Clinical Pharmacology for LUSUMA Notes

This is my final set of notes. I was never planning ever to submit this document online because it’s far too long and it was too large to send by email, so I’ve had to delete most of the pictures. However due to popular demand, I caved in, and here they are. Please use my notes sensibly just reading them will not do, and as comprehensive as they may seem Leicester Medical School manages to chuck a random question in the paper. Anyway I hope, as you’ve managed to get this far in the course, and you’ve bothered to download my final set of notes, that you found them helpful. Have fun, Mark Sims

Clinical Pharmacology Session 1- Safe Prescribing 1100 deaths occur from medication errors every year. Its occurring more because: • Medical o Shift work and reduced hours

•

o

Lower exposure to teaching

o

Working alone more often

o

Less ward teaching and feedback

o

Poor morale

o

Lack of continuity of care

o

Too many students

o

Lack of pharmo training

Pharmaceutical o

Vast numbers of new drugs

o

Clinical evidence is usually with drug used in isolation in:

o



Selected relatively healthier patients



And/or young volunteers initially

Some side effects come to light only during post marketing surveillance

o •

•

Blind adherence to guidelines leads to prescription where contraindications or serious interactions exists

Population o

Increasing numbers

o

Elderly patients with many co-morbidities, multiple drugs, ↑risk of side effects

Extended prescribing o

More doctors

o

Nurse practitioners

o

Pharmacists

o

Devolvement of prescribing

Process of error Reason’s model of accident causation Person approach – aberrant mental processes ‘bad things happen to bad people’ – countermeasures centred on person e.g. Fear, retaining, litigation, naming and shaming Or System approach – errors seen as consequences, unable to change human condition, countermeasures centred on barriers and safeguards. Latent conditions – processes inherent to an organisation or factors as a result of management decisions Error-producing conditions – poor environment, lack of individual or team communication Active failures Person making error knowingly did so Slips – erroneous performance Lapse - erroneous memory Mistakes – error in planning of action ‘Swiss cheese model Successive layers of defences, barriers and safeguards DEFENSES – senior review, near-patient pharmacy checks, reviews of prescriptions, electronic systems, patient identifiers Prevention – knowledge, meticulous, the environment, formulary development, do your own work Meticulous – use your mind and not just pen, legible writing, no abbrevs, review, clarify instructions Environment – time management, prioritisations, neat and tidy, use tech GFR calcs, toxbase, eBNF

Formularies Types of formulary – traditionally as a list of compounded medicines Now means list of recommended first-line drugs for common medical conditions. – Leicestershire medicines formulary. Factors for local formularies • Efficacy (how effective is it, compared with other drugs or placebo) • Safety (major and minor effects) •

Cost, but only if efficacy and safety of two drugs are equivalent

eBNF - lists all the drugs currently licensed in the UK. Lists some drugs that were used but which now been identified as less suitable for prescribing, either because lack of efficacy or ↑toxicity Role of pharmacist in reducing prescription error Pharmacists understand pharmacology better than most medics. They occupy a pivotal position in the NHS overseeing that prescriptions are correctly made out. In some hospitals pharmacists are also able to write discharging prescriptions. However, the primary role they play in detecting prescription error does not mean they take the responsibility for what is written on the prescription. This always lies with the prescribing medic; the legal responsibility of the pharmacist is to dispense according to prescription Consequently if they suspect an error has been made in the prescription then they must refer this back to the doc. There is evidence that some junior doctors overly rely on the specialist knowledge and experience of the pharmacist as a short cut to check over errors, instead of spending time carefully consulting the BNF prior to prescription. Instead of a short cut, unprofessional reliance on the pharmacist brings additional pressure in the system. The formal recording of error and querying the Hx behind a prescription means the short cut turns into a waste of time. Moreover, this may additionally compromise patient welfare, especially if the condition needs to be treated within a short time frame. Check list for avoiding medical error Along with the active application of your skill and knowledge, the use of an appropriate formulary provides the first and most important line of defence against serious prescription error. 1. Consider the patient 2. correct chart for the patient? – do not use the wrong chart and get the right patient 3. What is your diagnosis and therapeutic aim? 4. Is it the right drug for the patient?

a. Avoid therapeutic duplication (co-codamol and paracetamol) b. Any serious interaction that could lead to failure of treatment of other unintended consequence – ANTICOUGULANTS c. Any allergy to this agent or group of drugs that is already documented for the patient e.g. tazocin does not tell you it contains a penicillin d. The drug name is spelt correctly e. NO ABBREVS f.

The form of the drug is correct for the patient. E.g. liquids for children

5. Will the patients illness affect drug distribution/elimination? 6. Are there any alternatives to your choice? 7. Is the patient on any other non-prescription medication that may interact a. Eg. Antacids and statins. St. John’s wort used as an antidepressant has documented interactions with around forty drugs and OCP 8. route of administration appropriate – oral preferred to IV where possible for antibiotics 9. Is the correct dose prescribed? Check body weight, check decimal point, write out nano, and micro not n and m 10.Is the correct freq. And timing of drug given –diuretics in the morning, some drugs once weekly 11.What is the likely duration of treatment – how long for 12.What are the most serious side effects associated with the drug 13.Is drug/therapeutic monitoring required 14.How much information/explanation does the patient need? – compliance 15.Are there any special prescribing requirements for this drug? E.g. controlled drug prescriptions require total quantity in words and figures on TTO.

Pharmacovigilance/ ADRS Pharmacovigilance is the process of identifying and then responding to safety issues about marketed drugs. Therefore the survey the safety of drugs and develop strategies to ↓risk and optimise benefits

Why? The granting of a product licence for a new drug merely means that any hazards unacceptable to the licensing authority have not been identified. It does not ensure that a medicine will be safe in subsequent prescribing practice Frequency of adverse events: • Very common > 1 in 10 • common 1 in 100 •

Uncommon/less commonly 1 in 1000

•

Rare - 1 in 10000

•

Very rare 1 week. Therefore •

Needs loading doses to achieve a rapid therapeutic effect

•

Maintenance doses need reducing if renal failure leads to reduced clearance

•

Loading dose can remain much the same in renal failure unless renal failure is very severe.

Loading dose = Vd X [drug]target First order elimination the clinical effectiveness of the drug (after it is stopped) will depend on the therapeutic window and the minimal effective plasma drug concentration

Pharmacodynamics, Drug interaction and Toxicology Part of pharmacology that explores the effects of drugs and their mechanism of action on the body. Essentially the study of what drugs do to the body. Drugs exert their effects, either by physicochemical effects e.g. Antacids or interaction with enzymes, transport systems, second messengers, hormone or ion channels Drug receptor theory: • Agonists and antagonists • Partial agonists/antagonists •

Competitive antagonism and non-competitive antagonism

•

Specificity and selectivity

Partial signal An ideal drug would mimic the action of the endogenous controlling molecule. Real drugs act at more than one binding site. Specificity relates to complementary drug and receptors Selectivity relates to clinical effect of drug and can be measured with specific therapeutic index. Affinity defines the tendency of a drug to bind to a specific receptor type. Use notation Kd for agonist and Ki for antagonist

Kd and Ki values are the concentration at which half the available receptors are bound. Concentration and response Drug response is generally proportional to number of receptor sites bound by the drug. Target receptors can exist at different tissues throughout the body. Drug response curve Effectmax is the maximum response of the system to the drug EC50 is the concentration of the drug that brings on half of the maximum response of the drug Concentration on a logarithmic scale to ease calculation of EC 50 Potency is a measure of the amount of drug required to produce an effect of a given intensity Efficacy is a measure of the maximum effect of a drug or treatment regardless of dosage Drug A and B are more effective than drug C, Drug A is more potent than drug B. Therapeutic index is the relationship between concentrations causing adverse effects and concentrations causing desirable effects. Therapeutic index = EC50 (adverse effect)/EC5- (desired effect) Therapeutic window is the range of dosages that can effectively treat a condition while still remaining safe. It is the range between the lowest dose that has a positive effect, and the highest dose before the negative effects outweigh the positive effects. Narrow windows: digoxin, warfarin Drug-drug interaction –PD Interactions either enhance or reduce therapeutic outcome through actions on the receptors Drug interactions can occur via different receptors or different tissues Agonism/Antagonism at same R e.g. opiate analgesics and naloxone. βblockers and β2 agonist Agonism/antagonism at different R. – warfarin and aspirin Non-selective nature of drug e.g. antidepressants interact with many receptor subtypes

Drugs can be enhanced by other means e.g. digoxin toxicity enhanced by hypoK caused by a loopy D The same drugs account for the common significant drug-drug interactions time after time: • •

Anticonvulsants Anticoagulants

•

Antidepressants

•

Antibiotics

•

Antiarrhythmics

•

Infected depressed epileptic (with) AF [AF Rx both anticoagulants and antiarrhythmics] IDEA

QTc interval prolongation – drugs may prolong the QT interval and cause ‘torsade des pointes’: genetic and acquired forms; ion channel and sympathetic abnormalities; QTc lengthened by many antiarrhythmics; other drugs also prolong QT. Any drug that impairs metabolism of QTc prolonging drug may cause Long QT syndrome. Renal disease – falling GFR – ↓CL of renally excreted drugs and disturbances of electrolytes may predispose to toxicity. Nephrotoxins will further damage kidney Hepatic disease – ↓CL of hepatic metabolised drugs, ↓CYP 450 activity, long T1/2, toxicity, classic – opiates in cirrhosis. Cardiac disease – low CO will lead to: excessive response to hypotensive agents. ↓organ perfusion – ↓hepatic blood flow and CL, reduced renal blood flow and clearance Drug-food interaction – grapefruit juice inhibits several cYP450 isoenzymes affects CL. May lead to ↑exposures to drug of up to 16 fold Cranberry juice used to treat UTI, inhibits bacterial adherence to urothelium. Inhibits CYP2C9 isoform, ↓warfarin CL. Enhanced anticoagulant effect risk of haemorrhage. Drug monitoring – other changes likely to affect levels – prescription changes bad renal/hepatic function Or drug itself e.g. phenytoin due to low therapeutic index OR surrogate markers of effect/ADRS

