Pharmacy Flashcards

Question

LO 3.1 Understand the hormonal regulation of the female reproductive cycle

Answer 1

Beginning of Cycle Oestrogen, Progesterone, Inhibin levels low GnRH secretion due to lack of inhibition LH and FSH rise, FSH more due to low Inhibin levels so less inhibition at the pituitary FSH, followed by LH causes Follicles to Grow Antral Phase LH binds to Theca Interna in the ovaries - Producing androgens FSH binds to Granulosa cells in the ovaries - Produce enzymes which convert Androgens -> Oestrogen As the follicle grows, more oestrogen is produced for a given amount of LH and FSH Pre-Ovulatory Phase Follicle has grown, and is producing a high amount of Oestrogen LH receptors develop in outer layers of Granulosa Cells [High] Oestrogen positively feeds back LH Surge produced ~12 – 14 days into the Cycle o Timing may be influenced by environmental factors o Stimulates ovulation o Follicle size increases, collagenase activity o FSH still being inhibited by Inhibin Luteal Phase Remains of follicle reorganise into Corpus Luteum LH stimulates the Corpus Luteum Produces Oestrogen and Progesterone o Rising Oestrogen does not positively feedback on LH because Progesterone levels are also rising o Prevents new follicles from developing (reduced FSH) As the Corpus Luteum grows, more steroids are produced for a given LH level Follicular Phase Steadily rising titres of Oestrogen Fallopian Tube - Increased Secretion, motility, cilia Myometrium - Increased Growth, motility Endometrium - Thickness, glandular invaginations, Secrete a watery fluid, conductive to sperm Cervical Mucus - Thin, alkaline, conductive to sperm Vaginal Epithelium - Increased Mitosis Mildly anabolic Effects on CVS Luteal Phase Action of Progesterone on Oestrogen-Primed Cells Fallopian Tube - Reduced Motility, secretion, cilia Myometrium - Further thickening, reduced Motility Endometrium - Further thickening, increased secretion, Development of Spiral Arteries Cervical Mucus - Thickening, acidification. Inhibits sperm transport Mildly Catabolic Elevates basal body temperature Promotes change in Na+ and H2O excretion - With Oestrogen leads to net Na+ and H2O retention 14 Days after Ovulation In the absence of pregnancy the Corpus Luteum regresses spontaneously Progesterone and Oestrogen levels fall Triggering a menstrual bleed o The elaborate secretary epithelium of the endometrium collapses o Apoptotic cell death o Dead tissue shed as menstrual bleed. o Spiral arteries contract to reduce bleeding. Relieves inhibition on GnRH, FSH and LH, triggering the development of new follicles and the beginning of a new cycle Sudden Fall in Progesterone and Oestrogen Levels If Conception has Occurred The implanted embryo develops a placenta, which secretes Human Chorionic Gonadotrophin (hCG) hCG prevents the regression of the Corpus Luteum Continues to secrete Oestrogen and Progesterone Supports early weeks of pregnancy (Until about 12-14 weeks) Maintains suppression of the ovarian cycle

Answer 2

``` Actions Mild anabolic Sodium and water retention** Raise HDL, Lower LDL Decrease Bone Resorption Impair Glucose Tolerance Increase Blood Coagulability ``` ``` Side Effects Breast tenderness Nausea, vomiting Water retention Increased Coagulability Thromboembolism** Impaired glucose tolerance Endometrial hyperplasia & cancer ```

Answer 3

``` Actions Secretory endometrium Anabolic Increase bone mineral density Fluid retention Mood changes** ``` ``` Side Effects Weight gain Fluid retention Anabolic Acne Nausea vomiting Irritability Depression Lack of concentration Pre-menstrual syndrome (marked exaggeration of mood changes) ```

Answer 4

Actions Male secondary sex characteristics Anabolic Voice changes Side Effects Acne Aggression Metabolic adverse effect on lipids

Answer 5

Transported bound to Sex Hormone Binding Globulin (SHBG) (except progesterone) and albumin (mainly progesterone). Metabolism is via the Liver, Progesterone is almost totally metabolised in one passage through the liver Metabolites excreted in the Urine (as glucuronides and sulphates) Mechanism of Action Like all steroid hormones, sex steroids exert their effect via Nuclear Receptors. These receptors are found in the cytoplasm, complexed with heat shock proteins. Following the diffusion (or possibly transport) of their ligand into the cell and high-affinity binding, these receptors form a Homodimer with another ligand-receptor complex and translocate to the nucleus. In the nucleus, the steroid-receptor complex homodimers can Transactivate or Transrepress genes by binding to Positive or Negative Hormone Response Elements. Large numbers of genes can be regulated in this way by a single ligand. Steroids may also bind to receptors that are already present inside the nucleus, which will then bind to the HRE.

Answer 6

Hormonal Contraception Progesterone Thick, ‘hostile’ cervical mucus plug o Prevents sperm from entering uterus o Main contraceptive action of progesterone Negative feedback to hypothalamus / pituitary o Decreases frequency of GnRH pulses o Inhibits follicular development Oestrogen Oestrogen negatively feeds back on anterior pituitary Loss of positive feedback mid-cycle so No LH surge The COCP contains both an Oestrogen and a Progestogen (a Progesterone analogue). They work by mimicking the luteal phase of the menstrual cycle and suppress the release of gonadotrophins via negative feedback. As a result, follicular selection and maturation, the LH surge and consequently ovulation, do not take place. There is also an adverse effect on cervical mucus and the endometrium. Route of Administration Oral - One a day for 21 days, then break, placebo or iron pill for 7 days Indications Contraception and Menstrual Symptoms Contraindications Pregnancy, breast feeding, history or risk factors of heart disease, hypertension, hyperlipidaemia or any prothrombotic coagulation abnormality, diabetes mellitus, migraine, breast or genital tract carcinoma, liver disease Adverse Effects Venous thromboembolism, Hypertension, decreased glucose tolerance, headaches, mood swings, acne, flushing, nausea, vomiting, headache, amenorrhoea of variable duration on pill cessation

Answer 7

The POP consists of low-dose Progestogen (a Progesterone analogue). This causes thickening of cervical mucus, preventing sperm penetration. It also has an adverse effect on the endometrium, affecting implantation. Contraception is less reliable than the COCP. It also causes suppression of gonadotrophin secretion, and occasionally ovulation, but the latter effect does not occur in the majority of women. During treatment with the POP ovulation still takes place and menstruation is normal. Route of Administration Oral - Daily, at the same time, starting at day 1 of menstrual cycle. If delay in taking the pill is greater than 3 hours, contraceptive effect may be lost Indications Contraception – More suitable for heavy smokers and patients with hypertension or heart disease, diabetes mellitus, or other contraindications for oestrogen therapy Contraindications Pregnancy, arterial disease, liver disease or breast or genital tract carcinoma Adverse Effects Menstrual irregularities, nausea, vomiting and headache, weight fain, breast tenderness

Answer 8

COCP - Adverse Effects Venous Thromboembolism (rare) Hypertension Amenorrhoea of variable duration on pill cessation Flushing, headaches, nausea, acne, mood swings, weight gain (common) COCP - Drug Interactions Metabolism is by CYP450 o Therefore effected by inducers/inhibitors o Enzyme inducers can lower levels of COCP causing contraception failure such as carbamezepine and phenytoin (anti-epileptics) o Broad spectrum antibiotics (e.g. Amoxicillin) Enterohepatic recirculation of oestrogen increases the efficacy of the COCP. If gut flora is killed by a broad spectrum antibiotic this is reduced and may cause contraception failure

Answer 9

Oral o Most common route (HRT, contraception, fertility) Transdermal o May reduce risk in turns of DVT, Thromboembolism by bypassing the Liver and giving smaller doses o Important for people who complain of GI side Effects o Slow, gradual release of steroid (Progestin) Implants o Slow, gradual release of steroid (Progestin) Nasal Vaginal

Answer 10

Other Contraception Depot progesterone Intramuscular implant of progesterone, giving long term contraception Same mechanism of action as POP Emergency Contraception ‘Morning after pill’ – Up to 72hrs after sex Very high oral doses of progesterone (1.5mg) alone, or a Progestogen with an oestrogen to prevent implantation of fertilised egg o 75% effective o Indications – Emergency Contraception after unprotected sex o Contraindications – Oestrogen contraindications, need to ask about cycle and when they had sex to determine if the woman is already pregnant. If this is the case it would be illegal to prescribe (abortion). Up to 120 hours after sex o Progesterone receptor modulator – delays or inhibits ovulation o Copper IUD

Answer 11

The point where there is a cessation of menstrual cycles, usually from the age of 50 onwards. There are no more follicles which can be stimulated by GnRH. There is a dramatic decrease in oestrogen levels and FSH and LH levels will rise. The sudden rise in FSH is due to decrease amount of inhibin. Changes that occur: o Vascular changes - Transient rise in skin temperature and flushing o Changes to oestrogen sensitive tissue - Shrinking of endometrium/cervix, Loss of vaginal rugae, Involution of breast tissue and Skin/Bladder changes o Decreased bone mass - Oestrogen inhibit osteoclast function, therefore loss of oestrogen leads to osteoclast activity being greater than osteoblast activity. Leads to osteoporosis

Answer 12

Atherosclerosis Pathophysiology ``` Endothelial injury due to o Raised LDL o ‘Toxins’ e.g. cigarette smoke o Hypertension o Haemodynamic stress ``` Endothelial injury causes o Platelet adhesion, PDGF release, smooth muscle cell proliferation and migration o Insudation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages o Migration of monocytes into intima Stimulated SMC produce matrix material Foam cells secrete cytokines causing o Further SMC stimulation o Recruitment of other inflammatory cells ``` Pro-Atherogenic effects of Oxidated-LDL o Inhibits macrophage motility o Induces T-cell activation and vascular smooth muscle cell division/differentiation o Toxic to endothelial cells o Enhances platelet aggregation ```

Answer 13

Studies have shown that both total and LDL cholesterol concentrations correlate with clinical coronary atherosclerosis. Importantly, increasing HDL levels reduces CHD risk. ``` Prevention of Atherosclerosis o Lifestyle changes (diet, exercise) can reduce LDL and increase HDL o Statins o Cholesterol absorption inhibitors o Fibrates o Niacin o Bile Acid Sequestrants ``` Lipoprotein Transporters o Chylomicrons -Transport dietary triacylglycerols from the intestine to tissues such as adipose tissue. o VLDL -Transport of triacylglycerols synthesised in the liver to adipose tissue for storage. o LDL -Transport of cholesterol synthesised in the liver to tissues. o HDL -Transport of excess tissue cholesterol to the liver for disposal as bile salts.

Answer 14

Examples o Simvastatin - Short half life = 1-4 hours therefore is given at night o Atorvastatin - Half life = 20 hours therefore can be given at any point in the day, has a superior efficacy o Rostuvastatin - Contains sulphur, is more potent than simvastatin. Half life = 20 hours, so can be given at any time of the day o Pravastatin Route of Administration - Oral Indications Hyperlipidaemia which has not responded to changes in diet and exercise Secondary prevention in patients with serum cholesterol greater than 5.5mmol/L (value varies depending on local policy) Contraindications - Pregnancy, breastfeeding, liver disease Mechanism of Action o HMG-CoA Reductase inhibitor. Prevents cholesterol synthesis in the liver. Lower liver cholesterol concentration stimulates the production of LDL receptors, increasing the rate of LDL removal from plasma Adverse Drug Reactions - Serious ADRs tend to be limited, even at the highest does of statin given. o Increased transaminase levels - rapidly reversible, no evidence of chronic liver disease o Myopathy - Diffuse muscle pain, primarily seen when used in combination with cyclosporine and occasionally erythromycin & niacin. Can test levels of creatinine kinase if symptomatic to confirm the presence of myopathy o GI Disturbances o Arthralgia o Headaches o Drug-Drug Interactions o CYP450 inducers/inhibitors. o Inhibitors significantly increase the risk of myopathies as the drugs spends more time in the plasma and therefore is more likely to interact with muscle tissue

Answer 15

Fibrates can be used in conjunction with statins, but typically are only used as first line choices in hypertriglyceridemias. Examples o Bezafibrate o Ciprofibrate o Gemfibrozil Route of Administration - Oral Indications - Hyperlipidaemia which does not respond to dietary control Contraindications - Pregnancy, breast feeding, gall bladder disease, severe renal or hepatic impairment, Hypoalbuminaemia Mechanism of Action o Peroxisome Proliferator-Activated Receptor-α (PPAR-α) agonist o LDL lowering (variable amount) o HDL increases of 15-25% in hypertriglyceridemia o Decreases Triglycerides 25-50% ``` Adverse Drug Reactions o Gastrointestinal disturbances o Dermatitis, pruritus, rash o Impotence o Headache, dizziness, blurred vision ``` Drug-Drug Interactions - Increased chance of myalgia and myopathies when taken with statins

Answer 16

It is normally given as monotherapy in statin intolerant patients, however it will reduce LDL by a further 20% when given in combination with a statin. This is a better reduction than is gained by doubling statin dose and also reduces the risk of statin ADRs. Examples - Ezetimibe Route of Administration - Oral Indications o Hyperlipidaemia resistant to dietary control, in statin intolerant patients o Given in combination with a statin Contraindications - Breastfeeding Mechanism of Action o Blocks NPC1L1 in the intestinal brush border, inhibiting cholesterol absorption, increasing LDL receptor upregulation leading to further reducitons o Reduce LDL levels by 15-20% o Ezetimibe also undergoes enterohepatic circulation, increasing its half-life. Adverse Drug Reactions o Gastrointestinal disturbances (Diarrhoea, pain) o Headache

Answer 17

Examples o Colestyramine o Colestipol Route of Administration - Oral Indications - Elevated cholesterol resulting from a high LDL concentration Contraindications - Biliary obstruction Mechanism of Action o Bile acids are produced from cholesterol. The bile acid sequestrants will bind to bile acids in the intestine. This prevents their reabsorption and further conversion of hepatic cholesterol into bile acids. Lower levels of hepatic cholesterol leads to increased LDL receptor expression and lowered plasma cholesterol concentration. Adverse Drug Reactions o GI disturbances – Nausea, vomiting, constipation, abdominal pain, flatulence, heart burn o Very few systemic side effects as they are not absorbed

Answer 18

Niacin Used to increase HDL levels and is also found to decrease the risk of cardiovascular events. Inhibits lipoprotein-a synthesis Side effects include o Skin flushing and itching o Dry skin o Skin rashes -Eczema exacerbations or Acanthosis nigricans (thickened brown, leathery patches of skin)

Answer 19

There are considerable variations in pharmacokinetics and pharmacodynamics within the statin drug group o Intestinal absorption varies between 30 – 85% o Hepatic first pass uptake is extensive as it may occur either by diffusion or active transport by OATP2 o Systemic availability may fall to 5 – 30% of administered dose o Hepatic elimination includes CYP3A4 for some statins, whilst others are only metabolised by Phase 2 pathways o Exhibit Non-Linear Pharmacokinetics - Doubling of a dose results in ~6% reduction in LDL Short Acting Statins o Simvastatin - Half-life 1-4hrs, given at night to coincide with peak cholesterol in early morning Long Acting Statins Atorvastatin - Half-life ~20 hours. Given any time of day. Rostuvastatin - Half-life ~20 hours. Given any time of day.

Answer 20

Sulphonylureas (Insulin Release Stimulants) ``` Examples o Tolbutamide (t½ ~ 4hrs, duration of action 6-12hrs) o Glibencamide (t½ ~ 10hrs, duration of action 18-24hrs) o Glipizide (t½ ~ 7hrs, duration of action 16-24hrs) ``` Indications - Diabetes mellitus, in patients with residual β-cell activity Contraindications - Breastfeeding women, elderly, renal and hepatic insufficiency Route of Administration - Oral Mechanism of Action o Sulphonylureas antagonise β-cell K+/ATP activity, resulting in depolarisation. Voltage gated Ca2+ channels open, Ca2+ entry causes insulin vesicle fusion with cell membrane Adverse Drug Reactions o Hypoglycaemia o GI disturbance o Weight gain Drug-Drug Interactions o Highly protein bound (90-99%)

Answer 21

Biguanides (Insulin Sensitisers) Examples - Metformin Indications- Type II diabetes – Endogenous insulin presence required Contraindications o Compromised HRH function o In respiratory disease Mechanism of Action o Unknown o Increases insulin receptor sensitivity, enhancing skeletal and adipose glucose uptake o Inhibits hepatic gluconeogenesis o Reduces hyperglycemia, but does not induce hypoglycemia o Tends to be give 2-3 times a day prior to meals to provide acute negative feedback on top of a basal endogenous insulin signal Adverse Drug Reactions o GI disturbances – ameliorated by slow dose titration o Lactic Acidosis

Answer 22

Examples o Rosiglitazone o Pioglitazone Indications - Uncontrolled non insulin dependant diabetes Contraindications o Compromised HRH function o Especially heart failure – can cause oedema Mechanism of Action o PPAR-γ agonist. Agonistically bind to a nuclear hormone receptor site. o Reduction in gluconeogenesis and an increased glucose uptake into muscles Adverse Drug Reactions o GI disturbance o Weight gain Drug-Drug Interactions - Very heavily protein bound (~99%)

Answer 23

Examples o Repaglinide o Nateglinide Indications - Uncontrolled non insulin dependant diabetes Mechanism of action o K+/ATP channel antagonists on β-cells, resulting in depolarisation, calcium entry and fusion of insulin containing vesicles with membrane Adverse Drug Reactions o Relatively lower risk of hypoglycaemia than Sulphonylureas o Not associated with weight gain – useful in treating obese patients

Answer 24

Metformin is the first hypoglycaemic drug that you would use. If the patient is intolerant to Metformin, or is not overweight then Gliclazide (sulphonylurea) would be a better option as the first line of treatment. Pioglitazone is the second line treatment, which is added to Metformin or a sulphonylurea. This happens if: - Metformin and a sulphonylurea are not tolerated - Metformin or sulphonylureas are contraindicated.

Answer 25

Insulin analogues are manufactured on a large scale, using recombinant DNA technologies. There aqre many variations meaning that different formulations of insulin can be prepared, so the rate of uptake following sub-cutaneous injection can be varied. A mixture of these different insulins can be used together in a mix to give the best control. Ultra Rapid 3 – 4 Duration Meals/Acute hyperglycaemia Short Acting 2 – 5 Duration Meals/Acute Hyperglycaemia Intermediate 4 – 10 Duration Basal Insulin/Overnight control Intermediate/Long Acting 8 – 30 Duration Basal Insulin/Overnight Control Due to the absence of properly functioning control systems, the best way to mimic the optimal actions of insulins is to utilise mixtures of analogues. There are two main mixtures used: o Basal Bolus Regimen involves utilising a long acting insulin as background and then a fast acting insulin with meals. This involves injecting around 5 times a day yet does provide good flexibility. o Pre-mixed Insulin Regime involves administration of both fast and slow acting insulin twice a day. Whilst this does not provide optimised glycaemic control, it involves less injecting for the patient.

Answer 26

o Begin with no pharmacological intervention, therapy starting with Diet, Exercise and Lifestyle changes o A Biguanide (Metformin) started when necessary o Over time if HbA1c levels go above 7%, a Sulphonylurea (e.g. Tolbutamide) is added to therapy o Over time if HbA1c levels go about 7.5% a Thiazolidinedione (e.g. Rosiglitazone) may be added, or a newer hypoglycaemic, or start insulin therapy o If on this regime if HbA1c levels go above 7.5%, doses will be titrated upwards to regain adequate glycaemic control

Answer 27

Monitoring in Acute Treatment In patients with advanced diabetes, monitoring several times a day is required to determine dosing level with insulin. The regime in non-insulin therapies is frequently determined by dietary habit. With careful monitoring and control of their diet, patients can stay within normal glucose ranges. Monitoring in Chronic Treatment Glycosylated Haemoglobin - Glucose in the blood will react with the terminal valine of the haemoglobin molecule to produce glycosylated haemoglobin (HbA1c). The percentage of HBA1c is a good indicator of how effective blood glucose control has been. As RBCs normally spend ~3 months in the circulation the %HbA1c is related to the average blood glucose concentration over the preceding 2-3 months. Poorly controlled diabetics can have a HbA1c value above 10%.

Answer 28

Orlistat Mechanism of Action o Gastric and pancreatic lipase inhibitor, reducing the conversion of up to 30% of dietary fat to fatty acids and glycerol Adverse Drug Reactions o Broad GI disturbances o (Soft fatty stools, flatus, faecal discharge/incontinence) ``` Sibutramine Mechanism of Action o Noradrenaline and serotonin re-uptake inhibitor leading to appetite suppression, increased thermogenesis Adverse Drug Reactions Increased heart rate and blood pressure ``` Rimonabant Mechanism of Action - Endocannabinoid antagonist Adverse Drug Reactions - Depression – currently withdrawn in the UK by NICE

Answer 29

Bacteria are prokaryotic organisms. The chemotherapy of infections aims to selectively target the invading bacterial while having minimal effect upon the host. This is achieved by exploiting the differences that exist between the structure and physiology of the prokaryotic bacterial cells and the host eukaryotic cells. Antibacterial agents can be considered as bacteriostatic (inhibit bacterial growth, but do not kill them), or bactericidal (kill the bacteria).

