs and CYP450 inhibitors increase risk of hypoglycaemia
Agents such as corticosteroids, contraceptive pill and thiazide diuretics reduce glycaemic control
When are sulphonylureas contraindicated?
In type 1 or late stage type 2 diabetes as they require functioning beta cells to exert an effect
Give some examples of meglatidines?
Repaglinide
Nateglinide
What kind of agent is repaglinide?
A meglatidine for diabetes controle
How do meglatidines work?
Inhibit K+/ATP channel on beta cells of pancreas so depolarise cells, increase intracellular calcium and stimulate insulin release
When may meglatidines be used instead of sulphonylureas?
In obese patients as meglatidines don’t cause weight gain like sulphonylureas
What are some ADRs of meglatidines?
Flatulence
Loose stools
Diarrhoea
Abdominal pail
Give some examples of glitazones?
Rosiglitazone
Pioglitazone
What kind of agent is pioglitazone?
Glitazone used in diabetes control
How do glitazones work?
Bind to peroxisome proliferato activated receptor found on liver, adipose tissue and muscle. Acts to increase lipogenesis Reduce hepatic glucose production Increase fatty acid uptake Increase glucose uptake Increased Na retention
What are some ADRs of glitazones?
Weight gain Hepatotoxicity Fluid retention Fatigue Headache Increased bone metabolism GI disturbances
When are glitazones contraindicated?
Heart failure
Pregnancy
Breast feeding
Children
What are the main incretin based therapies for diabetes?
GLP-1 receptor agonists
DPP-4 inhibitors/gliptins
Give an example of a GLP-1 inhibitor?
Exenatide
What kind of agent is exenatide?
GLP-1 inhibitor used in diabetes
How do GLP-1 agonists work?
Mimic effects of Glucagon Like Peptide so increase insulin, reduce glucagon, reduce glucose production, reduce gastric emptying and reduce appetie.
Promote weight loss
What’s an ADR of GLP-1 agonists?
Pancreatitis
Give an example of a DPP-4 inhibitor/gliptin?
Sitagliptin
How do DPP-4 inhibitors/gliptins work?
Inhibit DPP-4 which normally acts to break down GLP-1
Act to increase isulin release, reduce glucagon release, increase peripheral glucose uptake and reduce hepatic glucose output
What are some ADRs of gliptins?
Nasopharyngitis
Headache
Nausea
How do sodium-glucose contransporter 2 inhibitors work?
Inhibit to SGLT2 transporter in the PCT so reduce glucose reabsorption
Give an example of a sodium-glucose contransporter 2 inhibitor
Dapagliflozin
What are some ADRs of sodium-glucose cotransporter 2 agents?
Increase risk of UTI
Polyuria
Hypoglycaemia
What are the two main antiobesity agents?
Orlistat
Sibutramine
What is sibutramine?
Antiobesity agent
How does sibutramine work?
Inhibits NA and 5HT at sites in hypothalamus that control appetite. It increases energy expenditure through thermogenesis so can reduce hyperglycaemia
What are some ADRs of sibutramine?
Dry mouth Increased heart rate Increased blood pressure Constipation Insomnia
How does orlistat work?
Inhibits gastric and pancreatic lipases so there’s reduced conversion of dietary fat into fatty acids and glycerol so reduced fat absorption
What are some ADRs of orlistat?
Faecal incontinence
Abdominal cramps
Flatus with discharge
How do DNA viruses replicate?
Viral DNA enters the host nucleus and is transcribed into mRNA by reverse transcriptase. mRNA is then translated into specific viral proteins. These can go on to make more viral DNA or structural proteins to make viral coat and envelope
Completed virion is then released either by budding or on host cell lysis
How do RNA viruses replicate?
Enzymes within the virion make their own mRNA which is then translated by the host cell into structural proteins and RNA polymerase
How do retroviruses replicate?
Virion contains reverse transcriptase which transcribes viral RNA into DNA, which then integrates into the host cell genome, forming a provirus. DNA can then be transcribed into viral RNA and mRNA to form structural proteins. Completed virion is released by budding, without damage to host cell
What needs to happen before a virus can enter a host cell and exert an effect?