CYPS and drug response

Several polymorphisms that affect genes encoding cytochrome P450 have been described The CYP 2D6 isoform is responsible for the metabolism of 25% of drugs (including antidepressants, antipsychotics, β-blockers, opioids), variability in the rate of metabolism between people is > 100-fold. 6% of the Caucasian population carrying two null alleles at the CYP 2D6 gene locus 19. There are >70 variant alleles of the CYP 2D6 locus. Other variants that ↓activity, alter substrate specificity or ↑activity have also been described. Absent or reduced CYP 2D6 activity can lead to ADRs by the following mechanisms: 1. ↓FPM and drug elimination 2. Accumulation of the drug as a result of reduced metabolism 3. Re-routing of metabolism Not a straight forwarded test for CYP 2D6 activity, random DNA testing has ethical issues too In the future patients may be screened for how effective the drug will be for them and their likelihood or a ADR. Types of ADR Type A dose dependent: • ‘On target’ ADR– are due to an exaggerated therapeutic effect of the drug most likely due to ↑dosing or factors affecting drug PK (e.g. ↓ GFR) and PD (e.g. inhibit cytochrome P450) • ‘Off target’ ADR – virtually all drugs will interact with other receptor type secondarily to the one intended for therapeutic effect. They can also occur with metabolites that subsequently act as a toxin e.g. paracetamol in overdose. Type B (20% of ADRs) – Idiosyncratic responses ADRs are due to unique individual disposition. Inappropriate immune responses also form another category of ‘off target’ ADRs. However much less predictable. Hospital patients are often on a cocktail of six or more drugs, which takes the overall chance of an ADR to 80%! HLA associated histocompatibility complexes these provide a wide range of ADR associated targets. Example is carbamazepine hypersensitivity causing idiosyncratic severe blistering and rash.

Pharmacogenetics Pharmacogenetics is the science of understanding how different individual genotypes relate to different drug. This enables physicians to know which drugs will therefore be safe and effective for an individual patient Pharmacogenomics is pharmacogenetics applied to the entire genome.

Some drugs aren’t effective for some people and more toxic to others. 6-7% patients have ADRs not all due to genetics but some. 30% of patients do not respond to statins. An everyday example – blacks/whites given Lisinopril. ACE i less effective in blacks. An individual’s response to ACEi/ARB is dependent on their own RAS activity. Young whites have higher RAS activity – therefore ACE i/ARB treatment will lower the BP more effectively. Older and blacks have lower RAS activity – first line therapy includes Thiazide diuretics/CCB. But genetic variation in races. Blacks more likely to get angioedema from ACEi/ARB. Genetic polymorphisms can affect PK and PD. Toxicity can occur due to someone having impaired metabolism (e.g. different CYP enzyme), and impaired efficacy can occur if the person say has an abnormal receptor. Haemolytic anaemia: in RBCs, glucose-6-phosphate dehydrogenase (G6DP) deficit results in loss of protection against oxidative damage. Sulphonamides and antimalarials can induce RBC oxidative stress resulting in severe idiosyncratic haemolytic anaemia. 10% of blacks have glucose-6phosphate dehydrogenase deficiency and will get severe haemolytic anaemia when they receive one of the drugs. Hepatic porphyria due to deficiency in haem synthesis capability – hepatic porphyrias are proteolytic rare pharmacogenetic disorders. Well intended use of sedatives, antipsychotics or analgesics in patients with undiagnosed hepatic propria can be lethal, however with appropriate support management most recover completely. These disorders are characterised by ↓of one of the enzymes required for haem synthesis, with the result that porphyrin containing haem precursors accumulate, causes rash, GI disturbance, behavioural disorders. Inducers of CYP450 can precipitate acute attacks in susceptible individuals. Conditions: sleeping disorders, hypothyroidism, schizophrenia The future – test Px for markers of disease, and the ability to detect how a Px will respond to a drug.

Session 3- The Gonadal Steroids and Inhibitors Sex steroids: oestrogen, progesterone’s and androgens All derived from cholesterol Oestrogens: • Actions – mild anabolic, Na and H2O retention, ↑HDL, ↓LDL, ↓bone reabsorption, impair glucose tolerance, ↑blood coagulability, improve mood and concentration, ↓Alzheimer’s,

•

SE– breast tenderness, nausea, vomiting, water retention, ↑coagulability, thromboembolism, ↓glucose tolerance, endometrial hyperplasia and cancer

Progesterones • Actions – secretory endometrium, anabolic, ↑bone mineral density, fluid retention, mood changes • SE – weight ↑, fluid retention, anabolic, acne, nausea, vomiting, irritability, depression, PMS, lack of concentration Testosterone • Actions/SE – male secondary sex characteristics, anabolic, acne, voice changes, aggression, metabolic adverse effects on lipids. Routes of administration • Oral o O – synthetic derivatives: ethinyloestradial, methoxy derivative, valerate o P – synthetic derivatives  o •

P derivatives: medroxyprogesterone, dihydrogesterone

Testosterone derivatives: norethisterone, norgestrel, ethynodiol

OTHER: Transdermal, Implants, Nasal and Vaginal

Transport of steroid – Transport bound to SHBG (except P) and albumin. Liver metabolism, P almost totally metabolised in one passage through liver. Metabolites excreted in urine (as glucuronides and sulphates) COCP – oestrogens high/low dose: 50, 35, 30, 20mg/day combined with a 1 st-4th generation progesterone. Regime: either monophasic – 21, triphasic (varied doses across cycle) – 21, or every day = 21 +7 placebo. Mode of action – suppression of ovulation inhibit FSH, LH • Adverse effect on cervical mucous • Adverse effect on the endometrium

Adverse effects: • Venous thromboembolism • MI, HTN – in small % in women) •

↓glucose tolerance

•

↑risk of stroke in women with focal migraine

•

Headaches

•

Mood swings

•

Cholestatic jaundice

•

↑incidence of gallstones

Serious ADRs are rare e.g. thromboembolism in 2 nd gen pills: 1.5/1000 users vs 1/1,000 in non-pregnant control vs 6/1000 pregnant non-users per year. Drug interactions – they undergo metabolism by both phase 1 and 2 hepatic pathways and are affected by CYP inducers including rifampicin, carbamazepine and St John’s wort. Use of broad-spectrum antibiotics can result in ↓efficacy due to effects on intestinal flora. These play a part in enterohepatic recycling as they ↓so does the amount of drug re-entering the systemic circulation. Risk of CV event higher in smokers Monitoring of BP and enquiry about other ADRs should continue over the period of prescription The POP 28 days of P, it primarily acts to thicken cervical mucus, secondarily hindering ovulation and endometrial implantation. Efficacy is about 96-98% and is usually offered to women for whom the COCP is contraindicated. A number of P implants (IM, SC or IUD) provide long term contraception. Causes: poor cycle control

Postmenopausal HRT HRT to control symptoms of menopause e.g. hot flushes/sweats  Can ↓osteoporosis, ↓ mood changes may have a negative effect on CVS. There are issues with long term use of single or combined HRT as clinical trial evidence points to ↑risk of ADR. Currently it is proposed to treat these symptoms with lower dose of HRT for shortest time. Steroids in HRT – oestradial 1-2mg/day premarin 0.625-1.25 mg/day with/without Medroxyprogesterone acetate, tibolene (O, P some T mix) Combined HRT either: continuous same dose or only O for 14 days then O, P for 12-14 Base line tests – LH, FSH, GnRH, P, O sonogram. Monitoring – hormone levels, breast cancer screening, possible hysterectomy Risks of HRT • Unopposed O: ↑endometrial cancer, and ovarian cancer •

↑breast Ca

•

↑IHD, and stroke

•

↑risk of venous thromboembolism

•

Uterine bleeding

•

Adverse effect on lipid profile

•

Adverse effect on thrombophilia profile

Administration: oral, transdermal, implant, transvaginal, nasal.

Anti- progestogens •

Partial agonist to P receptor, inhibits P action

•

Sensitises the uterus to prostaglandins

•

Used for medical termination of pregnancy, and induction of labour. ‘

•

E.g. mifepristone

Anti – androgen Cyproterone: progesterone derivative •

Weak progestogenic effect. Partial agonist to P receptor competes with dihydrotestosterone used in COCP.

Selective Oestrogen Receptor Modulators Raloxifene: protects against osteoporosis, no proliferative effects on endometrium, no proliferative affect on breast, ↑hot flushes This group of drugs exhibit mixed agonist/antagonist properties on the PD of which are tissue dependent. The specific action is dependent on: tissue specific expression of the nuclease O receptors: the genes associated with these receptors; presence of transcription co-factors. Weak oestrogens that block receptors: • Clomiphene – ovulation induction, inhibit O binding to ant pituitary, in negative feedback, results in ↑GnRH and FSH, LH • Tamoxifen – Rx of Breast ca and ovulation induction. ADR proliferation of endometrium

Corticosteroids: Corticosteroids are from the adrenal cortex, widespread metabolic effects, and important role in maintaining life. Negative feedback control system via the hypothalamic-pituitary-adrenal axis.

GFR = MGA (mineralocorticoids, glucocorticoids and androgens) Adrenal steroids- based on cholesterol molecule: mineralocorticoids, glucocorticoids, sex steroids Steroid hormone action – intracellular receptors form complexes which enter nucleus and alter DNA transcription. Different to peptide hormones (Cell surface receptors) Mechanism of GC action – GC receptors are intracellular, GC-receptor complexes bind to DNA, glucocorticoid response element  gene regulation – fundamental change in physiology Mineralcorticoid action – fluid retention, HT, hypokalaemia Aldosterone acts – promotes active Na and Cl reabsorption and secretion of K and H in DCT and CD. Receptor bound aldosterone ↑transcription of ENaC results in ↑extrusion of Na from cells into interstitium and secretion of K, H into lumen. Also more ATP and ↑expression of Na/K pump MC deficiency – hyponatraemia, hyperK and hypotension MC excess – hypernatraemia, hypoK and HT (conn’s tumour)

Glucocorticoid action The broad and systemic effects of glucocorticoids on intermediary metabolism are manifest as ↑in nutrient availability, ↑blood [glucose],[ AA], and TGA levels. In response to stress, this ensures critical organs receive adequate substrate supply. Effects of excess glucocorticoids however, ↑in AA levels are bought at the expense of protein synthesis, which can lead to fast twitch muscle wastage over time/ They can also lead to negative Ca balance, affecting absorption in the GI. Over time they can reduce bone resorption, affecting skeletal integrity and significantly ↑risk of fracture in the elderly and retarding linear bone growth in kids. Prolonged elevation of corticoid levels and the tendency to hyperG can lead to DM in susceptible individuals. Effects on the CNS are reported ranging from euphoria to psychosis in some people. • ↑glucose production

•

•

o

↑glycogen breakdown in liver

o

↑hepatic gluconeogenesis

o

↓glucose uptake by peripheral tissues

↑protein breakdown o

Protein breakdown to AA

o

Catabolic effect

o

Particularly proximal muscles.