Answer 30

``` Site - Peptidoglycan cell wall Reason - Peptidoglycan cell wall only present in prokaryotic cell. Antibacterial Drugs: o Penicillins o Cephalosporins o Glycopeptides ``` ``` Nucleic Acids Bacterial genome is a single, circular strand of DNA unenclosed by a nuclear envelope, in contrast to eukaryotic chromosomal arrangement within the nucleus Antibacterial Drugs: o Antifolates o Quinolones o Rifampicin ``` ``` Protein Synthesis Bacterial ribosome (50s+30s subunits) is different to the mammalian ribosome (60s+40s subunits) Antibacterial Drugs: o Aminoglycosides o Tetraclyclines o Macrolides o Chloramphenicol o Fusidic acid ``` Cytoplasmic Membrane Bacterial plasma membrane does not contain any sterols, unlike mammalian. Antibacterial Drugs: o Polymyxins

Answer 31

DNA, Protein, Cell Wall Synthesis

Answer 32

Prophylaxis of Bacterial Infections Prophylactic antibiotics are given to people who are at an increased risk of infection. o Peri-operative (Prevention of surgical site infections) o Short term - e.g. Meningitis contacts o Long term - e.g Asplenia (encapsulated bacteria) or Immunodeficiency Treatment of Significant Bacterial Infections o Treatment of cultured, proven infection o Empirical treatment of suspected infection

Answer 33

The ideal antibiotic therapy is one that gives: o Clean killing of infecting bacteria with minimal impact on non-target commensal organisms and leaves no resistance in any surviving pathogens o No adverse effects on patient ``` Factors to help determine the likely infectious agent o Anatomical Site o Duration of illness o Past medical history o Occupational history o Travel history o Time of year o Age o Personal background ``` Factors determining which antibiotics are likely to be effective o Community or healthcare onset? o Severity of infection o Baseline rate of resistance o Immune status of patient - Immunocompromised patients will need IV Antibiotics immediately ``` Which antibiotic is the best choice? Considerations o Efficacy o Cost o Administration Route o Safety o Patient age o Patient organ function o Patient Allergies o Toxicity and Drug Interactions o Pregnancy, breast feeding ```

Answer 34

Chromosomal Gene Mutation o Chromosomal gene mutates in one bacteria in a population, conferring a resistance to antibiotic o Antibiotic kills all other bacteria, acting as a selection pressure, giving resistant bacteria an advantage o Population of antibiotic resistant bacteria daughter cells Horizontal Gene Transfer o Transformation Bacteria with antibiotic resistance gene releases DNA Uptake of DNA by recipient cell, conferring antibiotic resistance o Transduction Phage infected, antibiotic resistant Bacterial donor cell Phage passes the DNA conferring resistance to recipient cell o Conjugation Connection is made between antibiotic resistant donor cell, and recipient cell Plasmid containing resistance gene is replicated and passes from donor cell to recipient cell Plasmid may even become incorporated into recipient cell DNA

Answer 35

Antibiotic Inactivation -Production of enzyme that inactivate the drug E.g. β-lactamase which inactivates Penicillins Alteration of Drug Binding Site - so drugs no longer have affinity for them E.g. Bacterial ribosome alteration, meaning Aminoglycosides and Erythromycin cannot bind Alteration of Metabolic Pathways - Development of altered metabolic pathways E.g. bacteria can become resistant to Trimethoprim due to acquired changes in their Dihydrofolate Redctase enzyme, which gives it very little affinity for the drug Reduced Intracellular Antibiotic Concentration o Active Efflux Mechanisms E.g. Active transport mechanisms used (e.g. p-glycoprotein) to pump a drug out of the bacterial cell because it accumulates to an effective level o Decreased permeability E.g. Some bacteria become resistant to Tetracycline because they alter their cell membrane to make it impermeable to the drug

Answer 36

Patterns of Emergence of Antibiotic Resistance o Local selection (e.g. in a hospital) o Clonal dissemination (e.g. around the country) o Global spread Main Antibiotic Resistant Organisms o Methicillin Resistant Staphylococcus Aureus (MRSA) o Glycopeptide Intermediate susceptibility Staphylococcus Aureus (GISA) o Glycopeptide Resistant Enterococci (GRE) o Extended Spectrum Beta Lactamase enterobacteriaceae (ESBLs) o Extensively Drug Resistant Klebsiella Pneumoniae (XDR-KP)

Answer 37

``` Antimicrobial Stewardship o Right antibiotic o Right time o Right dose, frequency and duration o Right route ``` Infection Control Prevent the spread of recognised resistant bacteria o Isolation or cohorting o Hand hygiene o Decolonisation of patients Prevent bacterial exposure to antibiotics o Minimise risk of infection o Monitor and control antibiotic prescribing

Answer 38

Administration - Oral or Intravenous (Required for Immunocompromised patients) Metabolism/Elimination - Renal or Hepatic o Time dependent killing Prolonged antibiotic presence at the site of infection, but not high concentration o Concentration dependent killing High antibiotic concentration at the site of infection, but short duration Minimum Inhibitory Concentration – MIC The MIC is the lowest concentration of an antibiotic that will inhibit the visible growth of a microorganism after overnight incubation. A MIC is generally regarded as the most basic laboratory measurement of the activity of a microbial agent against an organism.

Answer 39

1. Influenza virus binds to cell via Hemagglutinin onto sialic acid sugars on the surface of epithelial cells. 2. Entry of virus into cell via endocytosis 3. ATP driven proton entry into the endosome, allowing fusion of the viral membrane with the internal endosomal membrane 4. Entry of protons into the virus itself via the viral M2 Ion Channel. Low pH inside the virus results in breakdown in the viral coat of the nucleocapsid core. This releases viral RNA into the host cytoplasm 5. Virus replicates using host cell machinery 6. Viral protein assembly 7. New virus buds off the cell membrane, but many remain attached by re-attaching to the sialic acid on the cell surface 8. Viral Neuramidase enzyme breaks this bond, allowing viral release

Answer 40

``` Influenza A o Multiple host species which are able to infect humans o Antigenic drift and shift - Drift = different each year - Shift = leads to an epidemic ``` Influenza B o No animal reservoir o Lower mortality than influenza A Influenza C o Common cold like

Answer 41

Examples o Amantadine o Rimantadine Route of Administration - Oral Indications o Prophylaxis and treatment of acute Influenza A in groups at risk. Mechanism of Action o Inhibits the un-coating of a virus, therefore preventing it from being able to infiltrate into the cell. This occurs by the action of: o Inhibits H+ influx into the cell, therefore preventing the change in pH which stimulates the viral un-coating. o Blocks M2 Ion Channel, preventing breakdown of viral coat and release of viral RNA into host cell. Adverse Drug Reactions o Amantadine has more marked ADR risk than Rimantadine of ~5-10%, therefore Rimantadine is usually preferred o Dizziness o Hypotension o GI disturbance o Confusion, insomnia and hallucination can be problematic in the elderly (CNS) o Is nephrotoxic in high doses Therapeutic Notes o Limited to Influenza group A, ineffective against group B o Rapid emergence of M2 mutations in H5N1 viruses o Resistance can develop quickly as only a single point mutation is needed in order to change the shape. This causes the binding site to move away from the channel, so that when the drug binds it will no longer block the channel E.g. amantadine in chicken feed leading to resistance

Answer 42

Examples o Zanamivir o Oseltamivir Route of Administration o Zanamivir – Inhaled o Oseltamivir – Oral (80% bioavailability) Indications o Treatment of Influenza A or B virus within 48 hours after onset of symptoms when influenza is endemic in the community Contraindications - Breast feeding Mechanism of Action o Inhibits neuraminidase enzyme which cleaves the virus from receptors on the membrane, once the virus has been produced. It causes aggregation of the virus at the cell surface, therefore preventing the virus from spreading throughout the body and therefore to other people also. o Sialic acid analogues, with very high binding affinities for Neuramidase. o The receptor is not involved with antigenic shift or drift ``` Adverse Drug Reactions o Headache o Nose bleed o Respiratory depression (rarely) o Bronchospasm o GI disturbances ``` Therapeutic Notes o Zanamivir has low bioavailability therefore is given as a dry powder inhalant. It is not used for prophylaxis. o Oseltamivir is a pro-drug and by contrast is well absorbed, with 80% bioavailability. This enables it to be given orally for both treatment and prophylaxis. o Gives rise to: • 35-38% reduction in severity • 25-36% reduction in duration when given as soon after infection as possible

Answer 43

Initiation of Treatment The earlier treatment is started after symptom onset, the shorter the duration of symptoms. The time window for significant reduction goes up to 48 hours, little benefit accrues after this time. Mortality Oseltamivir could offer ~70% reduction in risk of mortality according to one Canadian study. This was achieved when dosing was delayed as long as 64 hours after symptom onset. Prophylaxis Treatment for six weeks with 75mg significantly reduced incidence of flu in both healthy adults and frail elderly subjects.

Answer 44

Some resistance has been reported to Oseltamivir in H1N1 viral strains. Virus still remains sensitive to Zanamivir.

Answer 45

Asthma is a chronic disorder characterised by Airway Wall Inflammation and Re-modelling. It is a Reversible Airflow Obstruction (greater than 12% reversibility with salbutamol). Airways in asthma have thickened smooth muscle and basement membranes (collagen deposition in BM). Triggers cause the airway smooth muscle to contract, reducing airway radius, increasing resistance and reducing airflow. Asthma is increasing in prevalence, more common in the developed world and increasing in populations who move from developing -> developed countries o 5.4 million people in the UK current receive treatment o Genetic risk o Sensitisation to airborne allergens such as House Dust Mite, Pollens, Air pollution and tobacco smoke (Pre-/post natal exposure, active) o Hygiene hypothesis The diagnosis of asthma is a clinical one. There is no standard definition of the type, severity or frequency of symptoms, nor of the findings on investigation. Asthma is defined as more than one of the following recurring symptoms: o Wheeze - High pitched, expiratory sound, Polyphonic o Dry cough - Often worse at night (Lack of sleep, poor performance at school) - Exercise induced o Breathlessness - With exercise o Chest Tightness o Variable Airflow Obstruction Examination Inspection o Chest - Scars, deformities, Hyper-expansion (Barrel Chest) o General health - Eczema, hay-fever, Lethargy, speaking? o Percussion - Hyper-resonant o Auscultation - Polyphonic wheeze Spirometry – Flow Volume Loop o Low PEFR o Low FEV1/FVC Ratio o >12% increase in FEV1 following salbutamol Allergy Testing o Skin prick to aero-allergens, e.g. cat, dog, HDM o Blood IgE levels to specific aero-allergens Chest X-Rays o Performed to exclude other diseases/inhalation of foreign body/pneumothorax

Answer 46

Sympathetic Innervation Sympathetic activity results in Bronchodilation, with nerves innervating bronchial blood vessels and glands, but not bronchial smooth muscle. However, β-adrenoreceptors are abundantly expressed on airway smooth muscle, epithelium, glands and mast cells (especially β2). Binding at these sites of β-agonists results in bronchodilation, reduced histamine release and increased mucociliary clearance. Parasympathetic Innervation Parasympathetic activity is normally dominant in maintaining smooth muscle tone in the airways. Muscarinic Receptors are present on airway and vascular smooth muscle and glands. The M3 Receptor is pharmacologically the most important.

Answer 47

Mechanism of Action - β2 agonists act on the β2 receptors found on bronchial smooth muscle. The receptors are coupled to Gs Proteins, which cause an increase in cAMP and consequent decrease in intracellular [Ca2+]. This reduces the binding of Ca2+ by light myosin, causing smooth muscle dilation. Additionally, the decrease in intracellular Ca2+ will also increase Ca2+ activated K+ currents, thus hyperpolarising muscle cells further and augmenting bronchodilation. Pharmacokinetics of β2 Agonists β2 Agonists are administered by inhalation in aerosol, powder or nebulised form and can also be administered intravenously. Deposition within the pulmonary tract is related to particle size, with 1-5microns being optimal. However, the majority of the drug (up to 90% depending on the inhaler device) is deposited in the upper airway and/or swallowed before being removed by the liver. Fast Acting β2 Agonists o Immediate Action o Salbutamol – Duration of action 3-5hrs o Terbutaline – Duration of action 3-5hrs Long Lasting β2 Agonists o Often given in adjunct with anti-inflammatories o Formoterol – Duration of action 13hrs o Salmeterol – Slower onset Adverse Drug Reactions o Inhaled high doses can cause skeletal muscle tremor (β2 activity) o Even though β2 agonists are very selective, they can still antagonise cardiac β1 receptors enough to induce tachycardia and dysrhythmia Drug-Drug Interactions o β-blockers such as Propranolol, which bind to both β1 and β2 receptors

Answer 48

Acts like normal steroid hormones, entering nucleus and binding to HRE. Therapeutic effects of changes in gene expression may only be apparent some hours after administration. Steroids may also bind to receptors that are already present inside the nucleus, which will then bind to the HRE. Anti-inflammatory Effects Reduced production of acute inflammatory mediators, especially eicosanoids (prostaglandins, leukotrienes), due to the production of Lipocortin, an enzyme that inhibits Phospholipase A2, preventing the formation of Arachidonic Acid and its metabolites. Glucocorticoids also reduce the number of circulating immunocompetent cells (neutrophils and macrophages) and decrease the activity of cells involved in the chronic stages on inflammation (macrophages, fibroblasts), decreasing inflammation and decreasing healing. Use of Glucocorticoids in Asthma They have both an anti-inflammatory action and increase the expression of β2 Receptors. Optimal effects are seen after weeks/months of therapy. Pharmacokinetics 10-50% of an inhaled dose is delivered to the lungs, depending on the inhaler device. A major proportion of the drug is deposited in the upper airway and/or swallowed and metabolised by the liver. Newer drugs are designed to undergo hepatic first pass metabolism to reduce ADR risk.

Answer 49

Step 1 Mild Intermittent Asthma Inhaled short acting β2 Agonist as required (E.g. Salbutamol) Step 2 Introduction of regular preventer therapy Inhaled short acting β2 Agonist as required (E.g. Salbutamol) Regular preventer therapy – corticosteroid (e.g. Beclometasone) Step 3 Add on therapy Inhaled short acting β2 Agonist as required (E.g. Salbutamol) Regular preventer therapy – corticosteroid (e.g. Beclometasone) Regular long acting β2 Agonist (E.g. Salmeterol) Step 4 Trial additional therapy Inhaled short acting β2 Agonist as required (E.g. Salbutamol) Regular preventer therapy – corticosteroid (e.g. Beclometasone) Trial of additional therapy, such as Muscarinic Antagonist (e.g. Ipratropium Bromide), Leukotriene Receptor Antagonist, Methylxantine (e.g. Theophylline) Step 5 Continuous or frequent use of oral steroids (e.g. Prednisolone)

Answer 50

Severe Acute Asthma – Status Asthmaticus ``` Severe Acute Asthma/Status Asthmaticus is defined as any one of: o Unable to complete sentences o Pulse ≥ 110 bpm o Respiration ≥ 25 per minute o Peak expiratory flow 33-50% of best or predicted Life Threatening features include: o Peak expiratory flow < 33% o PaO2 < 8kPa o PaCO2 > 4.5kPa o Silent chest o Cyanosis o Feeble respiratory effort o Hypotension, bradycardia, arrhythmia o Exhaustion, confusion, coma Severe, acute asthma is near fatal if PaCO2 is > 6kPa. Mechanical ventilation is required. ``` Management of Severe Acute Asthma (Status Asthmaticus) o Oxygen – High flow, aim to keep O2 94-98% saturation o Nebulised Salbutamol, continuous if necessary o Intravenous Hydrocortisone o Oral Prednisolone - ~40mg daily for 10-14 days If no response to above treatment, add: o Add nebulised Ipratropium Bromide o Consider IV Magnesium Sulphate 1.2-2g over 20 minutes o Consider IV Aminophylline if no improvement and life threatening features not responding to above treatment Beware if taking oral Theophylline

Answer 51

Autoimmunity is the state that is present when an individual has made an immune response to self-antigens. In many cases the presence of autoantibodies in serum provides evidence for autoimmunity, and these may be helpful in diagnosing and monitoring autoimmune diseases. Autoimmune Disease Autoimmune disease is the term applied to a disease in which autoimmunity is thought to play a significant pathogenic role. (I.e. where the tissue damage results from the autoimmune response). Autoimmune disease can be classified as being organ specific. i.e. the target antigen is located in one organ or non-organ specific, i.e. the target antigen is located on many different tissues/organs. Organ – Specific - Hashimoto’s - Thyrotoxicosis - Primary myxoedema - Chronic atrophic gastritis - Pernicious anaemia - Addison’s Disease - Myasthenia gravis - Diabetes mellitus (type 1) - Premature ovarian failure - Male infertility Intermediate / Mixed - Goodpasture’s syndrome - Primary biliary cirrhosis - Autoimmune haemolytic disease - Ulcerative colitis Non-Organ specific - Systemic Lupus Erythematosus - Rheumatoid arthritis - Sjogren’s syndrome - Progressive systemic sclerosis

Answer 52

``` Examples o Prednisolone (Oral) o Beclometasone (Topical/Inhaled) o Hydrocortisone (Cortisol) (Oral for replacement, IV for status asthmaticus and anaphylactic shock) ``` Indications o Immunosuppression o Anti-inflammatory therapy o Replacement of endogenous corticosteroids Contraindications - Systemic infection Mechanism of Action o Diffuse into cytoplasm and bind receptor. Complex moves to nucleus and binds Hormone Response Element (HRE). Inducers/Inhibits transcription. ``` Adverse Drug Reactions o Cushingoid effects o Suppression of HPA axis o Osteoporosis o Suppression of growth in children o Mineralocorticoid effects if the glucocorticoid also has those actions ``` Therapeutic Notes - Long term therapy must be withdrawn slowly, due to HPA suppression

Answer 53

Some immunosuppressants work by inhibiting the division of cells - E.g. Azathioprine, Methotrexate, Cyclophosphamide, Cyclosporin Some cancers are the uncontrolled division of immune cells and therefore immunosuppressants will work to suppress the cancer

Answer 54

Indications o Rheumatoid Arthritis, Inflammatory Bowel Disease o Prevention of graft and transplant rejection o Autoimmune conditions where corticosteroid therapy o alone inadequate o Leukaemia Route of Administration - Oral / IV Mechanism of Action o Azathioprine is a pro-drug, which is converted into 6-Mercaptopurine in the liver o 6-Mercaptopurine is a fraudulent purine nucleotide that impairs DNA synthesis and has a cytotoxic action on dividing cells Adverse Drug Reactions o Myelosuppression -> Leukopenia, thrombocytopenia, anaemia o Increased infection susceptibility o GI disturbances (nausea, vomiting, diarrhoea) o Drug-Drug Interactions o Interacts with Allopurinol (treats gout), necessitates lowering of dose Therapeutic Notes 6-Mercaptopurine is eliminated by the enzyme TPMT, which is subject to a high rate of genetic polymorphism. High levels of TPMT expression will lead to under-treatment, low levels of TPMT expression gives toxicity.

Answer 55

Examples - Cyclophosphamide Indications - Immunosuppression/Cancer chemotherapy Contraindications - Pregnancy Mechanism of Action o Pro-drug, that is activated by CYP450s. o Alkylating agent, which creates cross-links in DNA so that it cannot replicate. Therefore it selectively acts on cells with a higher mitotic rate. Adverse Drug Reactions o Induction of bladder cancer (urine concentration of acrolein metabolite) o Lymphoma and Leukaemia o Infertility & Teratogenesis Drug-Drug Interactions - Pro-drug is activated by CYP450s (inducers/inhibitors)

Answer 56

Examples Cyclosporin (Binds Cyclophilin) Tacrolimus (Binds Tacrolimus-Binding-Protein) Indications o Prevention of graft and transplant rejection o Prevention of graft vs. host disease o Atopic dermatitis, psoriasis Route of Administration - Oral, intravenous Mechanism of Action o Reduction in IL-2 synthesis and release, via Calcineurin inhibition suppressing both cell-mediated and antibody-specific adaptive immune responses. Active against T helper cells. o Ciclosporin binds to Cyclophilin and Tacrolimus binds to Tacrolimus-Binding-Protein o Drug/Protein complexes bind to and inhibit Calcineurin, which normally has a phosphatase activity on the Txn factor for IL-2. Therefore, inhibition of Calcineurin reduces IL-2 Adverse Drug Reactions o Nephrotoxic (proximal tubule), renal damage almost always occurs o Hypertension in 50% of people o GI disturbances Drug-Drug Interactions o Metabolism is by CYP450, so is affected by inducers/inhibitors Therapeutic Notes Unlike most immunosuppression agents, Cyclosporin does not cause myelosuppression

Answer 57

``` Antirheumatic Drugs (DMARDs) (DRUGS SLOW DOWN DISEASE PROGRESSION, DOESN'T JUST TREAT INFLAMMATION) ``` Indications - Immunosuppression and Cancer chemotherapy Contraindications - Pregnancy Route of Administration - Orally, intravenously, intramuscularly, intrathecally Mechanism of Action o Antifolate o Competitively antagonises Dihydrofolate Reductase (DHFR), preventing the regeneration of intermediates (tetrahydrofolate) essential for the synthesis of purines and thymidine, thus inhibiting DNA synthesis. ``` Adverse Drug Reactions o Mucositis o Myelosuppression o Hepatitis, cirrhosis o Increased infection risk o Teratogenesis ``` Drug-Drug Interactions o Adverse DDIs with drugs affecting renal blood flow and renal elimination, e.g. NSAIDs Therapeutic Notes o Essential to carry out clinical monitoring o Baseline chest X-ray, FBC, LFT, U+E + Creatinine o Monthly FBC, LFT, U+E + Creatinine o Oral bioavailability is dose dependent, so usually given IV o Plasma protein binding ~50% - NSAIDs displace, raising plasma concentration 90% renal elimination – glomerular active and tubular secretion o Intracellular/hepatic metabolism to polyglutamates. These polyglutamates accumulate in cells and also bind very strongly to DHFR. Polyglutamates can be retained in cells for weeks to months o Weekly, not daily dosing

Answer 58

``` Antirheumatic Drugs (DMARDs) (DRUGS SLOW DOWN DISEASE PROGRESSION, DON’T JUST TREAT INFLAMMATION) ``` Examples - Sulfasalazine Indications o Rheumatoid arthritis o Inflammatory bowel conditions Contraindication o Renal impairment o Hypersensitivity Mechanism of Action o Sulfasalazine is broken down in the gut to the active component 5-aminosalicylate (5-ASA) and sulfapyridine, which acts as a vehicle to transport the drug to the colon. o Inhibition of T-cell proliferation and IL-2 production. Reduced Neutrophil chemotaxis and degranulation. Adverse Drug Reactions o Mostly due to sulfapyridine (10-45% of patients) o Myelosuppression o Hepatitis o Rash o GI disturbances (Nausea, vomiting, abdominal pain) Therapeutic Notes o Few ADRs/DDIs seen in Pregnancy o Treating Rheumatoid Arthritis o Only 30-40% 5-ASA is absorbed o Molecular mechanism does not involve COX inhibition o Inhibit T-cell proliferation and IL-2 Production, reduced neutrophil chemotaxis and degranulation o Treating Inflammatory Bowel Disease o 5-ASA reaches the colon in large quantities, but acts via an unknown mechanism (again not COX inhibition)

Answer 59

Pain Perception Activation of Nociceptors Noxious thermal, chemical or mechanical stimuli can trigger firing of primary afferent fibres, through the activation of Nociceptors in the peripheral tissues. (Sharp Stabbing Pain - Alpha/Delta Fibres, Dull Nagging Pain C-Fibres) Transmission of Pain Information Transmission of pain information from the periphery to the dorsal horn of the spinal cord is inhibited or amplified by a combination of local (spinal) neuronal circuits and descending tracts from high brain centres. This constitutes the ‘Gate-Control Mechanism’. In the Gate-Control Mechanism: o Primary afferent fibres synapse in Lamina I, II and V of spinal cord dorsal horn o Transmitter peptides are involved in ascending pain pathways - Substance P, Calcitonin, Bradykinin, Glutamate, Nitric Oxide o The activity of the dorsal horn relay neurons is modulated by several inhibitory inputs. These include: - Local inhibitory interneurons, which release opioid peptides - Descending inhibitory noradrenergic fibres from the locus ceruleus area of the brainstem - Activated by opioid peptides - Descending inhibitory serotonergic fibres from the Nucleus Raphe Magnus and Periadueductal grey areas of the brainstem - Activated by opioid peptides Onward Passage of Pain Information The onward passage of pain information is via the Spinothalamic Tract, to the higher centres of the brain. Here, there is coordination of the cognitive and emotional aspects of pain and control of appropriate reactions. Opioid peptide release in both the spinal cord and brainstem can reduce the activity of the dorsal horn relay neurons and cause analgesia, known as ‘shutting the gate’.