It needs to attach to a neuraminc or sialic acid residue on the membrane of a glycoprotein. The complex can then enter by endocytosis.
Their then needs to be ATP driven H+ entry into the endosome so that the viral membrane can fuse with the internal endosomal membrane.
Finally, there needs to be proton entry into the virus itself via an M2 receptor. This reduces the pH within the virus so the viral coat breaks down and the viral RNA can be released into the cytoplasm
Give an example of an M2 ion channel blocker
Amantadine
What kind of agent is amantadine?
M2 ion channel blocker antiviral
How do M2 ion channel blockers work?
Inhibit proton entry into the virus and so inhibit the release of viral genetic information into the host cell cytoplasm
What are some ADRs of M2 ion channel blockers?
Dizziness COnfusion Hallucination Slurred speech Insomnia
How do neuramidase inhibitors work?
Inhibit neuramidase enzyme which is needed to break bond between new virion and neuraminic acid residue on cells. This means that virion can’t be released to infect more cells and so halts progression.
Give an example of a neuramidase inhibitor
Osteltamivir
What kind of agent is osteltamivir?
Neuramidase inhibitor antiviral
Give some ADRs of neuramidase inhibitors
GI disturbance Nose bleeds Headache Respiratory depression Bronchospasm
What are the three main ways by which antibiotics can exert their effects?
Affecting cell wall synthesis
Affecting DNA synthesis
Affecting protein synthesis
What are the main antibiotic classes that affect bacterial DNA synthesis?
Quinolones
Folic acid antagonists
Give an example of a quinolone
Ciprofloxacin
What kind of agent is ciprofloxacin?
Quinolone antibiotic
How do quinolones work?
Inhibit topoisomerase II enzymes which is needed for DNA synthesis and replication
What kind of bacteria are quinolones effective against?
Broad spectrum so gram positive and negative, and enterbacteriaceae
What are some ADRs of quinolones?
GI upset
headache
Nausea
Prolonged QT interval
Give some examples of folic acid antagonist antibiotics
Trimethoprim
Sulphonamides
How do sulphonamides work?
Act as analogues to precursors to folic acid synthesis and so prevent synthesis and prevent DNA synthesis
How does trimethoprim work (antibiotic)?
Inhibits dihydrofolate reductase enzyme and so inhibits folate and DNA synthesis
What are some dangers of folic acid antagonist antibiotics?
Can cross placenta and exert a teratogenic effect as affect folic acid synthesis
What are some ADRs of trimethoprim? (folic acid antagonist)
Thrombocytopenia
Hyperkalaemia
What classes of antibiotics affect protein synthesis?
Macrolides
Tetracyclines
Aminoglycosides
Give an example of an aminoglycoside antibiotic
Gentamycin
What kind of agent is gentamycin?
AN aminoglycoside antibiotic
How do aminoglycosides work?
Block action of 30S ribosomal subunit
What kind of agents are aminoglycosides effective against?
Gram negative, predominantly aerobic
What are some ADRs of aminoglycosides?
Ototoxicity
Nephrotoxicity
Anorexia
Confusion
Give an example of a macrolide?
Erythromycin
What kind of agent is erythromycin?
Macrolide antibiotic
How do macrolides work?
Bind to 50s ribosomal subunit and prevent elongation
What kind of agents are macrolide antibiotics good for?
Gram positive organisms
Why should macrolide antibiotics be used with caution?
Inhibitors of the CYP450 system so can increase risk of toxicity in some drugs, including statins where there’s an increased risk of myopathy
What are some ADRs of macrolide antibiotics?
Nausea
Prolonged QT interval
How do tetracyclines work?
Bind to 30s ribosomal subunit and prevent aminoacylt tRNA from binding
What are some ADRs of tetracyclines?
Phototoxicity
GI upsets
What are some contraindications of tetracyclines?
Shouldn’t be given to pregnant women, breastfeeding women or children under 8 as cause teeth discolouration
Also shouldn’t be used in liver failure
What antibiotic classes affect cell wall synthesis?
Beta lactams
Glycopeptides
Give some examples of beta-lactam antibiotics?
Penicillins
Carbapenems
Cephalosporins
How do beta lactam antibiotics work?
Inhibit cross linked of peptides in formation to peptidoglycan cell wall
What kind of agents are beta lactams good for?