Direct activation of lipolysis and redistribution of fat deposition. Central obesity and dorso-cervical fat pad.

•

Inhibition of B and T cell responses

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↓transcription of cytokines

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↓cell adhesion by leucocytes

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↓phagocytic function

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Immune suppression

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Inhibition of osteoblast formation

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↑osteoclast proliferation

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↓Ca absorption in gut

Endogenous GCs can also act as anti-inflammatory and immunosuppressant drugs. It is these properties that are therapeutically exploited through deliberate amplification of these effects in exogenous steroids. Widely used in many inflammatory disease and immunosuppression. Also used to replace in adrenal insufficiency and malignancy. Relative CG and MC action:

Drug

GC

MC

Reason for use:

Hydrocortisone

1

1

Corticosteroid replacement

Prednisolone

4

0.8

Inflammatory Disease

Dexamethason e

25

0

Tumour/oedema

Betamethason e

25

0

Eczema topical treatment

Fludrocortisone

10

125

Aldosterone replacement

Pharmacokinetics – Oral steroids, similar rates of absorption and similar bioavailability. T1/2 8-72 hours. Endogenous corticosteroids are about 90% bound in plasma; however synthetic ones vary in their degree of plasma binding. After crossing the cell membrane, they first bind with intracellular receptors. The hormone receptor complex forms a dimer with another HR complex. The dimer than translocates to the nucleus where it binds with a glucocorticoid response element. The bound form of the GRE then modulates transcription of the associated genes. This has profound effects on mRNA expression, as it appears at least 1% of nuclear genes can be regulated by the above pathways. Therapeutic effects of changes in gene expression may only be apparent some hours after administration. Inhaled steroids – 80% swallowed, lipophilic compounds retained longer in lungs. Hepatic and renal CL: CL ↓with age and ↑ hyperthyroidism. Small amounts excreted in breast milk. •

Intravenous – IV methylprednisolone

•

Oral - oral prednisolone; oral dexamethasone, oral hydrocortisone, oral fudrocortisone

•

Inhaled – inhaled beclomethasone, inhaled fluticasone (high 1 st pass metabolism)

•

Topical - Flexor > forehead > scalp > face > forearm – topical betamethasone

•

Intra-articular – intra-articular triamcinolone, intra-articular depo-medrone

With ↑systemic dosing PKs become no-linear, as plasma GC binding sites become saturated with resultant ↑in unbound plasma levels. Summary of clinical use – adrenal insufficiency, Inflammatory disease, immune-suppression, malignancy, diagnosis of Cushing’s Adrenal insufficiency – primary adrenal failure, Rx – hydrocortisone/fludrocortisone. Mimic normal physiology.

Inflammatory disease – vasculitis, sarcoidosis, RA, asthma, GI disease (crohn’s UC), inflammatory skin conditions, nephritic syndrome, haematological conditions, cerebral oedema Immuno-suppression – acute transplant rejection, acute leukaemia, pemphigus, exfoliative dermatitis Malignancy – hypocalcaemia, improve appetite, malignancy oedema (inhibit cytotoxic cytokines) Diagnosis of Cushing’s Syndrome – Dexamethasone suppression test, 2 days dexamethasone, measure cortisol levels before and after, normal individuals suppress < 50nmol/l). Failure to suppress in Cushing’s syndrome. Dexamethasone negatively feedbacks on hypothalamus and pituitary so no CRH and ACTH should be made respectively and thus cortisol.

SE of Steroids •

•

Mineralocorticoid effects o

Effects on MC receptor

o

Fluid retention – HT

o

Hypokalaemia

Glucocorticoid effects

Glucocorticoid effects o Diabetes o Impaired growth o

Skin Atrophy

o

Cataracts

o

Corneal damage

o

Osteoporosis

o

Avascular necrosis

o

Peptic Ulcers reduced arachidonic acid production

o

↑infections

o

HT

Adrenal suppression – Exogenous steroids all act on the HPA axis like cortisol, so CRH, ACTH and cortisol release all reduced. This occurs after 3 weeks. A dose of prednisolone > 20mg will suppress HPA axis and may persist for years if long term treatment. Abrupt withdrawal may lead to a hypo-adrenal crisis. Hypoadrenal crisis – hypotension, hypoglycaemia, hypokalaemia, severe dehydration,  DEATH Treatment – give fluid, glucose, steroids Subtle effects – fever, myalgia, arthralgia, weight loss, conjunctivitis, rhinitis Patients on long term steroid cannot mount an endogenous stress response  risk of peri-operative hypoadrenal crisis. Inform anaesthetist and surgical seniors early.

Laparotomy or major procedure – hydrocortisone 100mg IM at induction. Hydrocortisone 100 mg IM 6 hourly until eating and drinking. Double normal oral steroids until full recovery Less invasive surgery – HC 100mg at time of procedure, double normal oral dose until full recovery Intercurrent illness – double oral dose, IM injection if diarrhoea or vomiting, may need admission

Drug interactions Patients on steroids often on numerous medications enzyme inducers (phenytoin, primidone and rifampicin) may ↓steroid effects. Enzyme inhibitors (OCP) may ↑effects ‘Steroid sparing agents’ reduce steroid requirement, Azathioprine, cyclophosphamide, biological therapies, important for reducing steroid side effects. Can cause peptic ulcer, diabetes mellitus?, intercurrent infection

Guidelines for use Should be published evidence that steroids help the condition you are treating. Steroids are beneficial in asthma, this is less clear-cut in COPD. No beneficial effect on exacerbation rate. NICE – inhaled steroids indicated in COPD if low peak flow and more than two exacerbations per year otherwise risks of steroids outweigh benefits. Generally Have a specific Rx objective. Use only if other Rx fail. Administer for a sufficient time to allow response and do not administer for longer than necessary. Stop steroids if no response when expected or maximum benefit achieved. Stop if complications occur that are worse than the disease. Consider agents to prevent osteoporosis. Use of objective measure of response where possible (peak flow, ALT, CRP) Abrupt cessation of GCS due to SE or other reasons is not normally undertaken due to the risk of adrenal insufficiency. Even short term (> 3 weeks) Rx with greater than 20mg of prednisolone can lead to suppression of the HPA axis. Gradual tapering of doses allows reactivation of the HPA and return to its normal function. Failure to do this can lead to chronic adrenal atrophy, which can be fatal. Advice to patients – don’t top immediately, glucose/HTN will need to be monitored, need to carry a steroid card and to tell HCW’s they are on steroids if needed, go and see GP if any ADRs

Session 4 Diabetes mellitus – insulin, other hypoglycaemia agents and obesity drugs Elevated glucose leads to acute symptoms – polyuria, polydipsia and weight loss Chronically elevated glucose leads to complications Microvascular – renal, retinal, neurological Macrovascular – cerebrovascular, cardiovascular and peripheral vascular In a normal person, the rate of insulin production is continuous and very fine, governed by the ATP/ADP ratio in the β-cells. This in turn directly reflects the variations in blood glucose. Allied with a very short t1/ of endogenous insulin of 10 minutes, normal homeostatic control of glucose is very efficient. Type 1 - characterised by ketonuria  absence of insulin Type 2 – endogenous insulin does not work to control sugar adequately – insulin resistance and relative insulin deficiency. Insulin levels can be very high. Type II typically presents in those above 40 with obesity. Can go undiagnosed for years as it is a gradual disease. Insulin’s actions: • Fuel metabolism o

o

Glucose- action about which we are concerned 

Inhibits liver glycogen breakdown



↑uptake of glucose by liver



↑uptake by muscle and adipose tissue

Free fatty acids 

o

Insulin promotes clearance of free fatty acids

Amino acids 

Active transport of AA into cells



Inhibits catabolism of proteins



Inhibits gluconeogenesis in liver

Diabetes is a state of premature CV death associated with hyperglycaemia Management – glycaemia control – aim to achieve HbA1c target (7% exponentially causes vascular complications

o

Detect damage to renal, hepatic, cardiovascular and neurological function.

Human insulin is made up of 2 polypeptide chains linked by 2 disulphide bridges Fast acting native insulin – actrapid, humulin S Fast acting analogues – novorapid, humalog Intermediate – acting native insulin – insulatard, humulin I Intermediate/long acting analogues – levemir, glargine Insulin Type

Onset

Peak

Duratio n

Usage

Ultra rapid

0.20.5

1

3-4

Meals/acute hyperG

Short acting

0.5-1

2-5

6-12

Intermediate

1.5-3

4-10

16-24

Long acting

4-6

8-30

18-36

Basal insulin/ overnight control

•

Pre-mixed insulin regimen o

•

Humalog mix 25, novomix 30, mixtard 30 – taken twice a day with or before meals, lacks flexibility but only twice a day

Basal bolus regimen – intermediate or long acting insulin as background, fast acting insulin with meals, flexible but up to 5 times a day

Type 2 diabetes • Diet and exercise – around 90% are overweight/obese • Anti obesity drugs •

Oral hypoglycaemia drugs

•

Newer agents

•

Insulin is needed in the end if the patient lives long enough as type 2 is a progressive disease

Benefits of 10% weight loss Mortality

>20% ↓in total mortality >30% ↓in diabetes related deaths >40% ↓in obesity related deaths

Blood pressure

↓of 10mmHg/20mmHg systolic/diastolic

Diabetes

50% ↓in FBS 15% ↓in HbA1c (60% reduction in progression to diabetes)

Lipids

10% ↓total cholesterol 15% ↓in LDL

30% ↓in triglycerides 8% ↑in HDL Diet •

Reduced energy intake in overweight

•

Carbohydrate (>55%), Fat ( 60% Asia 2003-04, >90% US 2005-6

They use gene sequencing of protein, X-ray crystallography of Nuclear magnetic resonance to try and work out the structure of target sites for drugs and to evaluate them. Neuraminidase is essential for replication. Surface of influenza highly variable. Active site is conserved across subtypes. The existence of an unchanging molecular structure present in nature suggests a site that is essential to survival. Subsequent research demonstrates that this pocket is indeed the active site through which neuraminidase cleaves sialic acid (membrane glycoprotein residues on the cell membrane. Without this, the virus cannot break the cellular bond and is unable to spread. Ideal target for antivirals • Human and non-human influenza A • Influenza B •

M2 resistant viruses

•

Avian strains including H5N1

•

Reconstructed 1918 pandemic H1N1

Neuraminidase inhibitors (sialic acid derivatives) stop the cleaving of viruses effectively stop viral replication. The selectivity donates their lack of activity against human neuraminidase.