Answer 60

The main action of all the NSAIDs is inhibition of the enzyme Cyclooxygenase (COX). This enzyme is involved in the metabolism of Arachidonic Acid to form Prostanoids, i.e. the ‘classic prostaglandins’, Prostacyclin and Thromboxane A2. Inhibition of cyclooxygenase can occur by several mechanisms: Irreversible inhibition E.g. Aspirin causes acetylation of the active site. This is the basis for Aspirin’s effect on platelets Competitive inhibition E.g. Ibuprofen acts as a competitive substrate Reversible, non-competitive inhibition E.g. Paracetamol has a free-radical trapping action that interferes with the production of hydroperoxidases, which are believed to have essential role in cyclooxygenase activity.

Answer 61

Cyclooxygenase exists in two enzyme isoforms. Generally, NSAID action on COX-1 is rapid and competitive, on COX-2 is slower and often irreversible. COX-1 Expressed in most tissues, especially platelets, gastric mucosa and renal vasculature Involved in physiological cell signalling Most adverse effects of NSAIDs are caused by COX-1 Inhibition COX-2 Induced at sites of inflammation and produces the Prostanoids involved in inflammatory responses Analgesic and Anti-inflammatory effects of NSAIDs are largely a result of inhibition of COX-2

Answer 62

NSAIDs as Analgesics NSAIDs act as analgesics by reducing synthesis of Prostaglandins that sensitise Nociceptors to inflammatory mediators. Thought to reduce headache pain by cerebral vasodilation mediated by prostaglandins. May also have a secondary effect on prostaglandin facilitation of afferent pain signal in spinal cord dorsal horn neurones. Anti-Inflammation Along with Prostaglandins, there are a number of other mediators involved in the inflammatory response. Therefore NSAIDs will have an effect proportionate to prostaglandin involvement. Primarily reduce erythema, swelling and pain response associated with swelling. Antipyresis Fever due to bacterial endotoxins trigger macrophage release of endogenous pyrogen IL-1. This stimulates hypothalamic production of Prostaglandin E that elevates the set point on central ‘thermostat’. NSAIDs reduce PG-E synthesis.

Answer 63

NSAIDs are typically given orally, but there are also many topical preparations for local delivery to injured soft tissue. Most NSAIDS generally show First Order Elimination Kinetics Many heavily bound to plasma protein 90-99% Some NSAIDs have short half-lives (< 6 hours) o Ibuprofen – t½ = 2hrs Some NSAIDs have long half lives (> 10 hours) o Naproxen – t ½ = 14hrs Aspirin Pharmacokinetics o Low doses - First Order Elimination Kinetics (Dose dependant) o High doses (>12 300mg tablets) - Zero Order Elimination Kinetics

Answer 64

NSAID GI ADRs NSAID group ADRs at therapeutic levels are mainly due to COX-1 Inhibition. o PGE2 is involved in protection of gastric mucosa o Inhibition of PGE2 increases mucosal permeability and decreases mucosal blood flow and protection o NSAIDs can cause damage to stomach directly on ingestion o Ulceration, haemorrhage and even perforation seen with long term high dose elderly users o GI ADRs can be offset (long term) with PPIs or Misoprostol (synthetic prostaglandins) NSAID Renal ADRs Renal ADRs can occur in susceptible individuals, although therapeutic dosage in otherwise healthy patients does not cause problems. Neonates, the elderly and patients with compromised HRH function or reduced blood volume are particularly at risk. o Prostaglandins responsible for vasodilation of afferent arteriole o Reversible reduction in GFR occurs as a result of PGE2 and PGI2 inhibition Other ADRs o Skin reactions (15% for some NSAIDs) o Asthmatic bronchospasm (10% incidence) o Allergic response o Prolongation of bleeding time (platelet inhibition) o Aspirin is associated with risk of the post-viral Reye’s Syndrome in children Selective COX-2 Inhibitors Since most NSAID ADRs are due to COX-1 inhibition, drugs have been developed that only inhibit COX-2. Unfortunately their use was associated with an increased risk of hypertension and cardiac and renal failure. NSAID Drug-Drug Interactions Due to their wide availability some patients may already be self-medicating with NSAIDs. It is therefore appropriate to question patients prior to prescription to name other drugs they may be taking. o Aspirin is highly plasma protein bound and can displace other drugs, increasing their active free concentration. Competitive displacement of these drugs may require dose adjustment to avoid changes in PK and PDs. Warfarin - Increased Concentration -> More Bleeding Methotrexate - Increased Concentration -> Wide ranging, serious ADRs Sulphonylureas - Increased Concentration -> Hypoglycaemia NSAIDs can interact with ACE inhibitors and attenuate their action, blocking the production of vasodilating prostaglandins

Answer 65

Aspirin is used as the reference NSAID for efficacy and ADR severity. It is the only NSAID to irreversibly inhibit COX enzymes, via acetylation. It also has a unique pharmacokinetic profile, as its t½ is less than 30 minutes – it is rapidly hydrolysed in plasma to salicylate, which has it’s own t½ of ~4 hours. Atherothrombotic Disease The use of low dose (75mg) Aspirin in reducing platelet aggregation is very widespread in treating a range of conditions with a vascular component. Aspirin irreversibly inhibits COX-1 activity that drives pro-aggregative activity in both platelets and vessel walls to reduce the likelihood of thrombotic formation. GI Cancer Prophylaxis There is evidence that aspirin may reduce the risk of GI cancer of the colon, rectum and possibly upper GI. This is because these cancers synthesise PGE2, which promotes tumour growth. Clinical trials are on going.

Answer 66

Paracetamol is a unique ‘non-NSAID’, as it has virtually no anti-inflammatory action. It is very effective for mild/moderate analgesia and fever. At therapeutic doses (8x500mg tablets a day) is has a much better ADR than other NSAIDs, making it the agent of choice. Its pharmacokinetics is first order in a healthy patient, with a t½ of 2-4hrs. Paracetamol’s mechanism of action is currently unknown. It is possibly a weak COX-1/COX-2 inhibitor, but may also act in the CNS, possibly on a COX-3 isoform.

Answer 67

At therapeutic levels, Paracetamol has Linear Pharmacokinetics, and is conjugated with Glucuronide (60%) or Sulphate (30%) in Phase II Drug Metabolism. A small amount also undergoes Phase 1 Oxidation, to produce the toxic metabolite N-acetyl-p-benzo-quinone imine (NAPQI). If a toxic dose of Paracetamol is taken the Phase II pathways quickly become saturated and much more Paracetamol undergoes Phase I metabolism (Zero Order Kinetics), producing more NAPQI. Not only is NAPQI toxic to hepatocytes but it also undergoes Phase II conjugation with Glutathione, which is an important anti-oxidant, resulting in further damage from reactive oxygen species. Liver failure occurs over a period of several days. Unconjugated NAPQI is highly is highly reactive and binds with cellular macromolecules/mitochondria. Precipitous loss of function primarily leads to necrotic hepatic cell death. A single dose of over 10g (20 tablets) is potentially fatal. Treatment of a Paracetamol Overdose Paracetamol overdose must be treated as soon as possible and guided by blood levels of the drug. Treatment is time dependent, as delayed hepatotoxic effects peak at 72-96 hours post ingestion. Within 0-4 hours treat with Activated Charcoal orally which reduces uptake by 50-90% Within 0-36 hrs Start N-Acetylcysteine or Methionine by mouth if N-Acetylcysteine cannot be given promptly

Answer 68

Endogenous opioids are found distributed in specific parts of the CNS and peripheral nervous system, that play important roles in processing pain signals – The limbic system, thalamus, spinal cord and primary afferent peripheral terminals. Endogenous opioids are peptides derived from precursor proteins. There are three different forms, however the first four amino acids of all the endogenous opioids are conserved. o Enkephalins -Precursor: Proenkephalin o Endorphins - Precursor: Pro-opiomelanocortin (POMC) o Dynorphins - Precursor: Prodynorphin Exogenous Opioids Exogenous opioids include the natural, semi-synthetic and synthetic agents with actions on endogenous opioid receptors. These are chemically distinct from the endogenous opioids.

Answer 69

Three major types of opioid receptors have been identified. They are expressed in the CNS both pre and post-synaptically. o Mu (μ) (MOP) - Evidence for supraspinal analgesia in the CNS o Kappa (κ) (KOP) - Evidence for analgesia in the spinal cord o Delta (δ) (DOP) - Enkephalins. Widely distributed. Binding to μ or δ receptors causes hyperpolarisation of the neuron by opening potassium channels, decreasing excitability. They also inhibit voltage gated calcium channels and subsequently the release of Substance P. Binding to κ receptors inhibits voltage gated calcium channels and subsequently the release of Substance P. All opioid receptors are G-protein coupled receptors. They all have Gi mediated action, reducing cAMP levels.

Answer 70

Exogenous opiates work the same way as endogenous opiates. The majority of therapeutic effects are mediated by the μ receptor (MOP). Binding of an Opioid to the μ receptor causes hyperpolarisation of the neurone by opening of potassium channels and inhibition of voltage gated calcium channels. This reduces neuronal excitability and decreases the amount of Substance P neurotransmitter release. This inhibits the pain transmission pathway, reducing the feeling of pain. Exogenous Opioids – Agonists, Partial Agonists and Antagonists Full Opioid Agonists o Higher affinity for μ receptor o Morphine, Codeine, Methadone (Codeine and Methadone are relatively weak agonists compared to Morphine and lack dependence ) Partial Opioid Agonist o Developed to have mixed effects at all three receptors o Can provide excellent analgesia without euphoria o Nalbuphine - Mixed agonist/antagonist effects at μ, Partial agonist at κ, Weak against δ Full Opioid Antagonists o Bind predominantly to μ receptors and used to reverse potentially fatal agonist effects (Respiratory Depression) o Naloxone

Answer 71

Route of Administration o Oral (70% removed by first pass metabolism, necessitating larger doses) o Rectal o Intravenous - Most rapid response, avoids first pass metabolism, so often used for severe pain, with patient controlling the level of analgesia o Intramuscular o Intrathecally Dose adjustment necessary for Oral preparations. Normally the t½ of Morphine is about 2 hours. However, one of its metabolites Morphine-6-Glucoronide is at least pharmacologically equivalent to Morphine with a t½ of 4-5 hours. This extends the period of effective analgesia. Hepatic and Renal failure can increase half lives up to 50 hours, thus is a serious factor to consider in palliative care patients. Methadone has an oral bioavailability of ~90%. It also has a t½ of about 24 hours, making it more suitable for treating chronic pain. Codeine Pharmacokinetics Codeine is an important opiate, which is given orally. It needs to be metabolised by CYP2D6 into Morphine to become pharmacologically active. CYP2D6 is subject to Genetic Polymorphism, so that 10% of the Caucasian population cannot effectively convert Codeine to Morphine. Another polymorphism seen in Chinese people means codeine is less effectively converted to Morphine and dose may need to be adjusted upwards in this ethnic group.

Answer 72

``` Strong Opioids are used in the treatment of moderate to severe pain, particularly: o Visceral o Postoperative o Cancer-related o Myocardial infarction o Pulmonary Oedema o Peri-operative analgesia ``` Weak Opioids are used in the relief of mild to moderate pain, and as antidiarrhoeals:

Answer 73

Respiratory Depression The most serious opioid ADR is Respiratory Depression, and is the single greatest cause of death following opiate overdose. This is due to a μ receptor mediated action of opiates on CO2 sensitivity. Normally therapeutic levels do not cause excessive depression, but when combined with sleep, pulmonary deficit or other depressant drugs such as anaesthetics, alcohol or sedatives the risk of death can be much greater. ``` Other Opiate ADRs o Miosis (Important overdose sign) o Euphoria o Confusion o Psychosis o Coma o Tolerance and dependence o GI disturbances (nausea, vomiting, constipation) o Rarely anaphylactic responses, due to non-opiate receptor effects on mast cells, causing the release of histamine, leading to bronchoconstriction & hypotension ```

Answer 74

Treat with Naloxone, which is an antagonist of the μ receptor, rapidly reversing adverse agonistic effects, such as respiratory depression. Naloxone has a short t ½ (1 hour) therefore repeated doses may be needed.

Answer 75

Some opioid analgesics are controlled drugs o Misuse of Drugs Act 1971 o Misuse of Drugs Regulations 2001 ``` Schedule 2 (controlled drugs) o Diamorphine (heroin) o Morphine o Remifentanil o Pethidine ``` ``` Schedule 5 (controlled drug – invoice) o Includes preparations of certain controlled drugs (e.g. Codeine) ```

Answer 76

Bioavailability is the fraction of a dose that finds its way into a body compartment, usually the blood. For an IV bolus, bioavailability is 100%. Factors affecting bioavailability include: o Drug formulation o Age o Food (water soluble drugs are less likely to be affected by food) o Vomiting o Malabsorption o First pass metabolism. Oral Bioavailability is the proportion of a dose given orally (Or by any other route other than intravenous) that reaches the systemic circulation in an unchanged form. Bioavailability can be expressed as amount or rate. Amount – Measured by are under curve of blood drug level vs. time Rate – Measured by peak height and rate of rise of drug level in blood Oral Bioavailability(F)=(AUC oral)/(AUC IV) × 100 First Pass Metabolism Any metabolism occurring before the drug enters the systemic circulation is referred to as the first pass effect. This can occur in: o The Gut Lumen -Gastric acid, proteolytic enzymes, grapefruit juice o The Gut Wall - P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen, e.g. cicosporin o The Liver - Substances absorbed in the ileum enter the portal circulation and are taken to the liver, where enzyme systems metabolise them E.g. only 90% of an oral dose of paracetamol reaches systemic circulation E.g. Popranolol is extensively metabolised

Answer 77

The Volume of Distribution is a measure of how widely a drug is distributed in body tissues. It is a calculated pharmacokinetic space into which a drug is distributed. Volume of Distribution (Vd)= (Total Amount of Drug in Body)/(Plasma Concentration of Drug at Time Zero) Vd values that amount to less than that of a certain body compartment volume indicate that the drug is contained within that compartment. o When the volume of distribution is less than 5 Litres, it is likely that the drug is restricted to the vasculature. o If it is less than 15 Litres, this implies that the drug is restricted to the extracellular fluid o Greater than 15 Litres suggests distribution within the total body fluid. Some drugs (usually basic) have a volume of distribution that exceeds body weight, in which case tissue binding is occurring. These drugs tend to be contained outside the circulation and may accumulate in certain tissues. For example, very lipid-soluble drugs, such as general anaesthetics (e.g. Thiopental), can build up in fat, meaning the drug has a much longer half-life in an obese patient.

Answer 78

The volume of plasma that is completed cleared of drug per unit time Hepatic, renal and other secondary forms of elimination such as sweating or biliary elimination are measured in terms of Clearance. Hepatic and Renal Clearance are simply added together when calculating removal, so that: Total Clearance = Hepatic Clearance + Renal Clearance Calculating Renal Clearance The renal artery is the input to the kidney and the kidney has two possible outputs, the renal vein and the ureter. Therefore, if a substance is not metabolised or synthesised, an equal amount must leave in the urine and the renal venous blood. Renal clearance can be calculated with the equation: Clearance=(Amount in urine × Urine flow rate)/(Arterial Plasma Concentration) E.g. Substance X is present in the urine at a concentration of 100mg/ml. The urine flow rate is 1ml/min. The excretion rate of substance X is therefore: Excretion rate = 100mg/ml x 1ml/min = 100mg/min If Substance X was present in the plasma at a concentration of 1mg/ml then its clearance would be: Clearance=100/1=100 ml per min 100ml of plasma would be completely cleared of substance X per minute. Factors Affecting Clearance Heart – CVS/Circulatory factors affecting blood flow to the main organs of elimination Renal – Factors affecting Renal elimination Hepatic – Factors affecting Hepatic elimination Half-Life (t½) The half-life of a drug is the amount of time over which the concentration of a drug in plasma decreases to one half of the concentration value it had when it was first measured. Half Life= (0.693 × Volume of Distribution)/Clearance

Answer 79

``` Inhalational (Volatile) Agents o Nitrous Oxide (N2O) o Isoflurane o Desflurane o Sevoflurane ``` Intravenous Agents o Propofol o Ketamine

Answer 80

o Reticular Formation (Reticular Activating System) Depressed (Hindbrain, midbrain, thalamus) o Thalamus - Transmits and modified sensory information o Hippocampus depressed - Memory o Brainstem depressed - Respiratory and some CVS o Spinal cord - Dorsal horn (analgesia ) - Motor neuronal activity (MAC)

Answer 81

General Anaesthesia Affects the whole body and typically involves use of intravenous and inhalational anaesthetics with adjuvants. They reversibly inhibit sensory, motor and sympathetic nerve transmission in the CNS to produce unconsciousness and absence of sensation. Regional Anaesthesia This involves rendering large, specific regions of the body insensate. The region is determined by transmission block between that part of the body and the spinal cord. Both spinal and epidural anaesthesia can achieve this. The patient remains conscious, but may also be administered adjuvants depending on the procedure. Local Anaesthesia Involves a more defined peripheral nerve block with injection of a local anaesthetic. Used for tooth extraction, or for example, procedures on the hand and fingers, foot or big toe, or internally in the urethra when performing cystoscopy. Dissociative Anaesthesia Uses agents such as ketamine that inhibit transmission of nerve impulses between higher and lower centres of the brain. Used in children and the elderly for short procedures, as they are less susceptible to its postoperative hallucinogenic effects.

Answer 82

Anaesthetics mediate their effects by affecting postsynaptic transmission of both inhibitory and excitatory Ligand Gated Ion Channels. Importantly for inhalational agents, the interactions at these sites are very weak and easily reversed – an essential feature of anaesthesia. To carry out their action, they need to reach high concentrations in the cell membranes. Anaesthetic effect may be mediated by action at more than one target site. Inhibitory Ligand Gated Ion Channels GABAA Activated Chloride Channels o Many inhalational and IV anaesthetics have a primary effect on GABAA (Propofol exerts its main sedative effect on this channel) o Bound anaesthetics increase sensitivity to GABA and increase Cl- currents o This Hyperpolarises the neurone and decreases its excitability o There are multiple binding sites, depending on the anaesthetic being used Glycine Activated Chloride Channels o Bound anaesthetics increase sensitivity to Glycine and increase Cl- currents o This Hyperpolarises the neurone and decreases its excitability o Glycine ligand gated ion channels are especially important in signalling inhibitory neurotransmission in the spinal cord and brainstem and act to reduce the response to noxious stimuli Excitatory Ligand Gated Ion Channels Neuronal Nicotinic (N) Ach Receptors o Bound anaesthetics inhibit some subtypes of neuronal Nicotinic Ach receptors o This reduces excitatory Na+ currents caused by Ach binding o This is considered to likely contribute to analgesia and amnesia rather than sedation NMDA Receptors o NMDA receptors are responsive to glutamate, the major excitatory neurotransmitter in the brain o Nitrous Oxide (N2O) and Ketamine exert their action here o Bound anaesthetics reduce Ca2+ currents, which are involved in further modulation of synaptic responses

Answer 83

Administration All inhalational agents require careful titration using specialist equipment to vaporise the modern inhalational Fluranes, which exist as volatile liquids at room temperature. The principal anaesthetic agent is then mixed with a carrier of oxygen, air and often with Nitrous Oxide. This is then fed to the respiratory system by mask under spontaneous or controlled respiration. Minimum Alveolar Concentration (MAC) The alveolar concentration (at 1 atmosphere of pressure) at which 50% of subjects fail to move to surgical stimulus (unpremedicated breathing O2/air) The lower the MAC value, the more potent the inhaled anaesthetic is, as the MAC closely relates to its lipid solubility (able to get to the necessary high concentrations in the cell membrane easier). For modern Fluranes, MAC falls between 1-6% by volume of the inspired gas mixture. In anaesthetic practice, the MAC forms a standardised unit of delivery, e.g. 1 or 2 MACs for any inhalational anaesthetic. Surgical depth is typically achieved within 1.2 – 1.5 MAC. The MAC for individual agents can be significantly reduced when given in combination with other agents, such as Nitrous Oxide (N2O) or the potent opiate Fentanyl. Physiological states such as reduced cardiac output, ventilation rate or shock can significantly affect management of anaesthesia. Blood:Gas Coefficient Inhaled agents very readily pass down their concentration gradients from the alveoli into the bloodstream. The concentration of inhalational agents in the alveoli directly determines their concentration when they reach their target sites in the CNS. The blood:gas coefficient describes the volume of gas in litres that can dissolve in one litre of blood. o E.g. Isoflurane – Blood:Gas coefficient is 1.4 So a litre of blood could dissolve 1.4 litres of Isoflurane The higher the blood:gas coefficient, the more readily the gas will enter the blood. Blood Supply to Organs Once the gas is dissolved in the blood, it is then distributed by the vascular system to all tissues. However, the distribution around the body varies depending on two major factors; the relative blood supply to each organ or tissue and the specific tissue uptake capacity for the anaesthetic (the Tissue:Blood coefficient). ``` Relative blood supply at rest is o Brain, Liver and Kidneys – 75% o Muscle – 18% o Fat – 5% Tissue:Blood Coefficients Once the anaesthetic is in the blood, the Tissue:Blood coefficient determines how readily it will move into the tissues. This is specific to tissue type: ``` Isoflurane o Entry into the CNS The Brain:Blood Coefficient is 1.6 For an equivalent volume of brain to blood, the brain will take up 1.6 times as much anaesthetic. o Entry into Muscle The Muscle:Blood Coefficient is 2.9 So at equilibrium, the muscle tissue compartment takes up proportionately almost double the amount of Isoflurane than the brain o Entry into Fat The Fat:Blood Coefficient is 45 Fat absorbs nearly 30 times the amount of Isoflurane than the brain This gives a very large reservoir of anaesthetic that can redistribute during the recovery phase Metabolism Modern Fluranes undergo little transformation by hepatic metabolism, and does not contribute significantly to their elimination. Elimination Elimination is the reverse of distribution and absorption. As the surgery is finished the anaesthetist carries out a controlled withdrawal of anaesthesia, ensuring adequate oxygenation. As the concentration in the blood drops, the anaesthetic moves out of the cell membranes and back into the venous blood. This travels back to the alveolus to be eliminated unchanged. The rate of recovery is similar to the rate of induction for inhalational agents. The elimination is led by the well-perfused tissues (Brain, kidneys, liver), followed by muscle and then fat. Redistribution of Anaesthetics Importantly, full recovery from anaesthesia can take hours or days. The removal of the anaesthetic from the lungs occurs in a first order manner, but it is also free to redistribute around the body and gain entry back into the CNS. The levels achieved during this recovery phase can still very markedly affect conscious function. The duration of recovery is directly related to the length of procedure and the degree of loading of the muscle and fat compartments with anaesthetic agent. Pharmacokinetics of Intravenous Anaesthetics Induction of anaesthetic depth sufficient for surgery with inhalational agents alone would take a number of minutes. In contrast, use of an intravenous agent, most commonly Propofol, can result in sufficient anaesthetic depth within 20 seconds. This also bypasses the confusion of ‘excitement/aggression’ during Stage II of anaesthetic depth. However, use of IV agents requires further vigilance as their dose related effects are not easily reversed once administered. Their use is further complicated by a two-stage distribution profile as the drugs move between tissue compartments served by different rates of vascular supply Administration (Absorption) and Distribution of Propofol o IV bolus in the arm results in rapid distribution to the well vascularised CNS, with proportionately lower distribution to muscle and fat o Propofol then rapidly redistributes from the CNS to the other compartments  For a single dose, surgical anaesthesia is maintained for about 5 minutes  Muscle and fat have a much larger capacity for Propofol than the CNS o Further supplementary doses may be given if the anaesthetist is using Propofol as an adjunct in order to lower the fluranes MAC. It can also be used alone for surgical procedures of short duration of about 20-30 minutes. Metabolism and Elimination Unlike the fluranes, Propofol undergoes hepatic and extrahepatic conjugation. These result in a t½ of about 2 hours. This elimination means Propofol does not contribute to a prolonged post procedural ‘hangover’ during recovery.