Particularly gram positive.
Carbapenems and cephalosporins have increasing activity against gram negatives
What are some ADRs of penicillins?
GI upset
Allergic reactions
What are some ADRs of cephalosporins?
Nephrotoxicity
GI upset
Rash
Give an example of a glycopeptide
Vancomycin
What kind of agent is vancomycin?
A glycopeptide antibiotic
How do glycopeptide antibiotics work?
Bind to amino acids in bacterial cell wall and prevent addition of new units
What kind of bacteria are glycopeptides effective against?
Gram positive organisms
Those resistant to beta lactam antibiotics
What are some ADRs of glycopeptides?
Phlebitis
Nephrotoxicity
Neutropenia
How are glycopeptides administered?
Not absorbed in GI tract so can be taken orally if for GI infection, ie in treating Clostridium difficile
If systemic, given IV but risk of necrosis and phlebitis
How can bacteria confer intrinsic resistance to antibiotics?
By genetic mutations in bacterial chromosomes
How can bacteria confer extrinsic resistance to antibiotics?
By transformation as DNA is taken up from environment and incorporated
Conjugation as plasmid DNA is taken up
Transduction as plasmid DNA is transferred between bacteria of the same species
What is the minimum inhibitory concentration of an antibiotic?
The lowest concentration of an antimicrobial needed to inhibit visible growth of a microorganism after overnight incubation
What is time dependent killing?
Killing of an antimicrobial will depend on how long they’re active for. Potency not increased with increased dose
What is concentration dependent killing?
When killing of antimicrobial depends on its concentration at infection site. Killing is optimal when concentration is at least ten times the minimum inhibitory concentration at the infection site
What are some effects of rheumatoid arthritis, not involving joints?
Lung fibrosis Renal amyloidosis Skin changes Atherosclerosis Pericarditis Episcleritis Anaemia
How is rheumatoid arthritis diagnosed?
With morning joint stiffness lasting at least one hour Arthritis of hand joints Arthritis in at least 3 joints Symmetrical arthritis Presence of rheumatoid nodules Presence of serum rheumatoid factor X-ray changes
What are the aims of treatment in rheumatoid arthritis?
Give symptom relief
Prevent joint destruction
What is systemic lupus erythematosus?
A multi system autoimmune condition where there’s immune mediated apoptosis in healthy tissue
What are some symptoms of lupus?
Recurrent miscarriages Fever Headaches Ulcers Reynaud's Depression Nausea and vomiting Butterfly rash Oedema Hypertension Fatigue Anaemia Photosensitivity
What is vasculitis?
An auto-immune inflammation of blood vessels that can occur on it’s own or secondary to another condition eg RA
What are some symptoms of vasculitis?
Headaches Glomerulonephritis Palpable purpura Fever Weightloss Haemoptysis Headache MI Hypertension Blood in stool Abdominal pain Joint and muscle pain
What are the treatment goals of SLE and vasculitis?
Give symptomatic relief
Reduce mortality
Prevent organ damage
Reduce long term morbidity
Give an example of a corticosteroid
Prednisolone
How do steroids work?
Enter cells, binding to cytosolic receptors and then entering the nucleus to alter gene expression
How do steroids have an anti-inflammatory effects?
Reduce gene expression of inflammatory mediators and inhibit all stages of T cell activation
What autoimmune conditions can corticosteroids be used to treat?
SLE
RA
IBD
Vasculitis
What are some ADRs of corticosteroids?
Steroid psychosis Weight gain Increased risk of infections Glucose intolerance Increased risk of osteoporosis
Why shouldn’t steroid use be stopped suddenly?
Chronic use or high doses suppress to hypothalamic pituitary axis and so rapid removal could precipitate an addisonian crisis
How does azothioprine work?
Is a prodrug, converted to an analogue of purine synthesis so inhibits purine synthesis, reducing DNA, RNA and immune mediator synthesis
What needs considering before prescribing azothioprine?
TPMT levels. Azothioprine is converted into 6-MP which is then metabolised by TPMT, however TPMT levels vary greatly between different people so if levels are low, there may be toxicity and myelosuppression.
Therefore, TPMT levels need to be measured before prescribing
What are some ADRs of azothioprine?