Zanamavir – low bioavailability, dry powder aerosol, remains detectable in sputum up to 24 hours post dosing and is renally excreted Oseltamivir (tamiflu) – prodrug, 80% bioavailability Tamiflu if treatment commenced within 24hr of symptom onset it ↓the duration of the illness by 36%, and if given within 36hr the duration is 25%. Also ↓in severity of illness in influenza-infected patients. Is effective given up to 48hr after symptom onset. Even if the patient receives tamiflu after As seasonal prophylaxis – there is a 76% reduction in the number of patients with flu as compared with placebo 70% reduction in risk of mortality even 64 hours after symptom onset. 48 hours there chance of surviving is ↑. Little benefit after this time. Prophylaxis treatment for six weeks with 75mg significantly ↓incidence of flu in both healthy adults and frail elderly subjects. ADRs of both – generally not serious – GI disturbance, headache, nose bleed, rarely resp depression bronchospasm. Well tolerated in children. There is oseltamivir resistance in H5N1. Surveillance for resistance: • Influenza WHO system • Neuraminidase inhibitor susceptibility network •

National and European surveillance

•

Detailed evaluation of post treatment isolates.

Viruses tend to stay Zanamavir sensitive. This is because mutations around the active site does not affect binding it is smaller so more easily fits into the active site. Oseltamivir has a longer stalk. Tight fit into a pocket of active site. N1 has a smaller pocket than N2. Mutations around the site close it, oseltamivir no longer fits. The neuraminidase enzyme also appears to be evolutionary conservative, which is a great advantage for any antimicrobial therapeutic. So far very little resistance in swine flu H1N1

Session 6 – Pharmacology of Airway Control Asthma is a heterogeneous disease characterised by smooth muscle dysfunction (↑ contraction↑ cytokines/chemokines) , airway remodelling (mucus hypersecretion, subepithelial fibrosis, epithelium desquamation, airway wall thickening) and lastly inflammation (T cells and mast cells) There are a symptom patterns and triggers of exacerbations. Bronchoconstriction leads to increased lower airway resistance. Normally about 40-50% of flow resistance is in the URT where no gaseous exchange takes place.

The remainder of resistance is provided by the trachea and down to the 7 th generation bronchi. Bronchial hyperresponsiveness – a factor contributing to airway dysfunction. Defined as an exaggerator 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 and indirect activation of airway mast cells. Mast cell mediators then induce bronchoconstriction. Asthma attack: • Immediate phase in allergic asthma, is due to interaction with mast cell fixed IgE. This results in the release of histamine and a host of potent spasmogens leading the immediate bronchospasm • Late phase – Co-release of a range of mediators and chemotaxins activate a complex immune system response that bring leucocytes to the area  this causes exacerbated bronchospasm and congestion due to epithelial damage, thickening of the BM, oedema and mucus production. Additionally, the epithelial damage leads to ↑exposure of the sensory irritant receptors, which further exacerbates bronchial hyperactivity and sensitivity. While this dual response to allergen challenge is relevant to symptoms in some atopic individuals, the Pathophysiology of ongoing dayto-day symptoms and asthma exacerbations is undoubtedly much more complex and the mechanisms are poorly defined. Burden • High prevalence rate (10% in 13-14 yr olds) • 5.1 million : 0.5 who are refractory to therapy •

74,000 emergency hospital admissions/yr

•

1500 deaths

Asthma control means: • Minimal symptoms during day and night • Minimal need for reliever medication •

No exacerbations

•

No limitation of physical activity

•

Normal lung function (FEV1 and PEF > 80% predicted)

Aim for early control, with stepping up or down as required. Before initiating a new drug therapy check compliance with existing therapies and inhaler technique and attempt to eliminate trigger facts.

Step 1 – mild intermittent asthma Short-acting β2-agonists such as salbutamol or terbutaline. Uses: • •

Symptom relief through reversal of bronchoconstriction. Prevention of bronchoconstriction i.e. before exercise

•

Used on an as-required basis

•

If used regularly, they reduce asthma control.

•

Also cause reduced histamine release and increased mucociliary clearance

Its action is predominantly on airway smooth muscle, and potentially inhibits mast cell degranulation if only used intermittently. On regular use of β2-agonists, mast cell degranulation in response to allergen ↑.

•

STEP 1 β2 - Agonist binds at Receptor the β2 - adrenoreceptor (Gs GPCR).

•

STEP 2 Intermediate signalling via Gs a -sub unit to ↑cAMP production via adenyl cyclase

•

STEP 3 ↑cAMP production results in ↑activation of Protein Kinase A

•

STEP 4 Protein Kinase A directly ↓Ca binding by myosin in SM therefore inducing relaxation

•

β2 – Agonists binding will lead to ↑K+ efflux (Calcium activated) augmenting the relaxation.

SE of β2- agonists – adrenergic i.e. tachycardia, palpitations, tremor etc even though B2 agonists are very selective (?approx. 200-40 of B1) they can still agonist cardiac B1 receptors sufficiently to induce tachycardia and dysrhythmias. The most notable negative interaction is with β blockers which bind to both β1

and β2. This can lead to severe asthma refractive to any treatment with β2 agonists. Step 2 – Regular preventer therapy Inhaled corticosteroids – ↓mucosal oedema,↓ bronchoconstriction and↓ mucus plugging. Also ↓inflammation and stop airway remodelling so ↓bronchial hyperresponsiveness They improve symptoms  improve lung function  ↓exacerbations  prevent death

Lipophilic substituent’s on D-ring lead to combination of 3 key properties (they are added to the steroid. ) • A very high affinity for the GCS receptor •

↑uptake and dwell time in tissue on local application

•

Rapid inactivation by hepatic biotransformation following systemic absorption.

Patients with eosinophilic asthma have a better treatment response to inhaled steroids than non-eosinophilic patients. Additionally, they act to ↑the expression of β2-receptors and anti-inflammatory interleukin proteins. Optimal effects are seen after weeks/months of therapy. Some of the drug is swallowed and absorbed in the gut and some is absorbed from the lungs into the systemic circulation. From the gut it enters the liver which most of it is inactivated in FPM Systemic absorption of ICS – beclomethasone absorbed through gut and lungs, budesonide and fluticasone undergo extensive FPM. Lung absorption is still relevant and at high doses all ICS have the potential to produce systemic SE.

STEP 3- Add on therapy Re-check patient’s medication compliance and inhaler technique and eliminate risk factors. Typical indication of moving up to step 3 is if the patient still wakes up a night due to asthma. First choice – long-acting β2 – agonists such as (formoterol, salmeterol) Formoterol

Salmeterol

Usual dosage

12μg

50μg

Onset of action

1-3 min

10-20

Duration of action

12hr

12hr

Intrinsic B2-agonist activity

0.85

0.71

Molecular properties

Moderately lipophilic

Highly lipophilic

The lipophilic characteristic means they sit in the membrane. Formoterol is 5 times more potent than salmeterol and 400 times more than terbutaline Salmeterol is a partial agonist and can only achieve 40% of maximal relaxation. Salmeterol is less efficient at activating the receptor. Therefore: LABA • Reduce asthma exacerbations • Improve symptoms •

Improve lung function

•

Not anti-inflammatory on their own, and must always be prescribed in conjunction with an inhaled steroid.

Combined inhalers: • Budesonide/formoterol (symbicort) •

Fluticasone/formoterol (seretide)

•

Beclomethasone/formoterol (fostair)

Why? – Easier to use, greater compliance, only 1 prescription, potentially cheaper than 2 inhalers, safety as patient can’t take LABA on their own. Shown combinations ↓freq of severe exacerbations Step • • •

4 High dose ICS Leukotriene receptor antagonist Theophylline (methylxanthines)

LRA’s LTC4 released by mast cells and eosinophils can induce bronchoconstriction, mucus secretion and mucosal oedema and promote inflammatory cell recruitment. LRAs block the effect of cysteinyl leukotrienes in the airways at the CysLT1 receptor. Some anti-asthma activity but only useful in about 15% patients as off-on therapy. It’s not a wonder drug. Side effects: angioedema, dry mouth, anaphylaxis, arthralgia, fever, GI disturbances. All rare Administration - orally Methylxanthines 1. Antagonise adenoside receptors 2. Inhibit phosphodiesterase – so ↑cAMP – unlikely to be relevant in vivo 3. As with LTRAs, often poorly efficacious 4. Narrow therapeutic window 5. Frequent side-effects – nausea, headache, agitation tachycardia. 6. Potentially life-threatening toxic complications – arrhythmias, fits 7. Important drug interactions – levels ↑by cytochrome P450 inhibitors e.g. erythromycin, ciprofloxacin. 8. Can be used in COPD and status asthmaticus. They are administered orally. Step 5 • Oral steroids – (side effects)/ IV hydrocortisone • Step 5+ anti-IgE therapy – strict criteria for use, very expensive, potentially reduces exacerbation rates in patients not controlled on oral steroids (however many patients don’t get any effect from it) Asthma is a variable disease – many factors that contribute to the development and persistence of asthma also lead to variability. This variability is often beyond the control of either the patient or physician. The variable nature of asthma means that most patients experience periods of good control and periods of worsening symptoms. Bronchial hyperresponsiveness is a characteristic feature of asthma and leads to episodes of coughing, wheezing, chest tightness and breathing difficulties. Asthma exacerbations can be triggered by various stimuli including allergens, infections, environmental factors and exercise. During exacerbations, patients tend to use their reliever medication to control their symptoms without also ↑their anti-inflammatory medication as they should. Changes to the controlled medication dose are usually only made if asthma worsening persists long enough for the patient to make a visit to the physician.