Answer 84

Inhibitory Ligand Gated Ion Channels Glycine/ GABAA Activated Chloride Channels o Bound anaesthetics increase sensitivity to Glycine or GABAA, increasing Cl- currents o This Hyperpolarises the neurone and decreases its excitability Lower level of Glycine or GABA is needed to produce the same effect EC50 is lowered (measure of potency) Therefore, anaesthetics act to increase the potency of Glycine/GABA Pharmacodynamically this is known as Positive Allosteric Modulation o Propofol acts on GABA receptors Excitatory Ligand Gated Ion Channels Neuronal Nicotinic (N) Ach Receptors o Bound anaesthetics inhibit some subtypes of neuronal Nicotinic Ach receptors o This reduces excitatory Na+ currents caused by Ach binding NMDA Receptors o NMDA receptors are responsive to glutamate, the major excitatory neurotransmitter in the brain o Nitrous Oxide (N2O) and Ketamine exert their action here o Bound anaesthetics reduce Ca2+ currents, which are involved in further modulation of synaptic responses In Excitatory LGICs, the EC50 (potency) remains unchanged. However, the efficacy of the excitatory ligand decreases. This is typical of non-competitive allosteric antagonists. This non-competitive effect means that once bound by the anaesthetic antagonist is inactivating the receptor. The reduced pool of bound anaesthetic receptors results in reduced efficacy, but the ligand binding affinity of the remaining unbound receptors is unchanged.

Answer 85

Synergistic Interactions Adjuvant drugs are required to produce an effective and balanced anaesthesia. Individual agents usually have a specific effect on CNS function related to their group. These are normally given as adjuvants with one of the fluranes acting as the principal inhalational anaesthetic producing unconsciousness: o Benzodiazapines E.g. Midiazolam Exert agonist effect on GABAA receptors Used to induce anxiolysis (anxiety inhibition) and amnesia Given about an hour or so before surgery as a pre-med o Propofol Rapid induction of deep initial sedation o Nitrous Oxide (NO2) Reducing main inhalational agent MAC Does not produce sufficient anaesthetic depth on its own Allows for significant reduction in the effective MAC of fluranes. Rapid controlled pulmonary elimination is highly advantageous in minimising recover time o Opioids For analgesia Morphine and Fentanyl are two opiates commonly used during surgery Fentanyl is much more potent (100x) inducing analgesia almost immediately and acting over 30-60 minutes. o Neuromuscular blocking agents Abolish reflexes that occur with significantly invasive procedures and induce muscle relaxation Act as either competitive Nicotinic Ach receptor antagonists Tubocurarine, Pancuronium Or as Nicotinic Ach receptor depolarising agonists Succinylcholine

Answer 86

Additive MAC Scale o 50% [alveolar] NO2 = 0.5 MAC o 0.6% [alveolar] Isoflurane = 0.5 MAC These are added together to give a total of 1 MAC, which is nearly at the typical MAC of 1.2 – 1.5 needed for surgery. Opiates reduce pain, allowing for an additional reduction in MAC. They also further reduce the risk of cardiovascular depression of the fluranes.

Answer 87

The anaesthetist is directly responsible for patient assessment before surgery and for monitoring during the operation and over recovery. ``` Pre-Surgical Review Direct assessment of the patient, including: o Age o BMI o Prior medical and surgical history o Current medication o History of drug abuse o Fasting time o Airway assessment ``` Peri-Surgical Monitoring o Direct control and monitoring of gaseous mixture calculation for % partial pressures of O2, Flurane, N2O, Nitrogen o Mechanical rate of ventilation o Comprehensive systemic physiological monitoring is carried out for: o Cardiovascular function o ECG o BP o Respiratory function o Pulse oximetry o Expired CO2 used to assess ventilation state o Thermoregulatory function o Early detection of malignant hyperthermia EEG monitoring may be used as a further measure of CNS activity and anaesthetic depth. This reduces the risk of under/overdosing and is a further monitor of the efficacy of adjuvant synergy and interaction

Answer 88

High blood pressure very rarely causes symptoms. It is therefore not a ‘disease’, but a risk factor for future vascular disease. Higher Blood Pressure -> Increased arterial thickening -> Smooth muscle cell hypertrophy and accumulation of vascular matrix -> Loss of arterial compliance -> end organ damage The organs affected by sustained hypertension are the brain, heart, arterial system, kidney and eye. Epidemiologically, blood pressure is a strong predictor of risk of ischaemic heart disease and stroke. Aetiology Primary (Essential) Hypertension o High BP without any single evident cause o 90% of hypertensive population Secondary Hypertension o High BP with a discrete, identifiable underlying cause (e.g. Cushing’s) o 10% of hypertensive population

Answer 89

The Role of Antihypertensive Drugs The decision to offer drug therapy is influenced by: o The sustained level of blood pressure Hypertension is defined as 140/90mmHg 40% of the adult population of England are hypertensive Lowering diastolic BP by 10mmHg is associated with 58% reduction in strokes and 37% reduction in coronary heart disease ≥ 160mmHg Systolic and ≥100mmHg diastolic justifies drug treatment o The overall cardiovascular risk profile At levels of 140-159 systolic and 90-99 diastolic the decision depends on overall CVS risk profile. Is there > 15% risk of a cardiovascular event in the next 10 years? Presence of end organ damage? In the presence of diabetes the treatment threshold is 140/90mmHg It is important to address the full range of modifiable risk factors such as smoking, cholesterol level, obesity and physical activity. For patients with diabetes, high blood pressure is particularly adverse and should be stringently controlled. Non-Pharmacological factors At the borderline, these measures may avoid the need for drug treatment. o Optimum body weight (BMI 20-25 kg/m2) o Regular physical activity (>30 mins a day) o Moderation of alcohol and salt. (<3 units for men, < 2 units for women. < 6g salt) o Smoking cessation should be strongly advised, and supported as necessary (e.g. nicotine replacement therapy) British Hypertension Society Classification of Hypertension Category Systolic BP (mmHg) Diastolic BP (mmHg) Optimal <120 <80 Normal <130 <85 High Normal 130-139 85-89 Hypertension Grade 1 (mild) 140-159 90-99 Grade 2 (moderate) 160-179 100-109 Grade 3 (severe) >180 >110 Isolated Systolic Hypertension Grade 1 140-159 <90 Grade 2 >160 <90

Answer 90

Examples o Ramipril o Lisinopril o Captopril Route of Administration - Oral Indications o Hypertension o Heart failure o Renal dysfunction Contraindications - Pregnancy, renovascular disease, aortic stenosis Mechanism of Action o ACE inhibitors cause inhibition of Angiotensin Converting Enzyme, consequently reducing Angiotensin II and Aldosterone levels. This causes vasodilation and consequent reduction in peripheral resistance and reduced sodium retention. o Reduce breakdown of the vasodilator Bradykinin Adverse Drug Reactions o Characteristic dry cough o Angio-oedema (rare, but more common in black population) o Renal Failure o Hyperkalaemia o Hypotension, dizziness and headache, diarrhoea and muscle cramps

Answer 91

Combination therapy is commonly needed to achieve optimum blood pressure control. Although all of the above classes can be combined o Apart from Verapamil and beta blockers, severe bradycardia and hypotension can occur Step one – ACE inhibitor (under 55)/angiotensin receptor 2 blocker OR Calcium channel blockers (over 55 of african or Caribbean origin) Step Two – add Ca2+ channel blocker or ACE inhibitor/Angiotensin 2 receptor blocker Step Three – add a diuretic Step Four – add a beta blocker British Hypertension Society and NICE Hypertension Guidelines

Answer 92

Heart failure is ‘a state in which the heart fails to maintain an adequate circulation for the needs of the body despite an adequate filling pressure’. Ischaemic Heart Disease is the primary cause of Systolic Heart Failure. ``` Other causes of HF include: o Hypertension o Cardiomyopathies - Alcohol/Drugs/Poisoning, Iron overload, Pregnancy o Valvular heart disease / Congenital o Restrictive cardiomyopathy e.g. amyloidosis o Hypertrophic cardiomyopathy o Pericardial disease o Arrhythmia ```

Answer 93

o Correct underlying cause o Non-pharmacological measures o Pharmacological therapy Symptomatic improvement Delay progression of heart failure Reduce mortality o Treat complications/associated conditions/CVS risk factors E.g. arrhythmias

Answer 94

Drugs used to Treat Heart Failure B-blockers - Block B1 receptors on the myocardium ACE-Inhibitors - Prevent conversion of Angiotensin I -> II Ca2+ channel blockers - Reduce contractility of the myocardium Organic Nitrates Venodilator – Reduce preload on heart, lowering its O2 requirement Vasodilator – Coronary arteries dilate, supplying more O2. Cardiac Glycosides - Increase CO and heart contractility by inhibiting the Na/K pump. Raising intracellular Na inhibits NCX, so intracellular Ca2+ increases -> in. contractility

Answer 95

``` Drugs Acting on the Renal Tubules o Carbonic Anhydrase Inhibitors o Osmotic Diuretics o Loop Diuretics o Thiazide Diuretics o Potassium Sparing Diuretics o Aldosterone Antagonists o ADH Antagonists ```

Answer 96

Major Indications for Diuretic Use Heart Failure o Loop diuretics o Thiazide diuretics o (also ACE inhibitors/Angiotensin Receptor antagonists, β-blockers) Hypertension o Thiazide diuretics o Spironolactone o (also ACE inhibitors/Angiotensin Receptor antagonists, β-blockers) Decompensated Liver Disease o Spironolactone o Loop diuretics

Answer 97

When prescribing in renal disease there are two key issues: ``` 1.Drugs may reduce kidney function by direct or indirect toxicity o ACE inhibitors o Aminoglycosides (e.g. Gentamicin) o Penicillins o Cyclosporin A o Metformin o NSAIDs ``` 2.Drugs at normal doses may accumulate to toxic levels if they are excreted through the kidneys and renal function is impaired ACE inhibitors in Renal Disease In Renal Artery Stenosis, Glomerular Filtration Pressure falls, leading to a drop in GFR, leading to the activation of RAAS. This causes vasoconstriction of the efferent arteriole to maintain Glomerular Filtration Pressure. If ACE inhibitors are given, inhibiting RAAS, the Glomerular Filtration Pressure will drop, causing Acute Renal Failure. General Advice about Prescribing Drugs to Patients with Renal Failure o Avoid nephrotoxins if at all possible o Reduce dosages in line with GFR if metabolism or eliminated via the kidneys o Monitor renal function and drug levels if narrow therapeutic range o Hyperkalaemia is more likely o Uraemic patients have greater tendency to bleed

Answer 98

Haemostasis is the body’s response to stop bleeding and loss of blood. Successful Haemostasis depends on: 1) Blood Vessels o Constrict to limit blood loss 2) Platelets o Adhere to the damages vessel wall and to each other o Form platelet plug 3) Coagulation o Cascade, series of inactive components -> active components o 1ml of blood can generate enough Thrombin to convert all of the fibrinogen in the body to fibrin, so tight regulation is required o Balance of procoagulant and anticoagulant forces 4) Fibrinolytic System Virchow’s Triad o Changes in blood flow - Stagnation, turbulence o Changes in vessel wall - Atheroma, injury, inflammation o Changes in blood components - Smokers, pregnancy

Answer 99

Thrombosis – The formation of a solid mass of blood within the circulatory system during life Arterial Thrombi o Ischaemia o Infarction o Depends on site and collateral circulation ``` Venous Thrombi o Congestion o Oedema o Ischaemia (If Tissue Pressure due to Oedema > Arterial Pressure) o Infarction ```

Answer 100

Vitamin K antagonists (e.g. Warfarin) block the reduction of vitamin K epoxide, to its active form. ``` The reduced, active form of Vitamin K is necessary for its action as a cofactor in the synthesis of: o Factor II (Prothrombin) o Factor VII o Factor IX o Factor X ```

Answer 101

Indications o Prophylaxis and treatment of deep vein thrombosis and pulmonary embolism Deep Vein Thrombosis – Target INR of 2.0 – 3.0 for 3-6 months Pulmonary Embolism – Target INR of 2.0 – 3.0 or 6 months o Prophylaxis of embolization in atrial fibrillation/patients with prosthetic heart valves, Thrombosis associated with inherited thrombophilia conditions Atrial Fibrillation – Target INR of 2.0 – 3.0 until Risk > Benefit Prosthetic heartv valves – Target INR of 2.5 – 4.5 Pharmacokinetics Good GI absorption - Oral dosing o Slow onset of action - Heparin cover o Slow offset - Need time to synthesise new clotting factors and need to stop 3 days before surgery o Heavily Protein Bound - Caution with drugs that can displace it o Hepatic Metabolism (CYP450 system) Caution with Liver Disease Caution with CYP450 inducers/inhibitors Crosses Placenta - Do not give in 1st Trimester (Teratogen) or 3rd Trimester (Brain Haemmorhage) These factors lead to extreme variation in individual dose requirement: o Differing degrees of anticoagulation, depending upon condition o Gradual onset of activity o Persisting anticoagulant action on cessation of treatment o Number drug-drug interactions resulting in altered anticoagulant effect

Answer 102

The effect of Warfarin is monitored via Prothrombin Time, which is expressed as the International Normalised Ratio (INR). This is calculated from the ratio of Prothrombin times of test and control samples. It is a measure of the Extrinsic Pathway of coagulation, measuring: o Factor I – Fibrinogen o Factor II – Prothrombin (Requires Vit. K for synthesis – Warfarin site of action) o Factor V o Factor VII (Requires Vit. K for synthesis – Warfarin site of action) o Factor X(Requires Vit. K for synthesis – Warfarin site of action) INR Values o Treatment with Warfarin will Raise INR (inhibits coagulation) o Therapeutic range of Warfarin is an INR of 2.0 – 3.0 (DVT/AF/PE) o High risk patients (e.g. mechanical prosthetic valves) target INR of 2.4 – 4.5

Answer 103

Warfarin Adverse Effects o Bleeding / Bruising - Intracranial, Epistaxis, Injection site, GI loss o Teratogenic Warfarin Drug-Drug Interactions Drugs potentiating Warfarin (Increasing INR) o CYP450 inhibitors - "GO-DEVICES" o Inhibition of Platelet function - Aspirin (different site of action) o Reduce Vitamin K from gut bacteria - Cephalosporin (Antibiotics) o Displacement from plasma proteins (e.g. via NSAIDs) Drugs inhibiting Warfarin (Decreasing INR) o CYP450 inducers - "PCBRAS"

Answer 104

o Stop Warfarin treatment o Consider bleeding, INR, indication (e.g. if mechanical valve call cardiologist) o IV Viatmin K Slow acting, fresh clotting factors need to be synthesised Pro-coagulant Will affect re-warfarinisation for 6 weeks o Prothrombin Complex Concentrate (Fast acting) o Fresh Frozen Plasma (Fast acting) o Need to stop Warfarin 3 days before elective surgery

Answer 105

Unfractionated Heparin Dose response: Non-Linear Action: Variable - (Unpredictable due to binding to cells and proteins) Action: Variable - (Monitor with APTT test) Administration: IV Initiation: Bolus then IV Structure: Mix of variable long length heparin chains (12-15 kDaltons) Mechanism of action: Binds to and Increases the activity of Anti-Thrombin III - Inactivates Thrombin, Factor Xa and factors V, VII, IX, XI LMW Heparin Dose response: Linear Action: Predictable - (Less binding to cells and proteins) No monitoring - (Little affect on APTT)Administration: Subcutaenous Initiation: Once/Twice Daily Low Molecular Weight Heparins (LMWH) Structure: Smaller heparin chains (4-5 kDaltons) High bioavailability (> 90%) and Long t½ Action: More predictable dose response - No macrophage/endothelial cell/plasma protein binding) Mechanism of Action: Binds to Anti-Thrombin III - Inactivates Factor Xa ONLY AND DOES NOT INACTIVATE Thrombin (Factor IIa) (As not big enough to inactivater both, whereas unfractioned is bigger) CLearnace: Cleared by Kidneys – careful with dose in Renal Failure

Answer 106

Unfractionated Heparin o Loading dose, then IV infusion o Monitor APTT Low Molecular Weight Heparin o Prophylaxis SC once a day (until Warfarin loading is achieved) o Treatment SC once/twice a day o Never give Heparin Intramuscularly – Risk of Intramuscular Haemorrhage Activated Partial Thromboplastin Time aPTT o Used to monitor the Intrinsic Coagulation Pathway o Plasma sample taken, mixed with an Intrinsic Pathway Activator (e.g. Silica) and time to form Thrombus measured o Normal range 30 – 50 seconds Heparin Adverse Effects o Bleeding/Bruising - Intracranial, Injection sites, GI loss, Epistaxis o Heparin Induced Thrombocytopenia (HIT) Autoimmune response to Heparin on platelet surface, causing immune complex aggregation Thrombosis and depletion of platelets due to aggregation Lab assay for antibodies Stop Heparin, add Hirudin Heparin Reversal o Stop Heparin o Protamine Sulphate Dissociates Heparin from Anti-Thrombin III Irreversibly binds to Heparin Given in allergy, anaphylaxis and if patient is actively bleeding o Monitor APTT if using Unfractionated Heparin

Answer 107

Examples - Abciximab Route of Administration - Intravenous Indications o Prevention of ischaemic cardiac complications in patients undergoing Percutaneous Coronary Intervention (PCI) o Short term prevention of MI in unstable angina patients Contraindications Active bleeding Mechanism of Action o Monoclonal Antibody to Glycoprotein IIb/IIIa Receptors o Prevents platelet aggregation Adverse Drug Reactions o Haemorrhage, nausea, vomiting, hypotension Drug-Drug Interactions o Works synergistically with Warfarin to decrease Coagulability

Answer 108

``` Myocardial Infarction (MI) A MI is a complete occlusion of a coronary vessel, leading to an infarct (death) of the myocardium it supplies. ``` The fibrous cap of the Atheromatous plaque can undergo erosion or fissuring, exposing blood to the thombogenic material in the necrotic core. The platelet ‘clot’ is followed by a fibrin thrombus, which can either occlude the entire vessel where it forms or break off to form an embolism. MI presents with typical ischaemic chest pain (see above) that is very severe, persistent, occurs at rest and often with no precipitant. It is not relieved by rest or nitrate spray. The patient may also be breathless, faint (due to LV dysfunction) have a ‘feeling of impending death’ and will have autonomic features present such as sweating, pallor, nausea and vomiting. NSTEMI o Non ST Elevated Myocardial Infarction o Infarct is not full thickness of myocardium STEMI o ST Elevated Myocardial Infarction o Infarct is full thickness of myocardium Fibrinolytic Drugs The normal clearance mechanism for thrombi is by Plasmin, an enzyme that cleaves Fibrin (and fibrinogen and several other coagulation factors). Plasmin is formed from its circulating precursor Plasminogen. Fibrinolytic Drugs either generate Plasmin themselves (e.g. Tissue Plasminogen Activators (tPA) or bind to and activate endogenous plasminogen (e.g. Streptokinase).

Answer 109

Acute MI Fibrinolysis Fibrinolysis should be offered to people with an acute STEMI within 12 hours of onset of symptoms if Percutaneous Coronary Intervention (PCI) cannot be delivered within 120 minutes of the time when fibrinolysis could have been given. (Window longer for venous thrombo-embolism, but only ~3 hours for ischaemic stroke)

Answer 110

ADR's o Bleeding/Haemorrhage o Anaphylaxis to Streptokinase o Hypotension Contraindications o Peptic Ulcer (or other potential bleeding source) o Recent trauma or surgery o History of cerebral haemorrhage or stroke of uncertain aetiology o Uncontrolled hypertension o Coagulation defect o Previous Streptokinase therapy

Answer 111

Cardiac Resting Membrane Potential The cardiac resting membrane potential is the potential inside a cardiac cell relative to the extracellular solution. The difference between the two is achieved by the selective permeability of the membrane to different ions, by way of channel proteins. The cell membrane of myocardial cells is mostly permeable to K+ ions. So the cardiac resting membrane potential of ~ -90mV is largely due to the K+ equilibrium potential of -80mv (see membranes and receptor module). K+ ions move down their concentration gradient, from the inside to the outside of the cell, taking their positive charge with them. Ventricular Cells o In diastole, the resting membrane potential of cardiac cells is close to the equilibrium potential of K+. o Initial depolarisation due to spread of electrical activity from pacemaker cells. Once threshold has been reached, fast voltage gated sodium channels are opened, causing depolarisation towards Na+’s equilibrium potential . o Following the rapid depolarisation, a brief repolarisation caused by the outward flow of K+ returns the membrane potential to ~0. o Na+ channels deactivate, but the depolarisation causes the opening of voltage gated Ca2+ channels, which take longer to activate, keeping the membrane depolarised . o Influx of Ca2+ causes the release of further Ca2+ from cellular stores, causing contraction (See M&R Session 5). o After ~250ms, Ca2+ channels close. o Efflux of K+ returns membrane potential to resting. Pacemaker Cells o The maximum –‘ve voltage of pacemaker cells is ~-60mv, less than the -90mv of ventricular muscle cells. This persistently less –‘ve membrane voltage causes the fast Na+ channels to remain inactivated. o The spontaneous gradual depolarisation of pacemaker cells, the pacemaker or ‘funny’ current (If) is carried by Na+ ions through slow Na+ channels that open during the repolarisation of the cell as the potential approaches its most –‘ve values. o Once the cell reaches its threshold voltage due to the If, Ca2+ channels open, giving a relatively slow depolarisation. This is due to the deactivation of the fast Na+ channels. o Once Ca2+ channels close, the cell repolarises due to K+ efflux. Increasing Heart Rate The interval between beats depends on how fast the pacemaker potential depolarises. The interval is shortened by the action of the Sympathetic nervous system on the SAN. Noradrenaline (β1 Receptor) speeds up the heart rate by making the pacemaker potential steeper. Decreasing Heart Rate The interval between pacemaker potentials is lengthened by the action of the Parasympathetic nervous system on the SAN. Acetylcholine (M2 Receptor) slows the heart rate by making the pacemaker potential shallower. Baroreceptors Baroreceptors, located in the arch of the aorta and the carotid sinus have a role in controlling heart rate. When arterial blood pressure is high, the aorta/carotid arteries are stretched, activating the stretch sensitive baroreceptors. The baroreceptors pass the information to the medulla, which in turn causes parasympathetic innervation of the SAN. Parasympathetic innervation causes the pacemaker potential to become shallower, slowing the heart rate. Low BP has the opposite effect.