Bone marrow suppression Increased malignancy risk Increased infection risk hepatitis Nausea and vomiting Skin erruptions
What autoimmune conditions is azothioprine used in?
RA IBD SLE Vasculitis Leukaemia
How does cyclophosphamide work?
Is a pro-drug, metabolised by CYP 450 system. It is metabolised into cytotoxic substances that alkylate DNA irreversibly, causing apoptosis. It suppressed B cell proliferation
What conditions is cyclophosphamide used in?
Leukaemia Lymphoma Solid cancers Vasculitis SLE
What are some ADRs of cyclophosphamide?
Haemorrhagic cystitis as one of its metabolites is toxic to bladder epithelium but can be reduced by aggressive hydration Increased bladder cancer risk Infertility Nausea and vomiting Bone marrow suppression Lethargy FBCs and kidney function need monitoring
How does mycophenolate mofetil work?
Prodrug metabolised to mycophenolic acid which inhibits guanosine and so purine synthesis so reduces T and B cell proliferation
Why are only T and B cells affected by mycophenolate mofetil?
Other rapidly producing cells have other ways of synthesising guanosine
What are some ADRs of mycophenolate mofetil?
Nausea and vomiting Myelosuppression Leukopenia Neutropenia Increased risk of infection
What conditions is mycophenolate mofetil used for?
Transplantation
SLE
How does methotrexate work?
Binds to dihydrofolate reductase with a much greater affinity than folic acid, and inhibits it. This reduces DNA, RNA and protein synthesis.
What are some ADRs of methotrexate?
Mucositis Bone marrow suppression Hepatitis Cirrhosis Pneumonitis Increased infection risk Teratogenesis
Why does dosing of methotrexate need to be done very carefully?
Excreted by the liver but accumulates in cells and can remain for weeks/months so dosing needs to be altered.
Is only given weekly
What conditions is Methotrexate used for?
RA
Malignancy
Psoriasis
Crohn’s
Give examples of calcineurin inhibitors
Tacrolimus
Ciclosporin
How do calcineurin inhibitors work?
Normally when antigens meet T helper cells, calcineurin is activated which stimulates transcription of IL-2. Ciclosporin and tacrolimus bind to cyclophillin and tacrolimus binding protein respectively. These complexes then bind to calcineurin and inhibit it and so inhibit T cell mediated immunity
What conditions are calcineurin inhibitors used for?
Transplantation
Inflammatory skin conditions
What are some ADRs of calcineurin inhibitors?
Nephrotoxicity Hepatotoxicity Neurotoxicity Hypertension Anorexia Lethargy Paraesthesia Gingival hyperplasia Hirsuitism Thrombocytopenia Hyperglycaemia
What are some important reactions of methotrexate?
As it's excreted renally, anything that affects renal blood flow, renal elimination or protein binding Especially: Phenytoin Tetracyclines Penicillin
How may methotrexate act as a disease modifying anti-rheumatic drug?
May act to increase adenosine levels which is then generated in cellular injury or stress to regulate and reduce inflammatory cell function
What inflammatory condition can methotrexate be used to treat?
RA
What immune effects does sulphasalazine have?
Inhibits T cell proliferation
Reduces T cell IL-2 production
Reduces chemotaxis of neutrophils
Reduces neutrophil degranulation
What are some ADRs of sulphasalazine?
Myelosuppression
Hepatitis
Rash
Nausea, abdominal pain, vomiting
What inflammatory conditions is sulphasalazine used for?
IBD
RA
Give an example of an anti-TNF alpha drug?
Infliximab
What are the effects of anti-TNF alpha agents?
Reduce inflammation by impairing cytokine cascade and reducing recruitment of leukocytes
Reduce angiogensis by affecting VEGF levels
Reduce joint destruction
What are some ADRs of anti-TNF alpha agents?
Activation of latent TB Increased infection risk Hepatic and renal impairment Mild heart failure or worsening of existing heart failure May be risk of demyelinating disease
What are the main principles of asthma treatment?
Bronchodilators or relievers to give symptomatic relief
Anti-inflammatories to reduce inflammatory mechanism behind disease
How do beta 2 agonists work in treating asthma?