However, without additional controller therapy, inflammation may ↑– leading to airway obstruction that, in turn, may lead to the patient to be hospitalised or seek ER treatment, which often involves a course of oral steroids. Stepping down – once asthma is controlled stepping down is recommended. This stops patients receiving higher doses than necessary. Should aim for lowest possible dose of inhaled steroid. Self-management plans – every asthmatic should have a self-management plan with written instructions on when and how to step-up and step down treatment. This leads to better outcomes in terms of day-to-day control, frequency and severity of exacerbations. Drug delivery via inhaler: • 10 μ particles – deposited in the mouth and oropharynx • 1-5 μ particles- most effective as they settle in small airways •

0.5 μ – too small inhaled to alveoli and exhaled without being deposited in the lungs.

Inhaler devices – if a patient is unable to use a device satisfactorily an alternative should be found. The patient should have their ability to use the inhaler device assessed by a competent HCP. The medication needs to be titrated against clinical response to ensure optimum efficacy. Re-assess inhaler technique Severe + any of the below = life as part of a structured clinical review. threatening attack • PEF < 33% Acute severe asthma in adults • SpO2 < 92 Severe 1. Unable to complete sentences • PaO2 < 8 kpa 2. Pulse > 110 beats • PaCO2 > 4.5 kpa 3. Respiration > 25/min • Silent chest 4. Peak flow 33-50% of best or predicted • Cyanosis Near fatal CO2 > 6 kPa Treatment of acute severe asthma 1. Oxygen, high flow 2. Nebulised salbutamol – continuous if necessary O 2 driven 3. Oral prednisolone – 20mg daily for 10-14 days 4. If not responding add nebulised ipratropium bromide 5. Consider I.V MgS 1.2 – 2 g over 20min 6. Consider IV aminophylline if no improvement and life threatening features not responding to above treatment

Anticholinergic – ipratropium bromide – a quaternary anticholinergic agent. Bronchodilation develops more slowly and less intense than adrenergic agonists (acts on M3). Response may last up to 6 hours. Useful add-on in acute severe asthma not responding to high dose β2- agonist. Drug is not well absorbed across the lung, avoiding many systemic side effects. Used in COPD where the major bronchoconstrictive component is mediated via cholinergic innervation.

Immunosuppression and disease-modifying therapy – Rheumatology Rheumatology - inflammatory arthritis, SLE and systemic vasculitis RA is an autoimmune multi-system disease with a UK prevalence of 1%. Initially localised to the synovium, inflammation and proliferation of synovium leads to dissolution of cartilage and bone Diagnosis: •

Morning stiffness > 1 hour

•

Rheumatoid nodules

•

Arthritis of > or = 3 joints

•

Serum rheumatoid factor

•

Arthritis of hand joints

•

X-ray changes

•

Symmetrical arthritis

Treatment goals – symptomatic relief and prevention of joint destruction Strategy – early use of disease-modifying drugs, aim to achieve good disease control. Use adequate dosages and a combination of drugs, avoidance of longterm corticosteroids

Treatment goals in SLE and vasculitis • Symptomatic relief e.g arthralgia, Raynaud’s phenomenon in SLE • ↓mortality – induction of disease remission then maintenance (Wegener’s vasculitis) •

Prevention of organ damage e.g. renal failure in SLE

•

Reduction in long term morbidity caused by disease drugs

Immunosuppressants • Corticosteroids • Azathioprine

Other disease-modifying antirheumatic drugs (DMARDs) • Methotrexate • Sulphasalazine •

Anti-TNF agents

•

Rituximab

and

•

Ciclosporin

•

Tacrolimus

•

Mycophenolate mofetil

Corticosteroids Prevent IL-1 and IL 6 production by macrophages and inhibit all stages of T-cell activation. However have key adverse effects: Weight gain, fat redistribution, striae, growth retardation, osteoporosis, avascular necrosis, glucose intolerance, adverse lipid profile, infection risk, cataract formation Azathioprine in practice • SLE and vasculitis as maintenance therapy • RA – weak evidence for efficacy •

IBD

•

Bullous skin disease

•

Atopic dermatitis

•

Many other uses as ‘steroid sparing’ drug.

Action – cleaved to 6-mercaptopurine (6-MP) functions as an anti-metabolite to ↓DNA and↓ RNA synthesis PD – 6-MP is metabolised by thiopurine methyltransferase, TPMT gene highly polymorphic. Individuals vary markedly in TPMT activity. Those with low or absent TPMT levels are likely to develop myelosuppression. Therefore test this before prescribing ADRs – common – bone marrow suppression (monitor FBC), ↑risk of malignancy (all immunosuppressants) (-ESP transplant patients), ↑risk of infection. Rarely hepatitis (monitor LFT) Calcineurin inhibitors Active against helper T cells preventing the production of IL-2 via calcineurin inhibition. Ciclosporin binds to cyclophilin protein. Tacrolimus binds to tacrolimusbinding protein. Drug/protein complexes bind calcineurin. Calcineurin normally exerts phosphatise activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription. Micro-emulsion formulation (Neoral) is standard preparation – more predictable absorption. Tacrolimus is more popular. USES: • Transplant medicine

•

Also indicated for atopic dermatitis and psoriasis

•

Pimecrolimus only available as topical formulation-use in atopic dermatitis

•

Not commonly used in rheumatology – concerns about toxicity

•

Ciclosporin useful in RA/SLE patients with cytopenias as it has no clinical effect on bone marrow

•

Monitor for toxicity – check BP and eGFR

Adverse effects – nephrotoxic, hypertension, hyperlipidaemia, N&V diarrhoea, hypertrichosis (shaking), gingival hyperplasia (gum hypertrophy), hyperuricaemia. Multiple drug interactions are possible, primarily with agents affecting the cytochrome P450 system. People told not to drink grapefruit juice in the hour before taking dose of ciclosporin. Also medicine can cause K ↑so told to avoid high K foods such as bananas. Mycophenolate Mofetil Action – it is a prodrug derived from fungus Penicillium stoloniferum. It inhibits the enzymes inosine monophosphate dehydrogenase (required for guanosine synthesis). Impairs B and T-cell proliferation and spares other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells) Adverse effects – commonly N&V diarrhoea. Serious – myelosuppression USES: • Transplantation • Good efficacy as induction of maintenance therapy for lupus nephritis •

In transplantation medicine drug levels of the active metabolite mycophenolic acid may be monitored

•

Toxicity may be precipitated in by both renal and liver disease

Cyclophosphamide An alkylating agent – cross links DNA so that it cannot replicate so suppresses T cells and B cells USES: • Lymphoma, leukaemia • Lupus nephritis •

Wegener’s granulomatosis

•

Polyarteritis nodosa

PD – it is a prodrug, converted in the liver by oxidase enzymes and cytochrome P450 to active forms that have chemotherapeutic activity. The main active metabolite is 4-hydroxycyclophosphamide. This exists in equilibrium with its

tautomer, aldophosphamide. Most of the aldophosphamide is oxidised to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard. Cyclophosphamide is excreted by the kidney. Acrolein, another metabolite is toxic to the bladder epithelium and can lead to haemorrhagic cystitis. This can be prevented through the use of aggressive hydration and/or mesna. Considerations – significant toxicity – ↑risk of bladder cancer, lymphoma and leukaemia, - Infertility – risk relates to cumulative dose and patient age o Monitor FBC and adjust dose in renal impairment -

MMF may supersede cyclophosphamide in lupus nephritis (a trial is underway)

Methotrexate Gold standard treatment for RA. Other indications include malignancy, psoriasis and crohn’s. Also unlicensed roles in: inflammatory myopathies, maintenance therapy in vasculitis, steroid-sparing agent in asthma. Action – methotrexate competitively and reversibly inhibits dihydrofolate reductase. The affinity of methotrexate for DHRF is 1000x that of folate for DHRF. DHRF catalyses the conversion of the dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine (A, G) and thymidine synthesis. Methotrexate therefore inhibits the synthesis of DNA, RNA and proteins. Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. It therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI and oral mucosa) which replicate their DNA more frequently. However its mechanism of active in non-malignant disease e.g. RA, psoriasis is not clear. Mechanism is not via anti-folate action. Possible action – inhibition of enzymes causing ↑[ adenosine] Mean oral bioavailability is 33% Mean intramuscular bioavailability is 76% Administered, PO, IM or S/C Weekly not daily dosing, metabolised to polyglutamates with long half lives 50% protein bound – NSAIDs displace Renal excretion USES -

Well tolerated

-

50% of patients continue the drug for >5 years, longer than any other DMARD

-

Improved QoL

-

Retardation of joint damage

-

Anchor drug for DMARD combinations

Adverse effects - Mucositis - Marrow suppression both respond to folate supplementation -

Hepatitis, cirrhosis

-

Pneumonitis

-

Infection risk

-

Highly teratogenic, abortifacient

Methotrexate- toxicity monitoring – ACR and BSR recommendation. Baseline chest X-ray, FBC, LFT, U+E, regular e.g. monthly FBC, LFT, U+E + creatinine Sulfasalazine A conjugate of salicylate and a sulfapyridine molecule Action - T cell o Inhibition of proliferation

-

o

Possible T cell apoptosis

o

Inhibition of IL-2 production

Neutrophil o

↓chemotaxis and ↓degranulation

ADR –myelosuppression, hepatitis, rash. Milder SE N&V, abdo pain In practice - Effective - Favourable toxicity -