Answer 112

Ectopic Pacemaker activity o Damaged area of myocardium because depolarised and spontaneously active. o Latent pacemaker region activated due to ischaemia o Dominate over SA node After-Depolarisations o Abnormal depolarisations following the action potential o Thought to be caused by high intracellular Ca2+ o Longer AP leads to longer QT interval Re-entry loop o Conduction delay o Normal spread of excitation disrupted due to damaged area (e.g. scar after MI) o Incomplete conduction damage (uni-directional block) o May be due to aberrant conduction pathway, e.g. Wolff-Parkinson-White It is possible to get several small re-entry loops in the atria, e.g. from being stretched over time, leading to atrial fibrillation.

Answer 113

``` Vaughn Williams Classification Class I - Na+ Channel Blockers Class II - β-blockers Class III - K+ channel blockers Class IV - Ca2+ Channel Blockers ``` ``` 1a) Quinidine Procaeinamide Disopyramide Atenolol Bisoprolol Metoprolol Amiodarone Sotalol Verapamil Diltiazem ``` 1b) Lidocaine 1c) Flecainide Propafenone Class 1 (Voltage Gated Na+ Channel Blockers) Flecainide & Lidocaine are the most commonly used agents. They block fast, inward Na+ channels (Phase 0): o Redcued Conduction velocity o Increased Depolarisation threshold o Reduced Automaticity The sub-classes have different effects on the effective refractory period and duration of the action potential. 1a = increase in APD and ERP, moderate reduction in phase 0 slope = AF, SVT and VT 1b = decrease in APD and ERP, small reduction in phase 0 slope = VT 1c = no effect on APD and ERP, but greatly reduced phase 0 slope = life-threatening VT and SVT Class II. (B-adrenoceptor antagonists) β-blockers act on B1 receptors in the heart, blocking sympathetic action and decreasing the slope of the pacemaker potential in the SAN, decreasing chronotropy. This also inhibits adenyl cyclase, decreasing inotropy. o Redcued Automaticity o Redcued Phase 4 slope o Increased Threshold for activation in SAN and AVN o Increased AVN conduction time and refractory period Class III. (Drugs that block K+ channels) Prolong the action potential, by blocking K+ channels (responsible for repolarisation). o Increased absolute refractory period o Increased AP duration o Suppress re-entry circuits by closing excitable gap They are not generally used because they can also be pro-arrhythmic (Increased QT interval, increased risk of Torsades de Pointes). Class IV (Drugs that block Ca2+ channels) Decreases slope of pacemaker action potential at SA node and AV node. o Increased Refractory Period o Redcued Chronotropy and Inotropy

Answer 114

Spread of Excitation in Systole 1. The SA node fires an action potential, which spreads over the atria causing atrial systole. The AP reaches the AV node, where it is delayed for about 120ms. 2. From the AV node, excitation spreads down the septum between the ventricles 3. Excitation spreads from inner (endocardial) to outer (epicardial) surface 4. Ventricle contracts from the apex up, forcing blood towards the outflow valves. Ventricular muscle is organised into figure of eight bands that squeeze the ventricular chamber forcefully in a way most effective for ejection through the outflow valve. The apex of the heart contracts first and relaxes last to prevent back flow.

Answer 115

Inotropic Drugs o Digoxin Vasodilator Drugs o ACE inhibitors o Angiotensin Receptor Blockers

Answer 116

There are several routes that can improve ventricular stroke volume: - Increasing preload - Decreasing afterload - Increasing inotropy In heart failure (particularly systolic dysfunction), preload is already elevated due to ventricular dilation and/or increased blood volume. Increasing the preload further will not necessarily increase stroke volume because a heart in failure is usually functioning on the flat, depressed region of the Frank-Starling curve. Furthermore, increasing preload will exacerbate pulmonary or systemic congestion and edema, which occurs when end-diastolic pressure is greater than 20 mmHg. Therefore, increasing preload is not a viable option for increasing cardiac output in heart failure patients. Decreasing afterload with vasodilator drugs significantly enhances ventricular stroke volume (figure: B→D) and ejection fraction in failing hearts because the afterload is often elevated in heart failure and this reduces ejection velocity. Therefore, reducing afterload has been found to be very effective in the treatment of systolic dysfunction because it increases stroke volume and decreases preload, thereby improving ejection fraction. Increasing inotropy (figure: B→D) to increase stroke volume and ejection fraction is used in the treatment of heart failure; however, most positive inotropic drugs should only be used for acute systolic failure or end stage failure because prolonged use of these drugs have been shown to worsen the outcome and increase mortality in some patients. The short-term benefit of such drugs, and the reason why they are used in acute heart failure, is that they increase stroke volume, increase ejection fraction, and reduce preload, all of which are beneficial. However, inotropic drugs increase oxygen demand, which is deleterious with long-term use.

Answer 117

Mustard Gas Used in 1940s to treat lymphoma Cisplatin Found when passing electric currents through E. coli, found that the platinum electrodes were found to be responsible Chemical Engineering o Paclitaxel – Tubulin poison. Found in pacific yew tree, which is very rare therefore is very expensive. Then used in chemical engineering in order to produce a synthetic compound. o Find agents present in nature and investigate to see if these compounds have any effect in treatments and then chemically engineer them Molecular Targeting Approaches o Imatinib – Bcr-Abl tyrosine kinase inhibitor. Prevents development and progression of chronic myeloid leukaemia. o Magic bullet, tumour selective, efficacious, few side effects

Answer 118

DNA Structure Nitrogenous Bases – There are two types: o Purines – Two ring structure (G and A) o Pyrimidines – One ring structure (C, T and U) o A base pair is formed by one purine and one pyrimidine. G pairs with C and A with T. DNA Double Helix o 2 independent polymers o Entirely complimentary and antiparallel to each other (Top strand 5’prime 3’, bottom 3’ prime 5’) o One complete turn is 10 base pairs o Space between base pairs is 0.34nm o Purines and pyrimidines are planar and unsaturated o Within structure of sugar-phosphate backbone, major (exposed bases) and minor grooves exist DNA Replication 1) Initiation – recognition of an origin of replication. Helicase unravels the DNA double helix. Requires specific proteins to interact with DNA and recruit DNA polymerase (because DNA polymerase can only extend from 3’ ends of pre-existing chains to 5’, a special enzyme primase is required to initiate each strand) 2) Elongation – leading strand is replicated from 5’ prime 3’ as normal. However the lagging strand is replicated discontinuously in Okazaki fragments. These fragments are then joined by DNA ligase from OH group to Phosphate group covalently. 3) Termination – Replication forms move from the ends of the DNA strands towards each other. Lead strands move towards lagging strands and vice versa. The terms ‘leading’ and ‘lagging’ have no bearing once ligase has joined up all the fragments.

Answer 119

``` Highly Sensitive Lymphomas Germ cell tumours Small cell lung Neuroblastoma Wilm’s tumour ``` ``` Modest Sensitivity Breast Colorectal Bladder Ovary Cervix ``` ``` Low Sensitivity Prostate Renal cell Brain tumours Endometrial ```

Answer 120

For many types of cancer, chemotherapy regimen will consist of a number of different drugs (combination chemotherapy), although a drug may also be given on its own. Common Routes of Administration: o Intravenous - Most common – Bolus, infusional bag, continuous pump infusion o Oral - Dependent on bioavailability. Most convenient o Subcutaneous - Convenient in community setting o Into a body cavity - Bladder, pleural effusion o Intralesional - Directly into a cancerous area o Intrathecal - By lumbar puncture of omaya reservoir (directly into ventricles) o Topical o Intramuscular - Rarely

Answer 121

Vomiting Multifactorial, but includes direct action of chemotherapy drugs on central chemoreceptor trigger zone. Patterns of emesis: o Acute Phase – 4 to 12 hours o Delayed Onset – 2 to 5 days later o Chronic Phase – May persist up to 14 days ``` Alopecia o Hair thins at 2-3 weeks o May be total o May regrow during therapy o Marked with Doxorubicin, Vinca Alkaloids, Cylophosphamide o Minimal with Platinums o Scalp cooling may help ``` Skin Toxicity Local o Irritation and thrombophlebitis of veins o Extravasation General o Bleomycin - Hyperkeratosis, Hyperpigmentation, Ulcerated pressure sores o Busulphan, Doxorubicin, Cyclophosphamide, Actinomycin D - Hyperpigmentation Mucositis o GI tract epithelial damage o May be profound and involve the whole tract o Most commonly worst in Oropharynx o Presents as sore mouth/throat, diarrhea, GI bleed Cardio-Toxicity o Cardio-myopathy o Arrhythmias Lung Toxicity o Pulmonary fibrosis Haematological Toxicity o Most frequent dose limiting toxicity o Most frequent cause of death from toxicity o Different agents cause variable effects on degree and lineages - Neutrophils and Platelets

Answer 122

What causes variability in Chemotherapy Absorption o Nausea and vomiting – May vomit drugs back up o Compliance o Gut problems – E.g. mucositis Distribution o Weight loss o Reduced body fat o Ascites Metabolism o Liver dysfunction, other medications Elimination o Renal dysfunction Protein binding abnormalities o Low albumin o Drug-Drug Interactions

Answer 123

o Vincristine and Itraconazole (commonly used antifugngal) - Neuropathy o Capecitabine (oral 5FU) and Warfarin - Very important interaction!! Increases bleeding risk o Capecitabine (oral 5FU) and CYP450 enzyme inhibitors - GO-DEVICES o Methotrexate and penicillin, NSAIDs

Answer 124

``` Chemotherapy Monitoring o Response of the Cancer o Radiological imaging o Tumour marker blood tests o Bone marrow/cytogenics o Drug Levels o Methotrexate drug assays taken on serial days to ensure clearance from blood after folinic acid rescue o Checks for Organ Damage o Creatinine clearance o Echocardiogram ```

Answer 125

Log-Kill Ratio Need to kill a certain proportion of the cancer cells in order for a treatment to be describe as effective. Needs to kill 10*4 of cancer cells which equates to 99.9% of the total cells (start off with 10*9 as this is when clinical effects tend to be seen and when the tumour is the size of a small grape). o Need to weigh up the kill rate for cancer cells against the kill rate for healthy cells. o Difficult to access all cells at once – some are on the outside, some are one the inside (compartment A vs. compartment B) o Rate of regrowth of healthy cells in between chemotherapy sessions must be ahead of the rate of regrowth of cancer cells. Antimetabolites These are analogues of certain products needed for DNA synthesis. Therefore antagonising the action of producing DNA. e.g. methotrexate o Inhibits action of dihydrofolate reductase which prevents cell from producing tetrahydrofolate o Reduced folate production means a reduced production of purine and pyrimidine production e.g. Fluoruracil o Analogue of uracil, which inhibits thymidilate synthase and another co-enzyme so that they cannot release any stable product. o Causes thymidine-less cell death Spindle Poisons Arrests the cell in metaphase as it prevents correct spindle formation e.g. Vinca alkaloids (vincristine and vinblastine) o Polymerise the B-tubulin subunit to prevent formation of microfilaments which stimulates apoptosis. e.g. Taxanes (paclitaxel) o Stabilises microtubules to prevent their disassembly. Cannot pull apart the chromosome. Stimulates apoptosis. DNA Alkylating Agents Causes DNA cross-links to form between strands. Prevents replication and can cause strand breakage. e.g. Cipsplatin. o Has maximum effect in S phase as this is where DNA is most exposed DNA Intercalating Agents Intercalates between base pairs of DNA and acts to interfere with topoisomerase II. e.g. Anthracycline Antibiotics (doxorubicin and daunorubicin) o Molecular ring structure makes the intercalates inbetween base pairs (DNA intercalation) o Interfere with topoisomerase II, which interferes with DNA replication and repair

Answer 126

Epilepsy is an episodic discharge of abnormal high frequency electric activity in the brain leading to seizure. It is a common condition (Prevalence 0.5-1%, 450,000 in the UK). 70% of patients treated therapeutically Diagnosis required evidence of recurrent seizures unprovoked by any other identifiable causes. Epilepsies should be viewed as a symptom of underlying neurological disorder, not a single disease entity

Answer 127

``` Epilepsy at the Neuronal Level o Increased Excitatory activity o Reduced Inhibitory activity o Loss of homeostatic control o Spread of Neuronal hyperactivity - This determines the type of seizure ``` Classification of Epilepsy Partial (or focal) seizures o Simple (conscious) or Complex (impaired consciousness) o Loss of local excitatory/inhibitory homeostasis o Increased discharged in focal cortical area Symptoms reflect affected area Involuntary motor disturbance Behavioural change Impending focal spread accompanied by Aura, e.g. unusual smell or taste, déjà vu, jamais vu o May become secondarily generalised Generalised Seizures o Generated centrally and spread through both hemispheres o Loss of consciousness o Tonic (Initial Rigidity)-Clonic (Shaking) Seizures Grand Mal 60% o Absence Seizures (loss of expression, stare blankly, patient not aware of them) Petit mal 5% Status Epilepticus Most seizures are short lived, from seconds up to 5 minutes. However, some seizures are prolonged beyond this, or experienced as a series of seizures without a recovery interval. This is referred to as Status Epilepticus, and can occur for any type of epilepsy. Prolonged seizures are medical emergencies.

Answer 128

Sensory Stimuli o Flashing lights/strobes o Any other periodic sensory stimuli ``` Brain Disease/Trauma o Brain injury o Stroke/Haemorrhage o Drugs/Alcohol o Structural abnormality/Lesion ``` Metabolic Disturbances o Hypoglycaemia o Hypocalcaemia o Hyponatraemia Infections o Febrile convulsions in infants Therapeutics o Some drugs can lower fit threshold o Anti-Epileptic Drugs and Polypharmacy

Answer 129

``` Epilepsy at the Neuronal Level o Increased Excitatory activity o Redcued Inhibitory activity o Loss of homeostatic control o Spread of Neuronal hyperactivity This determines the type of seizure ```

Answer 130

``` Dangers in Severe Epilepsy o Physical injury relating to fall/crash o Hypoxia o SUDEP – Sudden death in Epilepsy o Varying degrees of brain dysfunction/damage o Cognitive impairment o Serious psychiatric disease o Significant adverse reactions to medication o Stigma/Loss of livelihood ```

Answer 131

Antiepileptic drugs generally act by inhibiting the rapid, repetitive neuronal firing that characterises seizures. They act by: o Inhibition of channels involved in neuronal excitability e.g. Voltage gated Sodium channels o Enhancement of inhibitory activity e.g.GABA-mediated inhibition Voltage Gated Sodium Channel Blockers (VGSC Blockers) VGSC blockers act by binding to the channel and keeping it in an inactivated state. This reduces the probability of high abnormal spiking activity. VGSC blockers only gain access to the channel binding site during depolarisation, hence are voltage dependent. They are also self regulating, as they detach from the binding site. VGSC blockers prolong inactivation state to return firing rates back to normal. Enhancing GABA Mediated Inhibition GABA plays a major role in post-synaptic inhibition, 40% of synapses in the brain are GABA-ergic. Increase in GABA is a natural anticonvulsant. The general mechanism is an increase in Chloride current into the neurone, increasing the threshold for action potential generation. This reduces the likelihood of epileptic neuronal hyper-activity. ``` Pharmacological targets: o Binding with GABAA receptor o Direct GABA agonists o Benzodiazepine Site – Enhance GABA action o Barbiturate Site – Enhance GABA action ``` ``` Drugs: Phenytoin Carbamazepine Lamotrigine Sodium Valproate Benzodiazepines ```

Answer 132

Anti-Epileptic Drugs – Basic Prescribing Rules o ADRs with AEDs are very common o Adjunctive drug use and Polypharmacy with epilepsy is very common - Monotherapy is the aim though! o Systematic use of one drug, replace if ineffective o Patients must remain under review o Variation in AED plasma levels – Monitor and titrate to therapeutic window o ITU sedation is a treatment

Answer 133

The treatment of epilepsy in pregnancy is a balance of risk: o Epilepsy vs. AED Teratogenicity o In mild epilepsy, stop the treatment? o In Severe disease or Status epilepticus how much harm will be done to the mother and baby if treatment is stopped? AEDs and Pregnancy o With multiple AEDs, the Teratogenic risk increases Neural tube defects Folate supplements reduce the risk Facial and digit hypoplasia Learning difficulties / mild neurological dysfunction Vitamin K deficiency in newborn leading to coagulopathy and cerebral haemorrhage Vitamin K supplement, 10mg/day in last trimester AED risk of birth defects ~8%, compared to ~2% normally o Use a single AED agent if possible at lowest dose o Valproate is best avoided – Neural tube defects o Lamotrigine may be the safest – Birth defect rate is ~2% (normal rate) Failure of Contraception with AEDs o Failure rate of OCP is 5-10% higher with Carbamazepine / Phenytoin 1-2% baseline OCP failure 5-10% failure rate with Carbamazepine / Phenytoin

Answer 134

o Sub-Therapeutic Levels Linear Kinetics Therapeutic Levels Non-Linear Kinetics Saturated enzymes Plasma t½ increases as dose is increased Steady State Concentration in Plasma (achieved with a daily dose) varies disproportionately with the dose (see image). The therapeutic range of Phenytoin is quite narrow, 40-100μmol. Drug monitoring of the plasma levels of Phenytoin is required, as due to its pharmacokinetic properties this therapeutic range can be exceeded quite rapidly, causing adverse effects (see above).

Answer 135

Medical emergency o Adult mortality ~20% o Risk increases with the length of Status Epilepticus Management of Status Epilepticus o ABC approach o Exclude hypoglycaemia o Hypoventilation may result with high AED doses o ITU for paralysis and ventilation if AEDs are failing AEDs in Status Epilepticus o Benzodiazepines Lorazepam (0.1mg/kg) Preferred to Diazepam due to longer t½ Given intravenously (rectal if IV access difficult) o Phenytoin Zero Order (Non-Linear) kinetics (15-20mg/kg) Rapidly reaches therapeutic levels IC Cardiac monitoring – Arrhythmias and hypotension Drugs to be used for each type of seizure (NICE Guidelines) o Absence = Ethosuximide or sodium valproate. If ineffective, move onto lamotrigine o Tonic Clonic = sodium valproate, then lamotrigine, then carbemezepine and oxcarbazepine o Focal Seizures = carbamazepine or lamotrigine o Myoclonic seizures = sodium valproate first, then levtriacetam or topiramate if sodium valproate is not tolerated o Tonic/Atopic seizures = Sodium valproate

Answer 136

Parkinsonism is a neurological syndrome categorised by: Tremor Low frequency rest tremor Abolished by movement Low dopamine and disturbance of other neurotransmitters Rigidity Lead pipe rigidity / Cog-wheel Low dopamine and disturbance of other neurotransmitters Bradykinesia Low Dopamine Postural instability ``` Non-Motor Manifestations o Mood changes o Pain o Cognitive change o Urinary symptoms o Sleep disorder o Sweating ``` Causes of Parkinsonism o Idiopathic Parkinson’s Disease o Dopamine blocking or depleting drugs Particularly antipsychotics

Answer 137

Pathophysiology of Parkinson’s Disease o Presence of neuronal inclusion called Lewy Bodies Contain tangles of α-synuclein and ubiquitin Gradually become more widespread as the condition progresses, spreading from lower brainstem -> Midbrain -> Cortex o Loss of Dopaminergic Neurones from the pars compacta of the Substantia Nigra in the midbrain that project to the striatum of the basal ganglia. Extent of nigrostriatal dopaminergic cell loss = degree of akinesia No symptoms until there is 50% cell loss Loss of pigment (dopaminergic cells in Substantia Nigra contain melanin)

Answer 138

Catecholamine Synthesis ``` Drug Classes in IPD o Levodopa (L-DOPA) o Dopamine receptor agonists o MAOI Type B inhibitors o COMT inhibitors o Anticholinergics o Amantadine ```

Answer 139

To reduce side effects of L-DOPA, use another drug as well but and reduce dose.

Answer 140

Prognosis in Parkinson’s Disease (15 year follow up) o Dyskinesia – 94% (writhing movement due to L-DOPA treatment) o Falls – 81% o Cognitive Decline – 84% (50% have hallucinations) o Somnolence – 80% o Swallowing Difficulty – 50% o Severe Speech Problems – 27%

Answer 141

Peptic ulcer disease (PUD): Peptic ulcer is break in superficial epithelial cells penetrating down into Muscularis mucosa of either stomach (GU) or duodenum (DU). Most DUs are found in duodenal cap and GUs are most commonly seen in lesser curvature of stomach Causes Leading cause in developed world is use of NSAIDs, which inhibit production of prostaglandins, prevents production of protective unstirred layer (innate protection against gastric acid). 50% of patients taking long term NSAIDs have mucosal damage and 30% when endoscoped have peptic ulceration but only 5% will be symptomatic and only 1-2% will have complication such as GI bleed. Epidemiology Duodenal Ulcers found in ~10% adult population and are 2-3 times more common than GUs. Prevalence is falling for younger people (especially men) and increasing in older people (especially older women). In developed countries increased prevalence of NSAID-associated DUs and decreasing prevalence of H pylori associated ulceration Clinical features o Recurrent, burning epigastric pain (pain is often worse at night and when hungry with Duodenal Ulcers and relieved when eating). Pain may subside with antacids Persistent, severe pain suggest penetration of ulcer into other organs Back pain suggest penetrating posterior ulcer o Can also get nausea, vomiting (though less common) o With GUs can get weight loss and anorexia o May be asymptomatic and present for first time with hematemesis when ulcer has perforated blood vessel(s) Investigations o Investigate H pylori infection o In older patients (over 55y/o) or with other alarming symptoms -> endoscopy to exclude cancer Management o If due to H pylori infection -> Triple Therapy Proton Pump Inhibitor – Omeprazole Antibiotics – Clarithromycin / Amoxicillin H2 Antagonist – Cimetidine o If taking NSAIDs – stop or review – use alternatives (NSAIDs with lower risk of causing PUD), or use prophylactic PPI as well as NSAID PPI – e.g. omeprazole Surgical Treatment of Peptic Disease o Resection of the Vagus Nerve o Anti-reflux surgery Complications of PUD o Haemorrhage of blood vessel which ulcer has eroded -> presents with hematemesis and melena o Perforation of the ulcer – more common in DUs than GUs – usually perforate into peritoneal cavity o Gastric outlet obstruction  can be pre-pyloric, pyloric or duodenal. Occurs either because of active ulcer with oedema or due to healing of an ulcer with associated fibrosis (scarring). Gastric outlet obstruction normally presents as vomiting without pain.

Answer 142

Defensive Factors Epithelial integrity Cell replication and restitution Mucous membrane barrier Vascular supply Mucus Mucus is Sticky, so is not easily removed from the stomach lining. It is also Basic, due to Amine groups on the proteins. The mucus forms a ‘unstirred layer’ that ions cannot move through easily. H+ ions slowly diffuse in and react with the basic groups on mucus and with HCO3- that is secreted by surface epithelial cells. Because of the unstirred layer, HCO3- stays close to the surface cells. This means the pH at the surface cells is well above 6. Mucus and HCO3- secretion from neck cells and surface cells respectively is stimulated by prostaglandins, which are promoted by most factors that stimulate acid secretion. Agressive Factors Breaching the Stomach’s Defences o Alcohol Dissolves the mucus, allowing the acid to attack the stomach o H. Pylori Surface cells become infected, inhibiting mucus/HCO3- production o NSAIDS Inhibit prostaglandins, therefore reducing defences Some, like aspirin are converted to a non-ionised form by stomach acid, allowing them through the mucus layer into cells before they re-ionise.