Act on beta 2 receptors present in bronchial smooth muscle to increase intracellular cAMP, reduce intracellular Ca2+ and so reduce myosin binding of calcium and increase K+ entry and so bring about bronchodilation
Also reduce release of inflammatory mediators from mast cells
Reduce TNF-alpha release from monocytes
Increase mucus clearance
How do the different half lives of beta 2 agonists impact on asthma therapy?
Shorted acting beta agonists, such as salbutamol, last for 3-5 hours and so are given for acute symptomatic relief
Longer acting agents such as salmeterol that last for 12 hours can be given twice a day if control isn’t achieved with corticosteroids, or to treat nocturnal asthma
What are some ADRs of beta 2 agonists?
Skeletal muscle tremor
Tachycardia
Dysrhythmia
What are some contraindications of Beta 2 agonists?
Shouldn’t be used in cardiac ischaemia or in arrythmias as can worsen effects
Give an example of a muscarinic receptor antagonist used in asthma treatment?
Ipatropium
How do muscarinic receptor antagonists contribute to treatment of asthma?
Act on M3 receptors in bronchial smooth muscle to block constricting effects of ACh and to reduce mucus secretion
When are muscarinic receptor antagonists used in asthma?
To augment beta 2 agonists in acute exacerbations
If Beta 2 agonists aren’t tolerated/ are contraindicated
Treat COPD
What are some ADRs of muscarinic receptor antagonists?
Dry mouth
Urinary retention
Glaucoma
Give an example of a methylxanthine
Aminophylline
How do methylxanthines treat asthma?
Mechanism not understood but bring about relaxation of smooth muscle and stimulate the CNS and respiratory system
What should be considered when prescribing methylxanthines?
Have a narrow therapeutic window and so require therapeutic drug monitoring
Also metabolised by the CYP 450 system so careful drug history is needed
What are some ADRs of methylxanthines?
Nausea Gastric reflux Headache Tachycardia Dysrhythmia Psychomotor agitation Seizures
When are methylxanthines used?
Severe asthma
COPD
What is transrepression and transactivation?
Action of steroids to either down or upregulate genetic expression
How do corticosteroids work in asthma?
Transrepress inflammatory mediators
Transactivate anti-inflammatory mediators that cause apoptosis in inflammatory cells and reduce mast cell numbers in mucus
Also transactivate Beta 2 receptors on bronchial smooth muscle
When are corticosteroids used in asthma?
As inhaler for regular use to reduce inflammation
Orally in acute exacerbations
IV in severe asthma
What are some ADRs of inhaled corticosteroids in asthma?
Oropharyngeal candidiasis
Sore throat
Croaky voice
Adrenal suppression
Describe the stepwise management of asthma
If mild and intermittent, manage with short acting beta 2 agonist as needed
If regular preventer therapy is needed, add on inhaled steroid
If control is not achieved and add on therapy is needed, give a long acting beta 2 agonist
If there’s persistent poor control, can give a daily oral dose of steroids alongside the inhaled and consider adding leukotriene receptor antagonist
What is involved in the immediate phase of asthma?
If atopic, is immediate response to an allergen but may be a response to a non-specific stimulus. There’s increased levels of mast cells and monocytes which react with the allergen to produce histamine, leukotrienes and prostaglandins which are spasmogens, causing bronchospasm
Mast cells also produce chemokines and chemotaxins which activate the late phase
What’s involved in the late phase of asthma?
Activated by the immediate phase, there’s infiltration of Th2 cells which release cytokines and activate inflammatory cells, particularly eosinophils. Eosinophils release toxic proteins which cause endothelial damage, as well as mediators such as IL-3 and IL-5. Also release growth factors, causing hypertrophy of smooth muscle.
Endothelial damage contributes to hyperreactivity, along with inflammatory cells.
All this causes bronchiospasm, wheezing and coughing
What changes occur in the airways in asthma?
Hyperplasia Inflammation Mucous gland hyperplasia Airway wall thickening Increase mass of smooth muscle Subepithelial fibrosis Sesquamation of epithelium
What are the signs signalling asthma that is well controlled?
Minimal symptoms at day and night Normal lung function Minimal need of reliever medication No exacerbations No limitation of physical activity
What are the signs of a severe acute asthma attack?