Long term blood monitoring not always needed

-

Very few drug interactions

-

No carcinogenic potential

-

Safe in pregnancy

ANTI TNF

NICE – a patient with RA is prescribed anti-TNF only if they have had an adequate trial of MTX and at least one other standard DMARD, both with at least 2 months at target dose. A patient with RA is prescribed anti-TNF only if there is evidence of clinically active RA. Rx is withdrawn if patient experiences an ADR or fails to response. Expensive £9000 per annum Drugs: Adalimumab, entanercept and infliximab Effects of blocking TNF-α - ↓ inflammation o Cytokine cascade – recruitment of leucocytes to joint. Elaboration of adhesion molecules and production of chemokines -

↓ angiogenesis – VEGF and IL-levels

-

↓joint destruction – MMPs and other destructive enzymes bone resorption and erosion, cartilage breakdown

ADR – does not ↑overall risk of malignancy. Risk of serious infections is similar to other DMARDs. Anti-TNF ↑risk of skin/soft tissue infections. TB reactivation and other intracellular bacterial infections – post marketing surveillance. Rituximab binds specifically to a unique cell-surface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type. B cells – present antigen to T cells and produce cytokines and antibodies. Rituximab works in three ways- activation of complement mediated B cell lysis; initiation of cell mediated cytotoxicity via macrophages, induction of apoptosis. Long term – development of hypogammaglobulinaemia and ↑risk of infection. Development of hypersensitivity or blocking immune responses

Session 7 – Non-steroidal Anti-inflammatory Drugs About 50 drugs – significant structural heterogeneity, principle action key enzymes in prostaglandin synthesis/ 3 primary therapeutic effects: analgesia, anti- inflammatory, antipyretic The inflammatory response • Fundamental response of body to injurious stimuli – includes wide variety of noxious agents: o Physical/chemical injury – structural strain

•

o

Infections

o

Many diseases – Autoimmune conditions

Normally a protective response to reduce risk of further damage to organism

•

Alerts body through signalling pain – ↓risk of further damage through continued use/activity

A wide range of local molecular mediators and signalling agents employed – the Autacoids including Bradykinins, Histamine, cytokines, leukotrienes, nitric oxide, neuropeptides and the eicosanoids (includes PGs) Signalling overlap to ensure robust anti-inflammatory response Key feature is localised release and short T1/2 allows fine control in signalling response Prostaglandins are synthesised from Arachidonic Acid Eicosanoids are 20C phospholipid derivatives used as signalling molecules. Variations in synthetic routes give rise to different classes. Prostanoids prostaglandins (PGs), prostacyclins, thromboxanes, All eicosanoid classes derived from arachidonic acid which is cleaved from cell membrane phospholipids. Specific PG enzymes an example is prostaglandin desynthase. COX-1 ISOFORM is constitutively expressed. It is in a wide range of tissue types. PG synthesis by COX-I has major cytoprotective role (Gastric mucosa, myocardium, renal parenchyma, ensures local perfusion – reduces ischemia) PG t1/2 short = 10 mins – need constant synthesis. Due to its constitutive expression, most ADRs causes by NSAIDS effects are due to COX-I inhibition. COX-2 isoform expression is induced by injurious stimuli. Expression induced by inflammatory mediators such as Bradykinin. COX-2 appears to be constitutively expressed in parts of the brain and kidney. Main therapeutic effects of NSAIDs occur via COX-2 inhibition. COX-1 and 2 do not work independently and PG synthesis of both dependent on tissue and organ type. COX-1/COX-2 specificity NSAIDs exhibits a range of selectivity for the two forms. Generally NSAID action on COX-1 is rapid and competitive, on COX-2 is slower and often irreversible.

PGs: general pharmacology. PGs bind with GPCRs specific actions depends on PG receptor types. E.g. PG E at lease four main types: EP 1-4. Often action includes synergising effects of other autacoids e.g. bradykinin/histamine. Inflammatory Response Mediators: Range of autacoids and prostanoids released post injury esp. PGE2 – also PGD2  released from local tissues and blood vessels. Autacoid release also induces expression of COX-2. Synergise with other autacoids – bradykinin/histamine. PGs act as potent vasodilators – but doesn’t ↑capillary permeability directly – synergise permeating effects of bradykinin/histamine. EP1 receptor – making response more sensitive, ↑C fibre activity EP 2 – vasodilation Pain: sensitising afferent nerve nociception. GPCr activation results in: ↑ neuronal sensitivity to bradykinin and inhibition of K+ channels/↑Na channels sensitivity. In combination these act to ↑C fibre activity. PGs may also activate previously silent C fibres. By reducing synthesis of PGs that sensitise nociceptors to inflammatory mediators, thought to ↓headache pain by cerebral vasodilation mediated by prostaglandins. May also have a secondary effect on PG facilitation of afferent pain signal in spinal cord dorsal horn neurones. Sensitising central nociception: ↑sustained nociceptive signalling peripherally result in ↑cytokine levels in the dorsal horn cell body/ this causes ↑ COX-2 synthesis and ↑ PGE2 synthesis. PGE2 acts via local GPCR receptor to ↑sensitivity and discharge rate of secondary sensory neurones. Central sensitisation by PGE2 thus causes ↑perception of pain, central sensitisation in dorsal horn of spinal cord Pyrexia – in infected and inflammatory states bacterial endotoxins stimulate macrophage release of IL-1. IL-1 within the hypothalamus (via induction of COX2?) stimulates PGE2 synthesis. PGE2 via EP3 receptor ↑cAMP levels in neurones regulating temperature  ↑ heat production and ↓ heat loss

Therapeutic Effects Main therapeutic effects achieved via COX-2 inhibition. Pharmacological action for nearly all NSAIDS via competitive inhibition of COX-1 and COX-2. Occupation of COX1/COX2 hydrophobin channel by NSAID competes with AA site occupation. With 50ish different NSAIDs wide variation in affinity

Nearly all have therapeutic efficacy as analgesics, anti-inflammatory and antipyretics. Often dominant disease state and individual patient response determine physician choice. PK typically given orally but many topical preparations for soft tissue injury. Linear PKs within therapeutic dose range. T1/2 mainly 2 groups 10. Many heavily bound to plasma protein 90-99% Anti-inflammatories very wide use in musculoskeletal disorders (RA/OA) Analgesia – mild to moderate pain though less effective than opiates but better ADR profile. Moderate pain accompanies many disease states very common with many medical procedures. ADRs Inhibition of COX-1 constitutive PG synthesis leads to many side effects. Long term use in elderly particularly associated with iatrogenic morbidity and mortality. Majority ADRs are seen in stomach/GI tract. Renal ADRs occur in compromised individuals HRH or Hypovolaemia. HRH is heart failure, renal disease, hepatic cirrhosis GI ARDS – stomach pain, nausea, heartburn, gastric bleeding, ulceration Gastric COX-1 PGE2 stimulates cytoprotective mucus secretion throughout GI tract, reduce acid secretion and promote mucosal blood flow. NSAIDs especially long term have high incidence of GI ADRs between 10-30%. PGE2 inhibition increases mucosal permeability and decrease mucosal blood flow and protection. Clinical burden due to ulceration, haemorrhage and even perforation. Renal/neovascular ADRS Renal ADRs in HRH compromised patients due to renal perfusion and blood flow. PGE2 and PGI2 maintain renal blood flow. If reduced by NSAIDs then GFR ↓ further risk of renal compromise. Na/K/Cl and H2O retention follow with ↑likelihood of HTN Vascular – ↑risk of prolonged bleeding time bruising and haemorrhage Hypersensitivity Skin rashes (up to 15% for some NSAIDs) range from mild to rare Stevens Johnson syndrome. Bronchial asthma and anaphylaxis. Particular care when prescribing to asthmatics. Aspirin also associated with risk of post-viral Reye’s syndrome in children. NSAIDS- specific COX-2 INHIBITORS Large research effort put into developing highly selective COX-2 inhibitors Rofecoxib (Vioxx) and celecoxib. Theoretically overcome ADRs due to COX-1

inhibition with equal efficacy to standard NSAIDs. Not completely free of GI ADRs. Clinical trials show significant ↑of CVD ADRs with long term use. US/EU approval for short term use only. More expensive so rarely used. Therapeutic in combination with low dose opiates (all NSAIDs) – extends therapeutic range for treating pain and reduces ADRs seen with opiates along. NSAIDS in combination • NSAIDS given in combination ↑risk of ADRs, often occurs due to self medication with NSAIDS. • NSAIDS together can affect each other PK/PDs due to competition for plasma protein binding sites – many NSAIDS heavily bound up to 90-99% •

NSAIDS + low dose aspirin – compete for COX1 binding sites – may interfere with cardio protective action of aspirin.

•

NSAID protein binding can affect PK/PDS o

Highly protein bound drugs such as sulphonylurea, Warfarin and methotrexate can all be displaced, so may require dose adjustment to avoid changes in PK and PG

o

↑ sulphonylurea – hypoglycaemia

o

↑ Warfarin – ↑bleeding

o

↑ methotrexate – wide ranging serious ADRs

ASPIRIN Aspirin used as reference NSAID for efficacy and ADR severity. Still in very widespread esp. acute self medication. Relatively higher long term risk of ADRs. The only NSAID to irreversibly inhibit COX enzymes by acetylation. Unique PK profile. T-half less the 30 mins rapidly hydrolysed in plasma to salicylate. Salicylate PKs dose dependent. At lower doses first order T1/2 – 4 hours. At higher doses – 12 X 300mg tablets/ day zero order kinetics apply. Widespread use as cardio protective (@75mb) increasing trial evidence as prophylactic for GI/breast other cancers – trials continue. Artero-thrombotic disease use of low dose aspirin (75mg) in reducing platelet aggregation is very widespread in treating a range of conditions with a vascular component. The irreversible inhibition of COX-1 stops its activity that usually drives pro-aggregative activity in both platelets and the vessel wall therefore ↓thrombotic formation. PARACETAMOL Unique NSAID as it has virtually no anti-inflammatory action. Very effective for mild to moderate analgesia and fever. At therapeutic doses has a much better ADR profile than other NSAIDs. It is agent of choice for these moderate pain and fever. Therapeutic doses 8 X 500mg/day

Currently unknown mechanism of action weak COX1/Cox 2 inhibitor. Considered to primarily act in CNS possibly on a COX3 isoform. Metabolite in CNS can combine with AA to block binding with COX1/COX2? T-half – 2-4 hours. Caution in those with compromised hepatic function or alcoholism. Toxicology single doses in excess of 10g potentially fatal, at high doses paracetamol PKs become zero order. Elimination involves both phase 1 and phase 2 metabolism and production of highly reactive intermediate. The intermediate is conjugated with glutathione and is then made non-toxic. At very high doses glutathione is depleted. When it is depleted a reactive intermediate is formed (NAPQI) exerting its toxic effect. This occurs by binding to many cellular macromolecules that result in necrotic cell death. Rx for OD must be given as soon as possible and guided by blood levels of drug. This additionally ↑a systemic burden as the liver is less able to cope with the normal levels of free radicals generated by the body. This results in further apoptotic damage and further compromise of hepatic function. OD should be treated within 8 hours, Rx. IV Nacetylcysteine or oral Methionine that ↑glutathione levels. Is still treatable up to 48 hours but if this is missed then the patient is very likely to die of liver failure. RTN and hypoglycaemic coma may follow.