Answer 143

Parietal Cells Parietal cells have lots of mitochondria, allowing them to produce H+ at a high rate. The H+ ions are formed from dissociation of water. The hydroxyl ions which are also formed in this process quickly combine with CO2 to form a bicarbonate ion in a reaction catylased by carbonic anhydrase. However, these produced ions cannot accumulate in cells. To overcome this problem, parietal cells have invaginations in their cells walls called canaliculi. Canaliculi have proton pumps, which expel H+ from parietal cells up a high concentration gradient. As the concentration gradient is high, this is a very energy intensive process. The proton pumps in canaliculi are a key target for drug action, as if inhibited they will reduce the amount of acid in the stomach. Control of Gastric Secretion A complex of neural and endocrine systems controls acid secretion. Parietal cells are stimulated by Acetylcholine, Gastrin and Histamine, which act via separate receptors to promote acid secretion. Acetylcholine Ach is released from postganglionic parasympathetic neurones, stimulated by gastric distension as food arrives. It acts on muscarinic receptors on parietal cells. Gastrin Gastrin is released from endocrine cells in the stomach, G-Cells. It is a 17-amino acid polypeptide, which binds to surface receptors on parietal cells. Gastrin secretion is stimulated by the presence of peptides and Ach from intrinsic neurones. It is inhibited by low pH in the stomach, which acts as a ‘feedback’ control. Histamine Histamine is released from Mast Cells and diffuses locally to bind H2 surface receptors on parietal cells. Acid secretion is then stimulated via c-amp. Gastrin and Ach stimulate mast cells, so Histamine works as an amplifier. Phases of Control of Gastric Secretion 1. Cephalic Phase The ‘brain led’ phase. The sight and smell of food, and the act of swallowing, activates the parasympathetic nervous system, which stimulates the release of Ach. This stimulates parietal cells directly and via histamine (Increased Acid). 2. Gastric Phase Once food reaches the stomach, it causes distension, further stimulating Ach release, and subsequently parietal cells (Increased Acid). The arrival of food will also buffer the small amount of stomach acid in the stomach in between meals, causing luminal pH to rise. This disinhibits Gastrin (Increased Acid). Acid and enzymes will then act on proteins to produce peptides, further stimulating Gastrin release as the pH falls and the initial disinhibition is removed (INcreased Acid). 3. Intestinal Phase Once chyme leaves the stomach in significant quantities, it stimulates the release of the hormones Cholecystokinin and Gastric Inhibitory Polypeptide from the intestines that antagonise Gastrin (Reduced Acid). Coupled with this, the small amount of acid left in the stomach is no longer being buffered by food, and the low pH inhibits Gastrin (Redcued Acid). The low pH of the stomach between meals can aggravate ulcers. Because of this, pain from ulcers is particularly bad at night.

Answer 144

Acid secretion may be reduced by inhibition of: o Histamine at H2 Receptors E.g. Cimetidine Removes the amplification of Gastrin/Ach signal by acting as a Histamine Receptor Antagonist o Proton Pump Inhibitors (PPIs) E.g. Omeprazole Prevents H+ ions being pumped into parietal cell canaliculi by targeting ATPase

Answer 145

GORD/Oesophagitis Treatment o Healing and maintenance o Treat complications (Barrett’s oesophagus, peptic stricture) ``` Step Up Treatment Step Down Treatment GP Setting, start with lifestyle modifications and move upwards Hospital settling, start with PPI treatment and work down o Lifestyle o Antacids o H2 Receptor Antagonists o PPI ```

Answer 146

``` PPI Adverse Drug Reactions o GI upset o Nausea o Headaches o Risk of gastric atrophy with long-term treatment ``` ``` H2 Receptor Antagonist Adverse Drug Reactions o Dizziness o Fatigue o Gynaecomastia o Rash ```

Answer 147

o H pylori is a gram negative, aerobic, helical, urease producing bacterium that resides in the stomach of infected individuals. o Production of Urease produces ammonia, which neutralises acidic environment, which allows bacterium to survive. o It colonises gastric epithelium – in mucous layer or just beneath. Damage to epithelia occurs through enzymes released and through induction of apoptosis. Damage also occurs due to the inflammatory response to the infection (inflammatory cells and mediators) H pylori causing gastric disease: o Gastritis Usual effect of infection, which is usually asymptomatic. Chronic gastritis causes hypergastrinaemia due to gastrin release from astral G cells -> this increased acid production is usually asymptomatic but can lead to duodenal ulceration (which will eventually produce symptoms) o Peptic ulcer disease Duodenal ulcers (DUs) -> prevalence of DU due to H pylori is falling due to decreased prevalence of H pylori infection. If ulcers due to H pylori infection, eradication of infection relieves symptoms and decreases chances of recurrence. The precise mechanism of ulceration is unclear (only occurs in 15% of infected people) -> factors implicated though are genetic predispositions, bacterial virulence, increased gastrin secretion and smoking Gastric ulcers (GUs) -> associated with gastritis affecting the body as well as antrum, which can cause parietal cell loss -> reduction in acid production. Ulceration thought to occur due to reduction in gastric mucosal resistance due to cytokine production as a result of infection o Gastric cancer Diagnosis o IgG detected in serum (relatively good sensitivity and specificity) o 13C-urea breath test (13C-urea ingested – if H pylori present the urease produced will break down 13C-urea to NH3 and CO2 – CO2 (where the carbon is 13C) will be exhaled on breath and detected). o Can also take gastric sample by endoscopy and detect by histology and culture

Answer 148

Triple therapy. Proton Pump Inhibitor – Omeprazole Two Antibiotics – Amoxicillin / Clarithromycin H2 Antagonist (if severe) This standard eradication therapy, depending on local resistance, is successful at eradicating infection in 90% of patients. 7-14 day treatment – 14 days more effective but side-effects of treatment may put patients off finishing two week course

Answer 149

The enteric nervous system is a collection of autonomous nerves within the gut wall. ``` o Auerbach’s Plexus Between circular and longitudinal muscle layers o Meissner’s Plexus Submucosa o Henle’s Plexus Circular muscle adjacent to submucosa o Cajal’s Plexus Circular muscle adjacent to longitudinal muscle ``` Together these autonomic gonglionated plexi control the functioning of the GI tract through complex local reflex connections between sensory neurones, smooth muscle, mucosa and blood vessels. Extrinsic parasympathetic fibres from the vagus are excitatory, extrinsic sympathetic fibres are inhibitory.

Answer 150

Extrinsic Nerves o Intestino-intestinal inhibitory reflex Distension of one intestinal segment causes complete intestinal inhibition (Peristalsis) o Anointestinal Inhibitory Reflex Distension of anus causes intestinal inhibition o Gastrocolic and Duodenocolic Reflexes Stimulates motility after material has entered the stomach or duodenum Neurotransmitters All endocrine hormones effective in the GI tract are peptides produced in endocrine cells of mucosa.

Answer 151

Motility in Small Intestine Intestinal contents must move very slowly (transit time in hours), whilst being gently agitated for effective absorption. This is achieved by a pattern of motility called Segmenting, which is very different to peristalsis. The small intestine is divided into sections, each with a pacemaker. The frequency of the pacemaker gets less from the duodenum to the terminal ileum (12 times a minute -> 8), a phenomenon known as the intestinal gradient. Each pacemaker drives a small section of intestine, causing intermitted contraction of smooth muscle along its length. These contractions separate the intestine into segments where the muscle is not contracted, whose contents are effectively mixed by movement from the portions that do contract. After a few seconds he contractions relax, and at the next pacemaker firing different areas contract. Segmenting itself does not propel contents along the intestine, merely mixes the contents. The intestinal gradient however means that there is a net movement, albeit slow, in a caudal direction. Motility in Large Intestine Haustral Shuffling The large intestine is divided naturally into segments known as Haustra, as the circular muscles are more complete than the longitudinal, which have been reduced to taenia coli (thick circular muscle, thin longitudinal – only 3 layers). Contraction of the smooth muscle in the walls of the Haustra shuffles the contents back and forth, as the slow absorption of remaining water and salts forms faeces. The contents slowly progresses towards the sigmoid colon, with control like segmenting. Mass Movement Infrequently (once or twice a day), there is a Peristaltic, propelling pattern from the transverse through to the descending colon. This forces faeces rapidly into the rectum, which is normally empty, inducing the urge to defecate. Mass movement is often triggered by eating, the Gastro-colic reflex. They often also happen at certain times of the day, as “people like to be regular”.

Answer 152

``` Laxatives Laxatives are drugs used to hasten transit time in the gut and encourage defecation. Laxatives are used to relieve constipation and to clear the bowel prior to medical and surgical procedures. It should be remembered that individual bowel habit can vary considerably. The frequency and volume of stool are best regulated by diet, but drugs may be necessary. The passage of food through the intestine can be hastened by: o Bulk Laxatives o Faecal Softeners o Osmotic Laxatives o Irritant / Stimulant Laxatives ``` What type of Laxative should be Used? ``` o History and/or examination reveals soft faeces Stimulant Laxatives (E.g. Senna, Bisacodyl) ``` o History and/or DRE reveals hard faeces Osmotic Laxatives (E.g. Lactulose, Movicol) Bulk-Forming Laxatives (E.g. Ispaghula)

Answer 153

Examples Codeine (opiate analgesic) Imodium (opiate analogue) Route of Administration Indications Contraindications Inflammatory Bowel Disease – Toxic Megacolon ``` Mechanism of Action Act on opioid receptors in the bowel Reduce motility (increase time for fluid reabsorption) Increase anal tone and reduce sensory defecation reflex ``` Adverse Drug Reactions Nausea, vomiting, abdominal cramps, constipation drowsiness Therapeutic Notes Imodium is 40 times more potent than Morphine as an antidiarrhoeal agent, and penetrates the CNS poorly

Answer 154

``` Irritable Bowel Syndrome Chronic: o Abdominal Pain o Discomfort o Bloating o Alteration of Bowel Habits ``` Treat with Mebeverine, which has a direct effect on colonic hypermotility. This will relieve the spam of intestinal muscle, thus managing the most complained about symptom of IBS.

Answer 155

Vomiting (Emesis) o Pyloric sphincter closes while the cardia and oesophagus relax o Gastric contents propelled by contraction of abdominal wall and diaphragm o Glottis closes with elevation of soft palate, preventing entry of vomit into the trachea and Nasopharynx If vomiting is due to alcohol, or patient has a cranial nerve lesion they are at a higher risk of aspiration as this does not work properly

Answer 156

o Biopsychosocial Model Predisposing, precipitating and perpetuating factors o Genetic vulnerability to the expression of the disease o Live events (divorce, bereavement) o Individuals personality, coping skills, social support o Environmental influences (e.g. viruses during pregnancy, toxins, other diseases)

Answer 157

Actions of CNS Drugs o Agonists or Antagonists of neurotransmitter receptors May be competitive for neurotransmitter binding site o Inhibitors of regulatory enzymes Those that make or break down neurotransmitters Less common

Answer 158

``` Key Transmission and Modulatory Pathways in the CNS o Noradrenergic Pathways o Dopaminergic Pathways o Serotonergic (5HT) Pathways o GABA-nergic pathways o Cholinergic pathways o Glutamate pathways ```

Answer 159

``` Commonly Treated Psychiatric Illnesses o Schizophrenia o Depression o Bipolar disorder o Eating disorders o Obsessive compulsive disorder ```

Answer 160

Depression Depression is extremely common. Everyone has a 10% lifetime risk of depression. Core Symptoms – Two of Three needed for diagnosis o Low mood o Anhedonia (lack of enjoyment) o Decreased energy ``` Secondary Symptoms o Decreased appetite o Sleep disturbance o Physical aches and pains o Irritability o Self harm or suicidal ideas or acts 10% with a history of recurrent, severe depression commit suicide o Can have psychotic symptoms ``` Pathophysiology of Depression Theory 1 – Monoamine Hypothesis o Depression is due to a deficiency of monoamine neurotransmitters (Noradrenaline and Serotonin) o Monoamine Oxidase Inhibits (MAOIs) block the enzyme monoamine oxidase from destroying the neurotransmitters Theory 2 – Neurotransmitter Receptor Hypothesis o Depression is due to abnormality in the receptors for monoamine transmission Theory 3 – Monoamine Gene Expression Hypothesis o Deficiency in molecular functioning o Hypothesised problem within the molecule events distal to receptor

Answer 161

Paranoid Schizophrenia o Lifetime risk is 1% If one parent has Paranoid Schizophrenia, lifetime risk is 10% If two parents have Paranoid Schizophrenia, lifetime risk is 45% o Schizophrenia is an example of mental illness with Psychotic symptoms Psychosis – a lack of contact with reality o 10% of people with paranoid schizophrenia commit suicide Symptoms of Paranoid Schizophrenia o Disturbances of thinking o Hallucinations A perception in the absence of an external stimulus Auditory, olfactory, visual, gustatory, tactile Auditory – Person hears a voice (external through their ears, not from inside their head), either talking directly to them or several voices talking amongst themselves. Feels completely real to patient. Delusions A fixed false belief that is out of keeping with someone’s cultural or religious beliefs You can argue or give evidence, but they will not believe you. It is fixed. E.g. “I am a member of the royal family”, “MI5 is watching me” o Unusual speech-thought disorder o Behavioural changes o Lack of insight o Negative symptoms o 10% No hypothesis completely explains schizophrenia. It is probably a result of a mix of: Dopamine Theory of Schizophrenia o Some evidence of increased dopamine function in schizophrenics o Dopamine antagonists are the best treatment for schizophrenia o Amphetamine causes symptoms similar to positive symptoms of schizophrenia o But: Amphetamines do not cause negative symptoms Dopamine antagonists do not treat negative symptoms Changes in dopamine function may be a response to long term drug treatment Is schizophrenia associated with increased 5HT function? o Many effective antipsychotics are antagonists at 5HT receptors o Precursors of 5HT (e.g. tryprophan) exacerbate schizophrenia o Under debate Is schizophrenia associated with decreased cortical glutamate function? o Non-competitive antagonist at NMDA-type glutamate receptors induces both positive and negative symptoms of schizophrenia o Post mortem studies have shown increased cortical glutamate receptors o Glutamate system is important, but mechanism unclear

Answer 162

Examples Haloperidol Chlorpromazine Route of Administration Oral Depot (every 2/3/4 weeks) ``` Mechanism of Action Dopamine D2 Receptor Antagonist Sedation – Within hours Tranquilisation – Within hours Antipsychotic – Several days or weeks ``` Adverse Drug Reactions Extrapyramidal effects – Hours or days Neuroleptic malignant syndrome – Severe rigidity, hyperthermia, autonomic instability, cognitive changes (delirium). Associated with elevated plasma creatine phosphokinase (CPK). Extremely rare, but very serious ADR of all antipsychotics. Weight gain Endocrine changes (e.g. prolactinaemia) Pigmentation ``` Toxicity CNS depression Cardiac toxicity Risk of sudden death with high dose Prolonged QT interval  Torsades de points Risk of sudden death with large dose ``` Therapeutic Notes Haloperidol is safe in emergencies

Answer 163

o Fear out of proportion to situation o Avoidance o Fear of dying, going crazy ``` o Physical symptoms Light headedness Dyspnoea Hot and cold flushes Nausea Palpitations Numbness Paraesthesia ```

Answer 164

Cognitive Behavioural Therapy o First line treatment ``` Benzodiazepines Examples Diazepam Lorazepam Clonazepam ``` Route of Administration Oral, intravenous Indications Diazepam / Lorazepam – Status Epilepticus Clonazepam – Absence seizures, short term use Anxiety Contraindications Respiratory depression Pregnancy Mechanism of Action Act at a distinct receptor site on GABA Chloride channel Binding of GABA or Benzodiazepines enhance each others binding, acting as positive allosteric effectors Increases Chloride current into the neurone, increasing threshold for action potential generation ``` Adverse Drug Reactions Sedation Tolerance with chronic use Dependence/Withdrawal with chronic use Confusion, impaired co-ordination Aggression Abrupt withdrawal – seizure trigger Respiratory and CNS depression ``` Drug-Drug Interactions Highly protein bound (85-100%) Some adjunct use Therapeutic Notes Well absorbed (90-100%), highly plasma bound (85-100%) Linear Pharmacokinetics, t½s vary between 15-45hours Side effects limit first line use Overdose reversed by IV Flumazenil Use may precipitate seizure/arrhythmia Teratogenic – Cleft lip and palate

Answer 165

Bipolar Disorder o High genetic component o Depression and hypomania/mania o Feeling unusually excited, happy, optimistic or feeling irritable o Overactive o Poor concentration and short attention spam o Poor sleep o Rapid speech, jump from one idea to another o Poor judgement (overspending) o Increased interest in sex o Psychotic symptoms – hallucinations, grandiose delusions Mood Stabilisers o Use of antidepressants may induce a manic episode o Lithium Also used in very treatment resistant depression o Anti-Epileptic drugs, which are also potent mood stabilisers Sodium Valproate Carbamazepine Lamotrigine (for depression, not mania) o Atypical Antipsychotics Olanzapine Risperidone

Answer 166

Pharmacological o Toxicities o Drug interactions -Allergic Reactions/Impact on normal flora o Clostridium Difficile infection Therapeutic drug monitoring is used to ensure and adequate, non-toxic dose. It is used with antibiotics such as: o Gentomicin - Aminoglycoside - Dose related ototoxicity and nephrotoxicity at high plasma levels o Vancomycin - Glycopeptide - Dose related ototoxicity and nephrotoxicity at high plasma levels - Fever, rashes - Local phlebitis at site of infection

Answer 167

Smooth Muscle Dysfunction o Increased Contraction/mass o Increased Cytokines/Chemokines Inflammation o Immune cells (Th2 Response, Mast Cells) ``` Airway remodelling o Mucus gland hyperplasia o Airway wall thickening o Increased smooth muscle mass o Subepithelial fibrosis o Epithelium desquamation ``` Early Phase Response In allergic asthma, the initial response to allergen provocation is due to interaction with Mast Cell fixed IgE. This results in the release of Histamine and a host of potent spasmogens, leading to immediate Bronchospasm. Late Phase Response Co-release of a range of mediators and chemotaxins activate a complex immune system response that brings leucocytes to the area. This sets off a further chain of event leading to exacerbated bronchospasm and congestion due to: o Epithelial damage - Increased exposure of the sensory irritant receptors, further exacerbating bronchial hyperactivity and sensitivity o Thickening of the basement membrane o Oedema o Mucus production Bronchial Hyperresponsiveness A key factor contributing to airway dysfunction in asthma is bronchial hyperresponsiveness, leading to ‘twitchy’ airways. Bronchial hyper-responsiveness is defined as an exaggerated bronchoconstrictor response to direct pharmacological stimuli such as histamine, or indirect stimuli such as exercise. These indirect stimuli cause bronchoconstriction at least in part through the direct or indirect activation of airway mast cells. Mast cell mediators then induce the bronchoconstriction.

Answer 168

Examples o Theophylline o Aminophylline Indications o Status asthmaticus o COPD Mechanism of Action o Antagonise Adenosine receptors Adverse Drug Reactions o Psychomotor agitation o Tachycardia Therapeutic notes o ADR profile means methylxanthines are 3rd or 4th line use for Asthma o Narrow therapeutic window

Answer 169

Examples o Ipratropium bromide o Tiotropium bromide Indications o Adjuncts to β2 agonists in asthma treatment o COPD Route of Administration o Inhaled Mechanism of Action o Bind to and antagonise M3 cholinergic receptors on bronchial smooth muscle. This blocks the constricting effect of Ach and also inhibits mucus secretion. Adverse Drug Reactions o Not well absorbed through the lungs, avoiding major systemic ADRs o Dry mouth

Answer 170

Indications - Transplant immunosuppression (agent of choice) Mechanism of Action o Inhibits the enzyme Inosine Monophosphate Dehydrogenase, which is required for Guanosine synthesis o Impaired B-cell and T-cell proliferation Adverse Drug Reactions o Myelosuppression -> Leukopenia, neutropenia o Increased risk of infection (especially viral) Therapeutic Notes o Highly selective. Spares other rapidly dividing cells, due to the presence of guanosine salvage pathways

Answer 171

``` Examples o Infliximab (Monoclonal Antibody) o Etanercept (Fusion protein) ``` Mechanism of Action o Blocks the effects of TNF-α o Decreased inflammation, decreased Angiogenesis, decreased joint destruction ``` Adverse Drug Reactions o Increased infections o Tiredness, dizziness o Itching o GI disturbances ```

Answer 172

Examples o Ibuprofen o Aspirin o Paracetamol Indications o Musculoskeletal and joint disease o Analgesia for mild to moderate pain o Symptomatic relief in fever Contraindications o Gastrointestinal ulceration or bleeding o Previous hypersensitivity to any NSAID o Caution in asthma and when renal function is impaired Mechanism of Action o Inhibit Cyclooxygenase enzyme, preventing Prostaglandin synthesis ``` Adverse Drug Reactions o GI – Ulceration o Renal – Reversible drop in GFR o Skin reactions (15% for some NSAIDs) o Asthmatic bronchospasm (10% incidence) o Allergic response o Prolongation of bleeding time (platelet inhibition) ``` Drug-Drug Interactions o Warfarin (protein binding reaction) o Methotrexate (protein binding reaction) o Sulphonylureas (protein binding reaction) o ACE inhibitors – Attenuate action Therapeutic Notes o Aspirin is associated with risk of the post-viral Reye’s Syndrome in children o Paracetamol overdose produces the toxic metabolite NAPQI via Phase I metabolism o Paracetamol has virtually no anti-inflammatory action, it is used to treat mild to moderate pain and fever

Answer 173

``` Examples o Morphine o Diamorphine o Codeine o Pethidine ``` Indications o Strong opioids used in moderate to severe pain (particularly visceral, post-operative and cancer) o Weak opioids are used in mild to moderate pain, and as antidiarrhoeals ``` Contraindication o Acute respiratory depression o Acute alcoholism o At risk of paralytic ileus o Head injuries (prior to neurological assessment) ``` Mechanism of Action o Bind to endogenous opioid receptors o Open K+ channels – hyperpolarise cells and reduce excitability o Close voltage gated Ca2+ channels, inhibit release of Substance P neurotransmitter ``` Adverse Drug Reactions o Respiratory Depression o Miosis (Important overdose sign) o Euphoria o Confusion o Psychosis o Coma o Tolerance and dependence o GI disturbances (nausea, vomiting, constipation) o Rarely anaphylactic responses, due to non-opiate receptor effects on mast cells, causing the release of histamine, leading to bronchoconstriction & hypotension ``` Drug-Drug Interactions o Naloxone – Opioid receptor antagonist. Reverses the adverse agonistic effects. Rapidly reverses respiratory depression. Therapeutic Notes o Morphine is the gold standard against which other opioids are compared o Diamorphine is twice as potent as Morphine, as it has greater penetration of the Blood-Brain Barrier. It is metabolised to 6-Acetylmorphine and therefore morphine in the body. o Pethidine is more lipid soluble than morphine, and it has rapid onset and short duration of action, making it useful in labour. o Buprenorphine has both agonist and antagonist actions at opioid receptors. May precipitate withdrawal symptoms in patients dependent on other opioids. o Codeine has about one twelfth the analgesic potency of Morphine. It needs to be metabolised by CYP2D6 into Morphine to become pharmacologically active (10% of people lack this enzyme).

Answer 174

Stages of Anaesthesia Induction Propofol is normally administered and the beginning of inhalational agent delivery. Adjuvants will also be administered intravenously. Maintenance The anaesthetist keeps the adjuvants in balance to maintain adequate anaesthetic depth. Recovery The agents are withdrawn and physiological function monitored closely to make sure it can be maintained without support. Antidotes may be given as necessary to facilitate this. Depth of Anaesthesia Anaesthetic depth is divided into four main stages. Called Guedel’s Signs 1.Analgesia Early effects on transmission in the Spinothalamic Tract 2.Excitement Delirium and aggressive behaviour are experienced. Now uncommon as induction occurs so rapidly with Propofol. 3.Surgical Anaesthesia Profound CNS depression Skeletal muscles fully relaxed Breathing may need to be assisted and cardiac function affected Attained with an effective integrated MAC between 1.2 and 1.5 Four levels describing increasing depth until breathing weak 4.Respiratory Paralysis and Death Once above 2.2 MAC (Isoflurane) there is an increasing risk of Stage 4, with severe medullary depression leading to respiratory and cardiac arrest and death

Answer 175