Any one of: Inability to complete sentences Pulse at least 110 bpm Resp rate at leas 25 breaths per min Peak flow 33-50% of best or predicted
How are severe acute asthma exacerbations treated?
High flow oxygen, aiming for sats to be 94-98% Nebulised salbutamol Oral prednisolone Nebulised ipratropium bromide Consider IV aminophylline
What are the signs of life threatening asthma?
PEF 4.5kPa Silent chest Cyanosis Feeble respiratory effort Bradycardia Hypotension Arrythmia Exhaustion Confusion Coma
What are the features of COPD?
Chronic cough that’s worse in the morning, particularly in winter and with purulent sputum
Progressive breathlessness
Airflow obstruction, improved by bronchodilator
Pulmonary hypertension
How are prostaglandins synthesised?
Arachidonic acid is formed from cell membrance phospholipids. Arachidonic acid then forms prostaglandins, stimulated by COX-1 and COX-2 enzymes
Other than prostaglandins, what other substances does arachidonic acid form?
Thromboxanes
Leukotrienes
Prostacyclins
What are the differences in expression of COX-1 and COX-2?
COX-1 is constantly expressed and its prostaglandins have cytoprotective role at gastric mucosa, renal parenchyma, myocardium and ensures optimal perfusion and reduces ischaemia
COX-2 expression is stimulated by injurious stimuli and inflammatory mediators
How do NSAIDs work?
Inhibit COX-1 and COX-2 enzymes to inhibit prostaglandin synthesis. Mainly exert therapeutic effect by COX-2 inhibition but aspirin irreversibly inhibits COX-1
Explain the anti-inflammatory effects of NSAIDs?
Inflammation involes a range of local mediators that induce COX-2 expression and so prostaglandin synthesis. Prostaglandins increase the permeating effects of bradykinin and histamine and so indirectly increase vascular permeability. They also increase peripheral nociception
Effect of NSAIDs is proportionate to effects of prostaglandins in inflammation (reduce erythema and swelling)
Explain the anti-pyretic effects of NSAIDs
Bacterial endotoxins stimulate IL-1 release from macrophages which increases prostaglandin synthesis at the hypothalamus. Prostaglandins act to increase Ca2+ concentrations inside neurons which regulate temperature and so increase heat production and reduce heat loss. They also elevate the set point of the central thermostat.
NSAIDs reduce prostaglandin levels and so reduce temperature
Explain the analgesic effects of NSAIDs
After injury, prostaglandin is released which binds to GPCRs on nociceptive pain fibres which sensitises them by increasing their sensitivity to bradykinin, inhibits K+ channels and increases sensitivity of Na+ channels so C fibres are hyperactive. There’s also increased Ca2+ concentrations so there’s increase in release of neurotransmitters.
If increased pain signalling is sustained then there’s increase in prostaglandin synthesis in the dorsal horn.
NSAIDs act to reduce this effect of sensitisation and reduce headache pain by reducing cerebral vasodilation
What are the main DDIs of NSAIDs?
Are highly protein bound and so can affect the protein binding of other drugs, especially warfarin, sulphonylureas and methotrexate. This causes increased bleeding, hypoglycaemia and wide ranging serious ADRs due to increased free concentrations
When used with opiate they extend the therapeutic range and so reduce ADR profile of opiods compared to if opiates are used alone
What are some ADRs of NSAIDs?
Increased risk of gastric ulceration, perforation and haemorrhage Stomach pain Nausea Heartburn Hypertension Increased bleeding time Increased bruising Skin rashes Asthmatic bronchospasm Stevens Johnson syndrome
What are the signs of aspirin overdose?
Vomiting Dehydration Hyperventilation Tinnitus Vertigo Sweating There's respiratory alkalosis that develops into metabolic acidosis
How does aspirin affect platelets?
It irreversibly inhibits COX-1 that normally has a pro-aggregative effect on platelets and the vessel wall, so it’s inhibition reduces thrombotic formations.
What is the neurotransmitter of pain perception?
Substance P
What are the main types of endogenous opioid and what is there precursor?
Endorphins from POMC
Enkephalins from proenkephalin
Dynorphins from prodynorphin