Drug interactions – patients may be self-medicating with NSAIDs. So ask. Aspirin also interacts with Warfarin, displacing it from plasma proteins. NSAIDS can interact with ACEi and attenuate their action blocking the production of vasodilation PGs NSAIDS can cause severe bronchospasm, angioedema and/or anaphylactoid reactions in about 2 of the population. These individuals are said to be aspiring/NSAID hypersensitive. If they take these drugs, the COX pathway is completely blocked and all AA metabolism occurs via the lipoxygenase pathway. The production of high levels of leukotrienes causes severe and prolonged bronchospasm, and the activation of cytokines from inflammatory cells can cause widespread mast cell degranulation.

Opioid Analgesics Pain has a physiological and psychological component. GATE THEORY Pain transmission  substania gelatinosa in the dorsal horn of the spinal cord Neurotransmitter: substance P Inhibitory descending pathways from higher centres of the brain synapse with substania gelatinosa and block pain transmission.  mind over matter Opioid drugs inhibit the release of substance P from nerve terminals.

Pain pathway: Sensory signals integrated and filtered then sent to primary sensory cortex conscious awareness of pain. Not fully understood Endogenous opioid peptides Prokephalins  enkephalins Pro-opiomelanocortin  endorphins Prodynorphin  dynorphins •

Met- enkephalin (tyr-gly-gly-phe-met)

•

Leu- enkephalin (tyr-gly-gly-phe-leu)

•

Dynorphin

•

Β-endophin – pain relief, award system in brain (exercise), immunosuppressant, regulating labour, (smooth muscle relaxant)

•

Opioid receptors

Evidence in CNS for, all GPCR • μ – analgesia (supraspinal) binding causes ↑ outward flux of K  hyperpolarisation  ↓ excitability AND causes ↓ cAMP • k – analgesia (spinal cord)  ↓ influx of Ca via channels •

d – enkephalins (widely distributed) present in neuromuscular junction  ↓ cAMP synthesis

Receptor subtypes: • μ1 – main effect –analgesia main target of opioids •

•

μ2 ADRS – o

Nausea, vomiting, constipation, drowsiness, miosis,

o

Respiratory depression

o

Hypotension

o

Also dependence and tolerance

k – pentazocine – dysphoria

Pharmacodynamics • Agonist – e.g morphine • Partial agonist e.g nalbuphine •

Antagonist e.g. naloxone – at μ receptor

Drug

Half-life (hrs)

Morphine

1.3-6.7

Diamorphine

0.08

Methadone

15-30

Buprenorphin e

2-4

Codeine

1.9-3.9

Dihydrocodei ne

3.4-4.5

Fentanyl

3-12

Pethidine

2-5

Nalbuphine

1.9-7.7

Tramadol

4.3-6.7

Morphine – ‘the best’ Metabolism – glucuronidation makes either morphine-6-glucuronide (still active) or morphine-3-glucuronide which are both in urine. It goes straight into phase 2 metabolism Heroin/diamorphine – is more lipid soluble version of morphine with a 5 minute t1/2. However hydrolysis converts the molecule to morphine with a 4 hour t1/2. Clinical uses of opioids •

Analgesic – chronic visceral pain (not stabbing pain)

•

Morphine – analgesic (terminal illness) and can be used as diarrhoea

•

Diamorphine – analgesic (terminal illness) 

Epidural analgesia (not licensed)

•

Codeine – mild analgesic (oral) (metabolised to morphine) 50% bioavailability cytochrome P450 changes it to morphine

•

Methadone – post-operative analgesia OR maintenance of dependence. Long term pain relief

•

Fentanyl

•

Alfentanil

•

Remifentanil – all 3 use in anaesthetics and cause histamine release (causing itching)

•

Pethidine – analgesia in labour (IM) however slows labour and slows inflammatory mediators and crosses the placenta so baby needs naloxone when born. Other uses sickle-cell crisis. (norpethidine (metabolite)  convulsions) do not give frequent repeat disease

Opioid agonists-antagonists – pentazocine, nalbuphine, butorphanl, buprenorphine, meptazinol all analgesic e.g antagonist at μ, partial agonist at k, weak agonist at d Opioid antagonists μ receptor antagonists: • Naloxone T1/2 1- 1.5h injection • Naltrexone T1/2 4 h – orally /Uses: opioid toxicity, reverse respiratory depression, treatment of dependence. However naloxone not long enough to keep opioids at bay (shorter T1/2) New endogenous opioid peptides and receptors Peptides – nociceptin, nocistatin (blocks effects of nociceptin), endomorphin-1 and 2 Receptor – ORL 1 (opioid receptor like 1 – nociceptin binds to it) Medico legal aspects opioid analgesics are class A controlled drugs. The misuse of drugs act 1971, misuse of drugs regulation 2001.

Session 8 Antiarrhytmic Drugs Types of Arrhythmias Too fast: AF, atrial flutter, AV re-entry tachycardia, ventricular tachycardia, torsades de pointes Too slow – heart block

Vaughan Williams Classification Class 1

Class 2

Class 3

Class 4

Na channel Blockers

Beta blockers

Prolonged AP (K channel blockers)

Ca channel blockers

Ia Quinidine

Atenolol

Amiodarone

Diltiazem

Ib Lidocaine

Bisoprolol

Verapamil

Ic Flecainide

Metoprolol

Sotalol (also βblocker)

NBKC – never buy Kellog’s cornflakes Class Myocardial AV AP duration contractility conduction

Effective refractory period

Ia

↓

↓

↑

↑

Ib

-

-

↓

↑↑

Ic

↓↓

↓↓

-

-

II

↓↓

-/↓

-

-

III

-

↑

↑↑↑

↑↑↑

IV

↓↓↓

↓↓

↓↓

-

Class 1 drugs Mainly block fast Na channels, weak K + channel block. Therefore: • ↓ conduction velocity •

↓ depolarisation amplitude

•

↓ automaticity

•

↓ phase 4 slope

•

↑ depolarisation threshold

•

Alter duration of AP

Lidocaine – class Ib agent. Rapid dissociation t1/2- 0.1s. Binds open and inactive Na channels. PK – extensive FPM, IV admin, short T1/2 Adverse effects – negatively inotropic, seizures, nystagmus Clinical use – ventricular tachycardia post MI Flecainide class 1c agent, also blocks outward K channels, long dissociation t1/2 10 s. Binds open Na channels only •

↑PR, QRS and QT intervals at normal rates

•

↑ AP in atrial tissue at fast rates

PK – well absorbed orally, metabolised by CYP2D6 & renal elimination. Elimination t1/2 10-18 hours Clinical use – prophylaxis and Rx of SVT/ Paroxysmal AF Adverse effects- contraindicated with Hx of IHD/HF – causes lethal dysrhythmias Beta Blockers • Non selective – propranolol, sotalol • β1 selective – Longer acting atenolol, bisoprolol Shorter acting metoprolol, nebivolol, esmolol •

Mixed β1α1 – Carvedilol, labetalol

Adverse effects – HF, bradycardia, bronchospasm, peripheral limb ischaemia, loss of hypoglycaemic symptoms, fatigue Clinical use: • Rate control of AF/atrial flutter • Cardioversion AVRT/ AVNRT •

Secondary prevention of VT/VF

•

Heart failure

•

Hypertension

•

IHD

Class 3 • ↑ AP duration • Block slow outward K+ channels

•

↑ refractory period

•

↑ QT interval

•

Suppress re-entry circuits

•

However can ↑ risk of early after depolarisation leading to torsade de pointes

•

Most commonly used are Amiodarone and sotalol

They ↑prolongation of AP ↑ wavelength, ↓ excitable gap Amiodarone all classes of action: •

Acute - blocks fast Na and Ca channels – class 1 and 4 action, use dependent, blocks Ach gate K channels (class 2 action), less negatively inotropic than class 1/2/4 agents

•

Chronic – blocks outward K channels – class 3 action o

Inhibits cell-cell coupling

o

Prolongs AP duration and refractory period

o

Slows AVN conduction

o

Prolongs QT interval

PK – 30% bioavailability. Large Vd = 66 L/kg (approx 5000L in a 70kg individual) IV or oral loading dosing required. Elimination T1/2 10- 100 days. Hepatic metabolism by CYP450 3A4 to desethylamiodarone. Dose adjustments not required in renal/hepatic/cardiac dysfunction Adverse effects – • Short term – phlebitis & hypotension wit IV administration Requires central access when given IV •

Long term – pulmonary fibrosis, hypo/hyperthyroidism, hepatic dysfunction, corneal microdeposits, slate grey skin/photosensitivity, peripheral neuropathy, proximal myopathy, ↑defibrillation threshold for ICDs

•

Drug interactions inhibits CYP3A4 and CYP2C9 and P-glycoprotein  dose reductions of Warfarin, Digoxin and Flecainide may be required.