``` o Examples  Losartan  Valsartan o Indications  Hypertension o Contraindications  Pregnancy, breastfeeding  Caution in renal artery stenosis and aortic stenosis o Mechanism of Action  Bind to and antagonise the receptor for Angiotensin II – Angiotensin 1 Receptor (AT1 R).  Inhibits vasoconstriction and aldosterone stimulation by angiotensin II. o Adverse Drug Reactions  Renal failure  Hyperkalaemia ```

Answer 176

o Examples  Bendroflumethiazide  Metolazone o Indications  Hypertension  Oedema secondary to congestive cardiac failure, liver disease or nephrotic syndrome o Contraindications  Hypokalaemia, Hyponatraemia, Hypercalcaemia o Mechanism of Action  Thiazide diuretics inhibit the Na+/Cl- co-transporter in the luminal membrane in the distal tubule of the kidney. This blocks the reabsorption of Na+ and therefore water. Result is lower blood volume and pressure. o Adverse Drug Reactions  Hypokalaemia, hyperuricaemia,  Impaired glucose tolerance  Hyponatraemia, hypermagnesemia, Hypercalcaemia,  Metabolic alkalosis  Cholesterol and triglyceride levels increase

Answer 177

o Examples  Propranolol  Atenolol  Bisoprolol  Metoprolol o Indications  Angina  Post myocardial infarction  Hypertension  Arrhythmias o Contraindications  Non-selective β-blockers (e.g. Propranolol) must not be given to asthmatic patients.  Bradycardia, hypotension, AV block, Congestive Cardiac Failure o Mechanism of Action  Antagonise β-adrenoreceptors. β1-receptors are found in the heart, when they are activated they cause increased Chronotropy and Inotropy.  Inhibit renin release o Adverse Drug Reactions  Bronchospasm, fatigue and insomnia, dizziness, cold extremities, hypotension, bradycardia and decreased glucose tolerance in diabetic patients o Drug-Drug Interactions  Prevents Salbutamol working (β2-adrenoagonist)  Verapamil – Both have –‘ve inotropic action

Answer 178

There are three pharmacological classes of Calcium Channel Blocking drugs. All are effective in lowering blood pressure, but some are predominantly vasodilators (Dihydropyridines, e.g. Amlodipine) while others appear to act mainly or partially via an effect on myocardial contractility (Diltiazem and Verapamil). Mechanism of Action o Calcium channel blockers bind to specific alpha subunit of L-type calcium channel, reducing cellular calcium entry o Vasodilates peripheral, coronary and pulmonary arteries o No significant effect on veins o Verapamil depresses SA node and slows A-V conduction 1. Dihydropyridine Calcium Channel Blockers o Examples  Nifedipine  Amlodipine o Properties  Good oral absorption  Protein bound > 90%  Metabolised by the liver o Adverse effects  Sympathetic nervous system activation – tachycardia and palpitations  Flushing, sweating, throbbing headache  Oedema  Swollen ankles with amlodipine  Gingival hyperplasia (rare)  Gynaecomastia (rare) 2. Phenylalkylamine Calcium Channel Blockers o Examples  Verapamil o Properties  Impedes calcium transport across myocardial and vascular smooth muscle cell membrane  Class IV anti-arrhythmic agent (prolongs action potential/effective refractory period)  Peripheral vasodilation and a reduction in cardiac preload and myocardial contractility o Adverse Effects  Constipation (can potentialte constipation that is already present)  Risk of bradycardia  Reduced myocardial contractility (-‘ve inotrope) so can worsen heart failure 3. Benzothiazepine Calcium Channel Blockers o Examples  Diltiazem o Properties  Impedes Calcium transport across the myocardial and vascular smooth muscle cell membrane  Prolongs the action potential/effective refractory period  Peripheral vasodilation and reduction in cardiac preload and myocardial contractility  Verapimil-lite – does not work quite to the same extent as the others o Adverse Effects  Risk of bradycardia  Negative inotropic effect (less than Verapamil) can worsen heart failure

Answer 179

o Examples  Aliskiren o Indications  Hypertension o Contraindications  Pregnancy  Caution in patients at risk of hyperkalaemia, Na+ and volume depleted patients, severe renal impairment and renal stenosis o Mechanism of Action  Antagonises Renin, preventing the conversion of Angiotensinogen  Angiotensin I.  Reduces plasma renin activity by 50-80% o Adverse Drug Reactions  Angio-oedema, hyperkalaemia, hypotension, GI disturbances o Drug-Drug Interactions  Furosemide o Therapeutic Notes  t½ of ~40 hours, supporting once daily doses  Mainly eliminated as an unchanged compound in faeces (78%)  Not metabolised via CYP450

Answer 180

o Identify cause o ECG Emergency o Reduce K+ effect on heart - IV Calcium Gluconate o Shift K+ into ICF via glucose and insulin IV - Remove excess K+ o Dialysis Longer Term o Remove excess K+ - Dialysis o Oral K+ binding resins to bind K+ in the gut - Reduce Intake o Treat cause ``` Serum [K+] ECG Changes 6.5 -7 mmol/L Tall, peaked T waves 8 mmol/L Prolonged P-R Interval Tall T waves ST Segment depression 9 mmol/L Widened QRS Interval 10 mmol/L Ventricular fibrillation ```

Answer 181

Route of Administration - Oral Indications Prophylaxis and Treatment of DVT, PE, AF, Prosthetic Heart Valves Contraindications Cerebral thrombosis, peripheral arterial occlusion, peptic ulcers, hypertension, pregnancy Mechanism of Action Blocks Vitamin K’s reduction to its active form, which is require for its action as a cofactor in the synthesis of factors II, VII, IX & X Adverse Effects Bleeding/Bruising, Haemorrhage, Teratogenic Drug-Drug Interactions CYP450 Inducers PCBRAS oPhenytoin, Carbamazepine, Barbiturates Rifampicin, Alcohol (chronic), St. John’s Wort CYP450 Inhibitors GO-DEVICES o Grapefruit Juice, Omeprazole, Disulfiram, Erythromycin, Volporate, Isoniazid, Cimetidine & Ciprofloxcain, Ethanol (acutely), Sulphonamides o Highly protein bound, can be displaced, raising plasma conc. Therapeutic Notes o Use INR to monitor, measure of the Extrinsic coagulation pathway o Reverse effects with Vitamin K IV (affects Warfarin use for 6 weeks), or Fresh Frozen Plasma, Prothrombin Complex Concentration

Answer 182

Heparin Route of AdministrationUnfractionated – Intravenous LMW – Subcutaneous ``` Indications o Prophylaxis Peri-operative (replace Warfarin) Immobilised patients o Treatment DVT, PE, AF, MI, Unstable Angina ``` Contraindications Haemophilia, Thrombocytopenia, Peptic Ulcers Mechanism of Action Activates Anti-Thrombin III Unfractionated – Inhibits Thrombin (Factor IIa) and Factor XaLMW – Inhibits Factor Xa Adverse Drug Reactions Bleeding/Bruising/Haemorrhage Heparin Induced Thrombocytopenia Therapeutic Notes Immediate onset, so can be used in an emergency / Warfarin cover Monitor Unfractionated with aPTT, LMWH no need to monitor Reverse effects with Protamine Sulphate

Answer 183

``` POP - Adverse Effects Menstrual irregularities and poor cycle control Nausea, vomiting and headache Weight gain Breast tenderness ``` POP - Drug Interactions Metabolism is by CYP450 o Therefore effected by inducers/inhibitors o Enzyme inducers can lower levels of POP causing contraception failure

Answer 184

Uterine Bleeding The COCP can be used to manage abnormal uterine bleeding. Basically ‘tricks’ the body into thinking it is in the post ovulatory, luteal phase so offers a good method of cycle control.

Answer 185

Hormone Replacement Therapy (HRT) can be used to control menopausal symptoms and can helpt to control well-being. Oestrogen and Progestogens are given to replace lost hormones either orally, topically via a patch or gel. What types of HRT can you get? o Combined HRT - With these, the patient is given the same dose of oestrogen and progesterone for 28 day continuously. The woman will have no withdrawal bleed, however this does have a risk of causing endometrial hyperplasia, so you will only give this form women who have had a hysterectomy o Sequential Combined HRT - The patient is given oestrogen only up till day 14-16 and then you will add progesterone. This combination will stimulate a withdrawal bleed but will reduce the risk of endometrial cancer as endometrial hyperplasia does not occur and so is given to women who have not had a hysterectomy Risks of HRT o Unopposed oestrogen – Inc. endometrial and ovarian cancers o Increase breast cancer risk o Increased IHD and stroke risk (if introduced early in menopause, but should not be given solely for this reason) o Increased risk of thromboembolism o Uterine bleeding Adverse effects o Adverse effect on lipid profile o Adverse effect on thrombophilia profile Benefits - Reduced risk of colorectal cancer - Improves sexual function (helps with dryness) - Small reduction in bone loss

Answer 186

Anti-oestrogens - These drugs block the effects of oestrogen on oestrogen receptors. Examples include: Clomiphene o Tends to be used in women who are having problems with fertility o Induces ovulation by inhibiting the binding of oestrogen to the anterior pituitary. This will then increase GnRH levels and therefore LH and FSH levels also. Tamoxifen o Treatment for breast cancer and is also used for inducing ovulation o Reduces oestrogen binding, therefore limiting progress/recurrence of breast cancer Anti-progesterone This is a drug which antagonises the effects of progesterone. o Used for the medical termination of pregnancy and for inducing labouro Sensitises the uterus to prostaglandins o Is a partial agonist for the progesterone receptors and inhibits the action of progesterone. Anti-androgen - Treatment for hirsutism and used in the COCP o Has a weak progestogenic effect by competing with dihydrotestosterone o Cyproterone Selective Oestrogen Receptor Modulators These are a group of drugs which act on oestrogen receptors, but have different actions depending on the tissue where the receptor is found. e.g. Raloxifene, Tamoxifen Raloxifene o Is used to protects against osteoporosis in postmenopausal women o No proliferative effects on endometrium and breast o Oestrogenic effects on bone, lipid metabolism and blood coagulation o Reduced risk of invasive breast cancer in postmenopausal women with osteoporosis o Increases hot flushes

Answer 187

Regulatory o Fluid balance o Acid-base balanceo Electrolyte balance Excretory o Waste products o Drug Elimination – Glomerular filtration and Tubular secretion Endocrine o Renin-Angiotensin-Aldosterone System o Erythropoetin o Prostaglandins Metabolism - Vitamin D andPolypeptides – Insulin and PTH

Answer 188

o Given systemically it interferes with Na+ and HCO3- reabsorption, giving it a weak diuretic effect. Danger of metabolic acidosis. Now only used to treat Glaucoma e.g. Acetazolamide/ Dorzolamide

Answer 189

Examples - Mannitol Route of Administration - IV Indications - Raised ICP Contraindications o Congestive heart failure o Pulmonary oedema Mechanism of Action o Freely filtered at the glomerulus, but only partially, if at all, reabsorbed o Passive water reabsorption is reduced by the presence of this non-reabsorbable solute within the tubule lumen o Increases the osmotic gradients throughout the nephron, theredore causing excessive water loss. Is more historically used. o Difficult to titrate o Causes significant changes to ion levels, especially hyponatremia Site of Action o Tubular segments that are water permeable o Proximal tubule, descending loop of Henle, collecting ducts Adverse Drug Reactions o Chills and fever Therapeutic Notes o Seldom used in heart failure, as expansion of blood volume can be greater than the degree of diuresis produced

Answer 190

Examples o Bendroflumethiazide o Metolazone Indications o Hypertension o Oedema secondary to congestive cardiac failure, liver disease or nephrotic syndrome Contraindications o Hypokalaemia, Hyponatraemia, Hypercalcaemia Mechanism of Action o Thiazide diuretics inhibit the Na+/Cl- co-transporter in the luminal membrane in the distal tubule of the kidney. This blocks the reabsorption of Na+ and therefore water. Result is lower blood volume and pressure. Adverse Drug Reactions o Hypokalaemia, hyperuricaemia, impaired glucose tolerance, Hyponatraemia, hypermagnesemia, Hypercalcaemia, metabolic alkalosis Drug-Drug Interactions o Steroids – Increased risk of hypokalaemia o Beta-Blockers – Hyperglycaemia, Hyperlipidaemia, Hyperuricaemia o Digoxin – Hypokalaemia increases digoxin binding and toxicity o Carbamazepine – Increased risk of Hyponatraemia

Answer 191

Examples o Furosemide – 50% uptake o Bumetanide – 90% uptake. More effective if there is presence of gut oedema, as the drug crosses the gut wall better. Can change to IV from oral to avoid this. o Torasemide Route of Administration o Oral, intravenous or intramuscular. Intravenous route used in emergencies as therapeutic effect is much faster (30 mins compared to 4-6 hours orally). ``` Indications o Acute pulmonary oedema o Oliguria (acute renal failure) o Resistant heart failure o Hypertension ``` Contraindications - Severe renal impairment Mechanism of Action o Inhibit the Na/K/Cl co-transporter in the luminal membrane o Blocks reabsorption of Na+ and therefore water. Can block up to 5% of Na reabsorption Site of Action - TAL of the loop of Henle Adverse Drug Reactions o Hypokalaemia, Hyponatraemia, hyperuricaemia, hypotension, hypovolaemia, metabolic alkalosis o Bumetanide can cause Myalgia (occasionally, not very common) o Furosemide can cause Ototoxicity Drug-Drug Interactions o Cardiac Glycosides – Hypokalaemia caused by loop diuretics potentiates the action of cardiac glycosides, increasing the risk of arrhythmias o Aminoglycoside Antibiotics – (E.g. Gentamycin) Will interact with loop diuretics and increase risk of ototoxicity and potential hearing loss o Steroids – Increased risk of hypokalaemia

Answer 192

``` Examples o Amiloride (Na+ channel blockers) o Spironolactone (Aldosterone Antagonist) o Canrenone ``` Route of Administration - Oral Indications o In conjunction with other diuretics in managing heart failure or hypertension. They are only mild diuretics. o Aldosterone antagonists used in the treatment of hyperaldosteronism o Primary – Conn’s Disease o Secondary – Result of heart failure, liver disease or nephrotic syndrome Contraindications - Renal failure Mechanism of Action o Na+ channel blockers o Block Na+ reabsorption by principal cells o Aldosterone Antagonist o Competitive antagonist at aldosterone receptors. This reduces the secretion of Na+ Site of Action Late distal tubule and collecting duct Adverse Drug Reactions o GI disturbances o Hyperkalaemia (in patients in renal failure) o Hyponatraemia o Spironolactone – Gynaecomastia, menstrual disorders, erectile dysfunction due to androgenic cross-reactivity (interacts with oestrogen synthesis) Drug-Drug Interactions o Interaction with ACE inhibitors, increasing risk of hyperkalaemia

Answer 193

Inhibits tubular Na/K-ATPase Drug-Drug interaction with Thiazide Diuretics. Hypokalaemia leads to increased digoxin binding and toxicity. Atrial fibrillation or heart failure, Not used as a diuretic, as it has minimalm diuretic effects.

Answer 194

Lithium and Demecocycline (Tetracycline antibiotic) have some action as ADH antagonists. By blocking the action of Anti-Diuretic Hormone, Aquaporin 2 is not inserted into the apical membrane of the co`llecting duct, meaning less water is able to be reabsorbed.

Answer 195

Can have over-treatment as well as patients not responding as well to the treatment, perhaps because they have not made the necessary life-style changes. o Incomplete treatment of primary disorder o Continuation of high Na+ intake o Patient non-compliance o Poor absorption o Volume depletion decreases filtration of diuretics o Volume depletion increases serum aldosterone, enhancing Na+ reabsorption o NSAIDs – Can reduce renal blood flow

Answer 196

Prophylaxis o Prevention of Thrombo-Embolism Peri-Operative (LMWH low dose) Immobility (Heart failure, frail or unwell patient) Used to cover thrombosis risk around operation in patients normally on warfarin, but who have had it stopped for surgery, as Heparin quick offset time allows cessation if bleeding occurs Treatment Deep Vein Thrombosis, Pulmonary Embolism and Atrial Fibrillation . Administered prior to Warfarin, as quick onset will cover patient whilst Warfarin loading is achieved. LMWH often used unless fine control is required Acute Coronary Syndromes Reduces recurrence/extension of coronary artery thrombosis MI, unstable angina Pregnancy Can be used cautiously in pregnancy in place of Warfarin.

Answer 197

Route of Administration - Oral Indications o Prevention and treatment of MI / Ischaemic stroke, Analgesic o Anti-inflammatory agent Contraindications - Children under 12 years who are at risk of Reye’s Syndrome, Breastfeeding, Haemophilia, peptic ulcers, known hypersensitivity Mechanism of Action - COX-1 Enzyme inhibitor, Prevents the formation of Thromboxane A2 from Arachidonic Acid in platelets. Thromboxane A2 stimulates phospholipase C, increasing calcium levels and causing platelet aggregation Adverse Drug Reactions - Bronchospasm, GI haemorrhage Drug-Drug Interactions - Displaces Warfarin from plasma proteins (PKs) Increases Anti-Coagulant effect of Warfarin at a different site (PDs) Therapeutic Notes Aspirin at 150mg daily after MI has been shown to decrease mortality

Answer 198

Route of Administration - Oral Indications o Used in conjunction with Warfarin in prophylaxis against thrombosis due to prosthetic mechanical heart valves Mechanism of Action o Inhibits Phosphodiesterase enzyme o Phosphodiesterase increases cAMP, which increases Ca2+, which causes platelet aggregation Adverse Drug Reactions Hypotension, nausea, diarrhoea, headache Drug-Drug Interactions o Works synergistically with Warfarin to decrease Coagulability

Answer 199

Route of Administration- Oral Indications o Secondary prevention of cardiovascular/cerebrovascular events Mechanism of Action o ADP Antagonists o Inhibits ADP-ADP receptor interaction, which aids platelet aggregation Adverse Drug Reactions o Haemorrhage o GI disturbances – Discomfort, nausea, vomiting Drug-Drug Interactions o Works synergistically with Warfarin to decrease Coagulability Therapeutic Notes If patient is allergic to Aspirin, Clopidogrel can be used instead

Answer 200

Streptokinase Route of Administration - IVIntravenous Indications Life-threatening venous thrombosis, pulmonary embolism, arterial thromboembolism, acute myocardial infarction Contraindications Recent haemorrhage, trauma, surgery, aortic dissection, coma, history of cerebrovascular disease Mechanism of Action Forms a complex with and activates Plasminogen  Plasmin Adverse Drug Reactions Nausea, vomiting, bleeding/haemorrhage Drug-Drug Interactions Often used in conjunction with anti-platelet and anti-coagulant drugs. Therapeutic Notes Streptokinase is derived from haemolytic streptococci, and is therefore antigenic. Repeated administration of streptokinase could therefore result in anaphylaxis. If already used once previously, use t-PAs instead Tissue Plasminogen Activators (t-PAs) Examples - Alteplase/Reteplase Route of Administration - Intravenous Indications Myocardial infarction, pulmonary embolism Contraindications Recent haemorrhage, trauma, surgery, aortic dissection, coma, history of cerebrovascular disease Mechanism of Action t-PAs are tissue-type plasminogen activators, Plasminogen -> Plasmin Adverse Drug Reactions Nausea, vomiting, bleeding/haemorrhage

Answer 201

Class 1 anti arrhythmic Route of Administration Oral (well absorbed) Intravenous ``` Indications Supraventricular tachyarrhythmias (Atrial arrhythmias) ``` Contraindications Heart failure, history of MI Mechanism of Action Blocks fast, inward Na+ ion channels (Phase 0) Adverse Drug Reactions Dizziness, visual disturbances, arrhythmias Drug-Drug Interactions Metabolised by CYP2D6 and eliminated renally. Inducers/inhibitors

Answer 202

Class 1 anti arrhythmic Route of Administration Intravenous Indications Ventricular arrhythmias following MI Contraindications AV block Heart failure Mechanism of Action Blocks fast, inward Na+ ion channels (Phase 0) Adverse Drug Reactions Hypotension, bradycardia (negative inotrope) Nystagmus Seizures

Answer 203

``` Examples Propranolol (Non-Selective) Atenolol (β1 Selective, Long acting) Bisoprolol (β1 Selective, Long acting) Metoprolol (β1 Selective, Short acting) ``` ``` Indications Angina Post myocardial infarction Hypertension Arrhythmias ``` Contraindications Non-selective β-blockers (e.g. Propranolol) must not be given to asthmatic patients. Bradycardia, hypotension, AV block, Congestive Cardiac Failure Mechanism of Action Antagonise β-adrenoreceptors. β1-receptors are found in the heart, when they are activated they cause increased Chronotropy and Inotropy. Inhibit renin release Adverse Drug Reactions Bronchospasm, fatigue and insomnia, dizziness, cold extremities, hypotension, bradycardia and decreased glucose tolerance in diabetic patients Drug-Drug Interactions Prevents Salbutamol working (β2-adrenoagonist) Verapamil – Both have –‘ve inotropic action

Answer 204

``` Examples Amiodarone Sotalol Low Dose – Class II action High Dose – Class III action ``` Route of Administration Orally or intravenously Indications Ventricular and supraventricular arrhythmias Contraindications AV block Mechanism of Action Block K+ channels (Phase 3) Adverse Drug Reactions Can cause arrhythmias (Torsades de Pointes) Drug-Drug Interactions Amiodarone inhibits CYP3A4, CYP2C9 and P-glycoprotein Dose reductions of Warfarin, Digoxin, Flecainide needed

Answer 205

Examples Verapamil Diltiazem Route of Administration Oral Indications Supraventricular arrhythmias Prophylaxis and treatment of angina and hypertension Contraindications Heart failure, bradycardia AV Node Block Mechanism of Action Blocks Ca2+ channels responsible for depolarisation of pacemaker cells. Adverse Drug Reactions Hypotension, bradycardia, heart failure, heart block

Answer 206

Route of Administration Oral bioavailability 70-80% ``` Indications Supraventricular Arrhythmias (Atrial fibrillation), Heart Failure ``` Contraindications Heart block, hypokalaemia Mechanism of Action Inhibits Na/K-ATPase o Direct Cardiac Effects o Increased Inotrope – Used in heart failure, no mortality benefit o CNS Effects o Decreased Sympathetic outflow o Increased Parasympathetic outflow o Sensitises baroreceptor reflex o Combined Effects o Decreased Automaticity of SAN and AVN o Increased AVN refractory period o Decreased Conduction velocity of AVN Adverse Drug Reactions Narrow therapeutic index Toxicity enhanced with hypokalaemia Cardiac toxicity – bradycardia, AVN block, atrial tachycardia Drug-Drug Interactions o Pharmacokinetic Increased Digoxin Levels – Popafenone, Quinidine, Amiodarone, Verapamil, Spironolactone, Cylosporine Redcued Digoxin Levels – Erythromycin, Tetracycline (gut bacteria metabolise digoxin) o Pharmacodynamic β-blockers, Verapamil, Diltiazem Loop and Thiazide Diuretics (Hypokalaemia) Therapeutic Notes o Large volume of distribution, loading dose required for rapid onset o Loading dose split into 2 doses to minimise toxicity risk. o Plasma levels checked 6-8 hours after dose at steady rate o 20-30% protein bound o Digoxin clearance is proportional to GFR (Reduce dose in elderly and renal impairment)

Answer 207

``` o AV node blocker o Decreased Automaticity o Increased AVN refractory period o t½ = a few seconds o Given as rapid IV bolus to diagnose and treat supraventricular tachycardias ``` Can be useful in distinguishing SVT with aberrant conduction from VT

Answer 208

Examples Ramipril Lisinopril Captopril Route of Administration Oral Indications Hypertension Heart failure Renal dysfunction Contraindications Pregnancy, renovascular disease, aortic stenosis Mechanism of Action ACE inhibitors cause inhibition of Angiotensin Converting Enzyme, consequently reducing Angiotensin II and Aldosterone levels. This causes vasodilation and consequent reduction in peripheral resistance and reduced sodium retention. Reduce breakdown of the vasodilator Bradykinin Adverse Drug Reactions Characteristic dry cough Angio-oedema (rare, but more common in black population) Renal Failure Hyperkalaemia Hypotension, dizziness and headache, diarrhoea and muscle cramps

Answer 209

Examples Losartan Valsartan Indications Hypertension Contraindications Pregnancy, breastfeeding Caution in renal artery stenosis and aortic stenosis Mechanism of Action Bind to and antagonise the receptor for Angiotensin II – Angiotensin 1 Receptor (AT1 R). Inhibits vasoconstriction and aldosterone stimulation by angiotensin II. Adverse Drug Reactions Renal failure Hyperkalaemia

Answer 210

Primary Epilepsy o No identifiable cause (Idiopathic) – ~65-60% Secondary Epilepsy o Medical conditions affecting the brain – ~30-35% o Vascular disease o Tumours

Answer 211

Route of Administration Oral, intravenous Indications All forms of epilepsy, except absence seizures Mechanism of Action Prolongs VGSC inactivation state Stops the spread of excitation from focus Adverse Drug Reactions CNS effects – dizziness, ataxia, headache, Nystagmus, nervousness Gingival Hyperplasia (20%) Rashes – Hypersensitivity (Stevens-Johnson Syndrome 2-5%) Drug-Drug Interactions CYP450 Inducer Many drug interactions, e.g. Warfarin, OCP Cimetidine -> Phenytoin Increase Well absorbed, 90% Protein Bound Competitive binding, e.g. with Valproate, NSAIDs Can exacerbate non-linear PKs Therapeutic Notes Phenytoin displays Non-Linear Pharmacokinetics at Therapeutic concentrations (linear at sub-therapeutic levels). This means close monitoring of free plasma levels is required.

Answer 212

Route of Administration Oral, rectal Indications All forms of epilepsy, except absence seizures Contraindications AV conduction problems Mechanism of Action Prolongs VGSC inactivation state ``` Adverse Drug Reactions CNS – Dizziness, drowsiness, ataxia, motor disturbances, numbness, tingling GI disturbances – Vomiting CVS – Variations in BP Hyponatraemia Rashes Rarely myelosuppression – neutropenia ``` Drug-Drug Interactions CYP450 Enzyme Inducer Many drug interactions, e.g. Warfarin, OCP Protein bound Another protein binding drug can raise Carbamazepine conc. Antidepressants (SSRIs, MAOIs, TCAs and TCA) interfere with Carbamazepine’s action Therapeutic Notes Well absorbed, 75% protein bound Linear Pharmacokinetics Initial t½ is ~30hrs, but is a strong inducer of CYP450s and therefore affects its own Phase I metabolism. In repeated use t½ falls to ~15hrs Drug monitoring required to adjust dosing due to falling t½

Answer 213

Route of Administration Oral Indications All forms of epilepsy Contraindications Hepatic impairment Not first line use in paediatric patients due to ADRs Mechanism of Action Prolongs VGSC inactivation state Adverse Drug Reactions Less marked CNS dizziness, ataxia, somnolence (drowsiness) Nausea Some mild (10%) and serious (0.5%) skin rashes, which limits child use Drug-Drug Interactions Adjunct therapy with other anti-epileptic drugs Oral Contraceptives reduce Lamotrigine plasma levels Valproate increases Lamotrigine plasma levels (protein binding) Therapeutic Notes Increasingly first line anti-epileptic drug Appears to be safer in Pregnancy

Answer 214

Route of Administration Oral, intravenous Indications All forms of epilepsy Contraindications Acute liver disease/hepatic dysfunction Mechanism of Action Weak inhibition of GABA inactivation enzymes -> Increased GABA A Weak stimulus of GABA synthesising enzymes -> Increased GABA A Weak VGSC blocker and Weak Ca2+ channel blocker -> Redcued Discharge Adverse Drug Reactions Generally less severe than with other AEDs CNS sedation – Ataxia, tremor Weight gain Hepatic Dysfunction – Transaminases increased in 40% of patients Rarely hepatic failure Drug-Drug Interactions Adjust therapy with other AEDs Care needed with adjunct therapy, as both Valproate and adjunct PKs are affected. E.g. displaces Lamotrigine and Phenytoin, raising their free plasma concentrations Antidepressants (SSRIs, MAOIs, TCAs and TCA) inhibit Valproate Antipsychotics antagonise Valproate, by lowering convulsive threshold Aspirin displaces Valproate from plasma proteins, raising its free conc. ``` Therapeutic Notes 100% absorbed, 90% protein bound Linear Pharmacokinetics, t½ = 15hrs Close monitoring of free plasma concentration is required Monitor for hepatic disorders ```

Answer 215

Examples Diazepam Lorazepam Clonazepam Route of Administration Oral, intravenous Indications Diazepam / Lorazepam – Status Epilepticus Clonazepam – Absence seizures, short term use Anxiety Contraindications Respiratory depression Mechanism of Action Act at a distinct receptor site on GABA Chloride channel Binding of GABA or Benzodiazepines enhance each others binding, acting as positive allosteric effectors Increases Chloride current into the neurone, increasing threshold for action potential generation ``` Adverse Drug Reactions Sedation Tolerance with chronic use Dependence/Withdrawal with chronic use Confusion, impaired co-ordination Aggression Abrupt withdrawal – seizure trigger Respiratory and CNS depression ``` Drug-Drug Interactions Highly protein bound (85-100%) Some adjunct use Therapeutic Notes Well absorbed (90-100%), highly plasma bound (85-100%) Linear Pharmacokinetics, t½s vary between 15-45hours Side effects limit first line use Overdose reversed by IV Flumazenil Use may precipitate seizure/arrhythmia

Answer 216

Route of Administration Oral (only 1% reaches the brain due to peripheral metabolism) Indications Parkinsonism (excluding drug-induced extrapyramidal symptoms) Contraindications Closed angle glaucoma Mechanism of Action L-DOPA is the immediate precursor of Dopamine and is able to penetrate the blood brain barrier to replenish the dopamine lost in the Neostriatum. ``` Adverse Drug Reactions Nausea and vomiting Psychiatric side effects (Schizophrenia-like symptoms) Cardiovascular effects (hypotension) Dyskinesia ``` Drug-Drug Interactions L-DOPA is given in combination with a peripheral DOPA decarboxylase inhibitor (Sinemet, Madopar), reducing necessary dose, side effects and increase the amount of L-DOPA reaching the brain Vitamin B6 increases peripheral breakdown of L-DOPA Therapeutic Notes Extensive peripheral metabolism of L-DOPA means that large doses have to be given to produce therapeutic effects. These large doses are more likely to bring about adverse effects. Absorbed in competition with amino acids (note – high protein meals) 90% inactivated in intestinal wall by MAO and DOPA decarboxylase 9% converted to dopamine in peripheral tissues 1% crosses BBB to enter the CNS (competes with amino acids) ``` Advantages Highly efficacious Low side effects Disadvantages Precursor, needing enzyme conversion# Long term loss of efficacy and development of involuntary movements ```

Answer 217

``` Examples Bromocriptine Ropinirole Pergolide Apomorphine ``` Route of Administration Oral Apopmorphine is always given subcutaneously Indications Used in combination with L-DOPA in an attempt to reduce it’s late adverse effects, or when it does not control symptoms Mechanism of Action Agonists for Dopamine D2 Receptors ``` Adverse Drug Reactions Similar to that of L-DOPA, but more common and more severe Nausea Hypotension Psychiatric symptoms ``` Therapeutic Notes Bromocriptine is most used

Answer 218

Examples Selegiline Route of Administration Oral Indications Used on their own in mild cases of parkinsonism Used in conjunction with L-DOPA to reduce end-dose ADRs Mechanism of Action Selegiline selectively inhibits the MAOB enzyme in the brain that is normally responsible for the breakdown of dopamine. By inhibiting breakdown, the dose of L-DOPA Adverse Drug Reactions Nausea Hypotension Psychiatric symptoms

Answer 219

Examples Entacapone Route of Administration Oral Indications Adjunct to L-DOPA therapy to reduce end-dose ADRs Contraindications Phaeochromocytoma Mechanism of Action Inhibits the enzyme COMT, which degrades dopamine Adverse Drug Reactions Nausea and Vomiting Abdominal pain Diarrhoea

Answer 220

Examples Benzatropine Procyclidine Orphenadrine Route of Administration Oral Mechanism of Action Antagonists at the muscarinic receptors that mediate striatal cholinergic excitation Main action in treatment of Parkinson’s disease is to reduce excessive striatal cholinergic activity Adverse Drug Reactions CNS effects – Mild memory loss, acute confusional states Dry mouth and blurred vision (less common) Therapeutic Notes Termination of anticholinergic treatment should be gradual, as parkinsonism can worsen when these drugs are withdrawn

Answer 221

Route of Administration Oral Indications Synergistic effect when used in conjunction with L-DOPA Mechanism of Action Stimulates neuronal dopamine release and inhibition of its reuptake Additional muscarinic blocking actions Adverse Drug Reactions Anorexia Nausea Hallucinations Therapeutic Notes Modest anti-parkinsonian effects, but it is only of short-term benefit, since most of its effectiveness is lost within 6 months

Answer 222

o An autoimmune destruction of the end-plate ACh receptors o Loss of junctional folds at the end-plate o A widening of the synaptic cleft The crisis point is when it affects respiratory muscles Presenting Symptoms: o Drooping eyelids o Fatigability and sudden falling due to reduced ACh release o Double vision o Effected by general state of health and emotion Treatment o Acetylcholinesterase inhibitors (e.g. Pyridostigmine) Prevent breakdown of Ach in synaptic cleft Can cause muscarinic side effects (parallel those effects seen with excessive release of Ach) - Miosis/SSLUDGE Syndrome o Corticosteroids Decrease immune response o Plasmapheresis Removes AchR antibodies and gives short term improvement ``` SSLUDGE Syndrome o Muscarinic side effects o Salivation o Sweating o Lacrimation o Urinary Incontinence o Diarrhoea o GI upset and hypermotility o Emesis ```

Answer 223

``` Examples Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole ``` Route of Administration Oral Indications Short term treatment of peptic ulcers Severe GORD Confirmed oesophagitis Eradication of H. Pylori (part of triple therapy) Zollinger-Ellison Syndrome (Gastrin secreting pancreatic tumour) Mechanism of Action Irreversibly inhibit Na/K-ATPase that is responsible for proton secretion from parietal cells. Adverse Drug Reactions GI upset, nausea Headaches Risk of gastric atrophy with long-term treatment Drug-Drug Interactions Omeprazole is a CYP450 enzyme inhibitor Avoid use with patients being treated with Warfarin, Phenytoin etc. Therapeutic Notes PPI action is delayed as not all pumps are active all of the time. Maximum efficacy is after 2-3 days. Restoration of stomach acid requires de novo synthesis, so after treatment stops it will take a few days for acid to return to normal

Answer 224

Examples Cimetidine Ranitidine Route of Administration Oral Indications Peptic ulcer disease and GORD Mechanism of Action Competitively antagonist H2 receptors, blocking the amplifying action of Histamine on Parietal cells ``` Adverse Drug Reactions Dizziness Fatigue Gynaecomastia Rash ``` Drug-Drug Interactions Cimetidine is a CYP450 enzyme inhibitor Avoid use with patients being treated with Warfarin, Phenytoin etc. Therapeutic Notes Given at night when acid buffering by food is at its lowest

Answer 225

Examples Ispaghula Bran Methylcellulose Route of Administration Oral Indications Constipation, particularly when hard stools are present ``` Contraindications Dysphagia Intestinal obstruction (Adhesions, ulceration) Colonic atony Faecal impaction ``` Mechanism of Action Increases the volume of the non-absorbable solid residue in the gut, distending the colon and stimulating peristaltic movement. Adverse Drug Reactions Flatulence Abdominal distension GI obstruction Therapeutic Notes A normal fluid intake is essential Clinical effects may take several days to develop

Answer 226

Examples Arachis Oil Glycerol Route of Administration Arachis Oil – Enema Glycerol – Suppository ``` Indications Constipation Faecal impaction Haemorrhoids Anal fissures ``` Contraindications Children less than 3 years old Mechanism of Action Lubricate and soften stools Therapeutic Notes Safe, but not always effective Relatively slow to take effect

Answer 227

Examples Lactulose Magnesium and Sodium Salts Movicol Route of Administration Lactulose – Oral Magnesium and Sodium Salts – Rectal Movicol – Orally with fluid (powder) Indications Constipation Lactulose - Liver failure (reduced production of ammonia) Contraindications Intestinal obstruction Mechanism of Action Increase water content of the bowel via osmosis Lactulose – Disaccharide (galactose/fructose) that cannot be hydrolysed by digestive enzymes. The fermentation of lactulose by colonic bacteria gives acetic and lactic acid. This has an osmotic effect ``` Adverse Drug Reactions Flatulence Cramps Abdominal discomfort Caution required to prevent intestinal obstruction ``` Therapeutic Notes Magnesium and Sodium act quickly and are quite severe, so should be reserved for ‘resistant’ constipation if urgent relief is required Lactulose takes 48 hours to work Movicol takes 2-4 days to get relief

Answer 228

``` Examples Anthraquinone Group Senna Danthron Bisacodyl ``` Route of Administration Oral Indications Constipation and bowel evacuation prior to medical/surgical procedures Contraindications Intestinal obstruction Mechanism of Action Increase gastrointestinal peristalsis and water and electrolyte secretion by the mucosa. Possibly by excitation of sensory enteric nerves. Adverse Drug Reactions Colonic atony (thus constipation) Hypokalaemia (Changing electrolyte balance in the gut) Therapeutic Notes Anthraquinone group is the most frequently used. Senna can be bought O.T.C. (Senokot) Abuse can be detected via Melanosis Coli (pigmentation of bowel wall)

Answer 229

Examples Fluoxetine (Prozac) Citalopram Paroxetine Route of Administration Oral (almost completely absorbed from gut) Indications Depression Mechanism of Action Act with a high specificity for potent inhibition of serotonin reuptake into nerve terminals from the synaptic cleft Only minimal effects on noradrenaline uptake Adverse Drug Reactions Common – Anorexia, nausea, diarrhoea (normally settles in 2-3 weeks) Rare – Precipitation of mania, tremor, extrapyramidal syndromes Drug-Drug Interactions MAOIs – Used in combination can cause potentially fatal serotonergic syndrome of hyperthermia and cardiovascular collapse Therapeutic Notes First line treatment for depression Citalopram is the most selective reuptake inhibitor Paroxetine is the most potent reuptake inhibitor Long elimination t½ (once daily dosage), metabolised in the liver Relatively safe in overdose if taken on their own

Answer 230

Examples Venlafaxine Duloxetine Indications Depression Contraindications Hypertensive patients, as Venlafaxine raises blood pressure ``` Mechanism of Action Inhibit the reuptake of both serotonin and noradrenaline, thus potentiating neurotransmitter activity in the CNS Dose dependent Low dose blocks Serotonin High dose blocks Noradrenaline ``` Adverse Drug Reactions Common – Anorexia, nausea, diarrhoea (normally settles in 2-3 weeks) Rare – Precipitation of mania, tremor, extrapyramidal syndromes (Similar to SSRIs, but occur with less frequency) Sleep disturbances Hypertension Dry mouth Hyponatraemia Drug-Drug Interactions MAOIs – Used in combination can cause potentially fatal serotonergic syndrome of hyperthermia and cardiovascular collapse Therapeutic Notes Second line treatment for depression Similar to TCAs, but adverse effects are reduced as Venlafaxine has little affinity for histamine or α-adrenoreceptors Relatively short t½ – may be a withdrawal syndrome on discontinuation

Answer 231

``` Examples Amitriptyline Imipramine Clomipramine Lofepramine ``` Route of Administration Oral Indications Depression Amitriptyline – Chronic, neurological pain Clomipramine – Good evidence for OCD treatment ``` Contraindications Recent MI or arrhythmias (especially heart block) Manic phase Severe liver disease Epilepsy (TCAs lower seizure threshold) ``` Mechanism of Action Block serotonin and noradrenaline reuptake. Also have affinity for H1, muscarinic and α1 and α2 receptors. Adverse Drug Reactions Noradrenergic uptake block in the heart – Arrhythmias Muscarinic blocking effects – Dry mouth, constipation α-adrenergic blocking effects – Postural hypotension H1 blocking effects – Sedation Weight gain Constipation Therapeutic Notes Lipid soluble, long t½ (once/twice daily dose), metabolised by liver

Answer 232

Examples Phenelzine Tranylcypromine Isocarboxazid Route of Administration Oral Indications Depression Mechanism of Action MAOIs block the action of monoamine oxidase, the enzyme that metabolises monoamines (noradrenaline and serotonin). There are two subtypes, MAOA and MAOB. Inhibition of MAOA gives the best antidepressant efficacy. Adverse Drug Reactions Hypertension CNS stimulation causing excitement and tremor Dry mouth, blurred vision Drug-Drug Interactions MAOIs reduce the metabolism of barbiturates, opioids and alcohol. Therapeutic Notes Response to treatment with MAOIs may be delayed for ~3 weeks.

Answer 233

Examples Olanzapine Risperidone Route of Administration Oral ``` Mechanism of Action Higher affinity for 5-HT2A receptors than Dopamine D2 Receptors Sedation – Within hours Tranquilisation – Within hours Antipsychotic – Several days or weeks ``` Adverse Drug Reactions Vary between drugs Olanzapine – Significant weight gain, suppressed “full” signals Risperidone – Increased prolactin Sedation Extrapyramidal side effects at high doses ``` Toxicity CNS depression Cardiac toxicity Risk of sudden death with high dose Prolonged QT interval -> Torsades de points Risk of sudden death with large dose ``` Therapeutic Notes Atypical antipsychotics have less extrapyramidal side effects, so are therefore more acceptable to patients First line treatment in schizophrenia

Answer 234

Dementia Medication (Note – For Alzheimer’s Disease dementia, there is no medication for vascular dementia) ``` Acetylcholinesterase Inhibitors Ach plays a role in arousal, memory, attention and mood. NICE guidance advises medication be made available for mild and moderate dementia. Treatment slows down the progression of Alzheimer’s Disease, giving you ~1 year extra at home before residential care. Examples o Donepezil o Galantamine o Rivastigmine Important Adverse Drug Reactions o Nausea, vomiting, anorexia, diarrhoea (most common) o Fatigue, insomnia, headache o Bradycardia (particularly with Polypharmacy, e.g. β-blockers) o Worsening of COPD o Gastric/Duodenal ulcers ``` ``` NMDA Antagonists Not used a lot as they are not as effective or as well tolerated as Acetylcholinesterase inhibitors, so are therefore a 2nd line treatment. Examples o Memantine Common Adverse Drug Reactions o Hypertension o Dyspnoea o Headache o Dizziness o Drowsiness ```

Answer 235

Examples Administered as Lithium Carbonate Indications Mood stabiliser (Antimanic and Antidepressant activity) Prophylaxis of Mania and Depression in bipolar disorder Augmentation of antidepressants in unipolar depression ``` Contraindications Renal impairment (renal excretion) ``` Mechanism of Action (Theories) Electrolytes and channels – May compete with Mg2+ and Ca2+ channels Neurotransmitters – Lithium increase 5HT. Chronic Lithium may reduce 5HT receptor sites Second messenger systems – Lithium attenuates the effects of neurotransmitters on their receptors, without altering receptor density ``` Adverse Drug Reactions Memory problems (learning new information) – 52% Thirst – 42% Polyuria – 38% Tremor (very fine) – 34% Drowsiness – 24% Weight gain – 18% Hair loss Rashes ``` ``` Toxic Effects Vomiting Diarrhoea Coarse tremor (progression from fine tremor) Dysarthria (difficulty speaking) Cognitive impairment Restlessness Agitation ``` Drug-Drug Reactions NSAIDs will raise Lithium plasma concentration Therapeutic Notes Good evidence for reducing suicides Drug monitoring for toxic levels in case of toxic effect Toxicity is treated with supportive measures, anticonvulsants, increased fluid intake/IV fluids, Haemodialysis may be necessary

Answer 236

There are both modifiable and non-modifiable risk factors for coronary atheroma – and by extension Ischaemic Heart Disease. Non-Modifiable Age Male Family history ``` Modifiable o Hyperlipidaemia o Smoking o Hypertension o Diabetes mellitus – Doubles IHD risk o Exercise o Obesity o Stress ```

Answer 237

Ischaemic Chest Pain Any IHD can cause chest pain that is central, retrosternal, or left sided. The pain may also radiate to the shoulders and arms, with the left side more common than the right along with the neck, jaw, epigastrium and back. It may even present with pain at these sites without chest pain. The pain is described as ‘tightening’, ‘heavy’, ‘crushing’, ‘constricting’, and ‘pressure’. Occasionally the pain is described as burning epigastric pain, particularly in inferior MI. The pain varies in intensity and duration, the onset, precipitating, aggravating and relieving factors and associated symptoms all vary and get progressively worse from stable angina  unstable angina  MI.