Use: Acute – AF, atrial flutter, VT, when other antiarrhythmics contraindicated Chronic indications – secondary prevention of VT/VF when other antiarrhythmics not tolerated

Sotalol • Racemate • D-sotalol pure class 3 agent, I-sotalol has β-blocker and class 3 action •

Blocks outward K+ channels

•

Reverse use dependence

•

Lowers defibrillation threshold for ICDs

•

Doses < 120mg bd has mainly β blocker action

•

Higher doses have class 3 action

Adverse effects – β blocker adverse effects, Torsade de pointes Clinical use = paroxysmal AF Class 4 Diltiazem & verapamil block slow inward Ca channels on SAN and AVN. Slow phase 4 depolarisation, slow conduction velocity, ↑refractory period on AVN. Dihydropyridine CCB (e.g. nifedipine, amlodipine) acts on vascular smooth muscle and have no antiarrhthymic effects. Block L type Ca channel Verapamil – IV or oral, sustained release preparations, negatively inotropic, drug interactions with Digoxin and Amiodarone Diltiazem – less negatively inotropic than verapamil sustained release preparations Adverse effects (both)- bradycardia, HF, constipation Clinical use (both) – rate control of AF, cardioversion of AVRT/AVNRT, antianginal/antihypertensive

Other antiarrhythmics Adenosine Main action as an AV node blocker: activates α1 receptor in the heart. α1 receptors are Gi linked  inhibits adenylate cyclase  ↓ cAMP levels Activates Ach K channels in SAN and AVN  hyperpolarises cells Reduces automaticity, ↑AVN refractory period’ T1/2 – few seconds Associated with transient chest tightness, and used as an IV bolus to diagnose/treat AVTs

Digoxin – inhibits Na/K ATPase. • Direct cardiac effects + inotrope • CNS mediated effects - ↓ SNS outflow, ↑ PNS outflow, sensitises baroreceptors reflex •

Combined effect - ↓ automaticity of SAN and AVN, ↑ refractory period of AVN, ↓ conduction velocity of AVN

PK – oval bioavailability 70-80%, large Vd (4 – 7 L/kg), 20-30% protein bound, loading dose required for rapid onset of action. 2 compartment model kinetics, T1/2 36-48 hours with normal renal function. Renal excretion unchanged by Pglycoprotein. Digoxin clearance proportional GFR. Reduce dose in elderly & renal impairment. Loading usually in 2 divided doses to minimise risk of toxicity. Plasma Digoxin levels checked 6-8 hours after dosing Drug interactions • ↑ Digoxin levels – propafenone, Quinidine, Amiodarone, verapamil, Spironolactone, cyclosporine, likely mediated by P-glycoprotein • ↑Digoxin levels – erythromycin, tetracycline PD – beta blockers, verapamil, Diltiazem, Flecainide, diuretics Adverse effects – narrow therapeutic index – plasma level 1-2.6 nmol/L, toxicity enhanced with ↓ plasma K • Cardiac toxicity – bradycardia, atrial/ventricular/functional ectopics o AVN block o

Atrial tachycardia with AVN block

o

Accelerated idioventricular tachycardia

•

Signs and symptoms – delirium, fatigue, confusion, nausea, vomiting, anorexia, diarrhoea, blurred and yellow vision (xanthopsia)

•

Severe toxicity can be treated with antibody fragment therapy (digibind)

Clinical use – main use is rate control in AF; heart failure however no mortality benefit Magnesium IV mg2+ used to treat Torsades de Pointes; Digoxin toxicity’ mechanism of action is unknown, no benefit to chronic administration

Clinical use of Antiarrhythmics Identify & treat precipitating factors – ischaemia, drug therapy, electrolyte/endocrine disturbance, sepsis Establish goals of Rx – rhythm control, rate control, prevention

Minimise risks – avoid multiple antiarrhythmics, drug-drug interactions, short and long term adverse effects

Diuretics Renal physiology • Regulatory – fluid balance, acid-base balance, electrolyte balance • Excretory – waste products, drug elimination •

Endocrine – RAAS, erythropoietin, prostaglandins

•

Metabolism – Vitamin D, polypeptides (insulin, PTH)

Pharmacology Drugs acting on the renal tubules • Carbonic anhydrase inhibitors – cause NaHCO3 diuresis, excretion of Na, K and PO3 causes metabolic acidosis/hypokalaemia • Osmotic diuretics – filtered at glomerulus, ↑osmotic gradient through nephron, excessive water loss, hypernatraemia •

Loop diuretics – thick ascending limb of henle inhibits NaCl/2k and reabsorption, concurrent Ca/Mg excretion, causes hypokalaemia in the collecting duct

•

Thiazides – inhibit NaCl reabsorption in DCT, promotes Ca reabsorption however causes hypokalaemia and hyperuricaemia

•

K sparing diuretics

•

Aldosterone antagonists – Spironolactone inhibits, Na retention (NA/K ATPASE activity↓ and ENaC expression ) blunt K and H secretion, androgenic cross reactivity, hyperkalaemia

•

ADH antagonists – include lithium/demeclocycline – ↓concentrating ability of urine in CD

Other drugs with diuretic activity: • Digoxin - inhibit tubular Na/K ATPase • Amiloride – inhibits Na channels in DCT/ CD, K sparing Generic ADRs for diuretics Anaphylaxis/rash etc- Hypovolaemia & hypotension leading to ARF, electrolyte disturbance, metabolic abnormalities Common specific ADRs • Thiazides – gout, erectile dysfunction • Spironolactone – hyperkalaemia, painful gynaecomastia

•

Frusemide – ototoxicity

•

Bumetanide – myalgia

Drug interactions Interacting drugs

Potential interactions

ACE inhibitors/K sparing diuretics

↑hyperkalaemia

Aminoglycosides/loop d

Ototoxicity and nephrotoxicity

Digoxin/Thiazide & loop D

Hypokalaemia  ↑ Digoxin binding and toxicity

Β-blockers/Thiazide diuretics

Hyperglycaemia, hyperlipidaemia, hyperuricaemia

Steroids/Thiazide and loop D

↑ risk of hypokalaemia

Carbamazepine/Thiazide diuretics

↑ risk of hyponatraemia

Diuretic Resistance = incomplete treatment of the primary disorder. Continuation of high Na intake, patient non-compliance, poor absorption, volume depletion ↓filtration of diuretics, volume depletion ↑serum aldosterone which expresses ENaC. NSAIDs – can reduce renal blood flow DIURETIC USE Heart failure – loop D, Thiazide D, Spironolactone ACEi/ang II antagonists, βblockers Hypertension – Thiazide D, Spironolactone, ACEi/ARBs, B-blockers Decompensated liver disease – Spironolactone, loop diuretics Conn’s Syndrome – Spironolactone Drugs may reduce kidney function by direct or indirect toxicity. Drugs may accumulate to toxic levels if they are excreted through the kidneys and renal function is impaired. Potentially nephrotoxic drugs • ACEi- do not use ACEi with renal artery stenosis – under these conditions GFR↓ causing RAAS to ↑ BP and vasoconstriction affects renal output. ACEi and ARBs preferentially dilate efferent arteriole ↓↓ GFR as no pressure over glomerulus • Aminoglycosides – e.g. gentamicin •

Penicillins

•

Cyclosporin A

•

Metformin

•

NSAIDs

•

Loads more – double whammy if renal function is impaired

Prescribing in CRF - Avoid nephrotoxins - Reduce dosages in line with GFR metabolism or eliminated via the kidneys -

Monitor renal function and drug levels

-

Hyperkalaemia is more likely

-

Uraemic patients have greater tendency to bleed

-

BNF

Prescribing in the elderly - Renal function is over-estimated as creatinine is dependent on body mass - So start low, titrate cautiously -

Polypharmacy more likely

Management of hyperK - Indentify cause - ECG - Rx – calcium gluconate, insulin/dextrose, calcium resonium, NaHCO3, salbutamol

Session 9 - Treatment for Hypertension and Heart Failure Blood pressure Physiological control by the ANS, RAAS and others such as Bradykinin, endothelin, nitric oxide, ANP

Angiotensin converting enzyme is also involved in the breakdown of Bradykinins which vasodilate. Therefore ACEi potentiate bradykinin action causing an additional vasodilation. HTN  ↑arterial thickening  SMC hypertrophy accumulation of vascular matrix, loss of arterial compliance  target organ damage  heart, kidneys, brain, eyes CV morbidity and mortality

Epidemiology – defined as 140/90mmHg, 40% of the adult population of England are hypertensive although the proportion ↑with age. Lowering diastolic BP by 10mmHg is associated with reductions in stoke of 58% and CHD of 37% Primary (essential) HTN – high BP without any single evident cause, 90% hypertensive population Secondary HTN – high BP with a discrete, identifiable underlying cause, 10% hypertensive population Rx – identify and Rx underlying cause if present. Identify and treat other CV risk factors or co-morbidities. Lifestyle advice/non-pharmacological therapy, Drugs Category

Systolic BP (mmHg)

Diastolic BP (mmHg)

Optimal

15% of CV event in the next 10 years) and the presence or absence of end organ damage in the heart, eye or kidney. In the presence of diabetes the Rx threshold is 140/90 with a target level of veins) selective action on heart, peripheral vasculature, cerebral circulation, used in resistant/severe HTN Minoxidil – open ATP-modulated K channels thus inhibits influx of Ca, usually given with by a diuretic and β-blocker to ↓effects of tachycardia and fluid retention. SE is hirsutism Hydralazine – mechanism unclear, oral/IV, main ADRs, flushing, tachycardia, and mild fluid retention Secondary causes of HTN •

Endocrine – conn’s syndrome, bilateral adrenal hyperplasia, glucocorticoidremediable aldosteronism, congenital adrenal hyperplasia, Cushing’s, pheochromocytoma, thyroid disease, acromegaly, hyperparathyroidism, carcinoid

•

Mogenic renal tubular defects – liddle’s syndrome, Gordon’s syndrome

•

Renal causes – renovascular HTN, chronic pyelonephritis, diabetic renal disease, renal parenchymal disease

•

Miscellaneous – coarctation of the aorta, neurologic disorder, psychogenic, sleep apnoea, drug-induced, oral contraceptive, HRT, pregnancy

Pheochromocytoma – adrenal catecholamine –secreting tumour. Adrenaline/NA/dopamine. Paroxysmal symptoms very sustained high BP. Diagnosed – urinary catecholamines/imagining Treat with non-selective αblockers – direct effect on α-1 and α2 adrenoreceptors preventing the action of released NA. βB are given after a-blockage Primary hyperaldosteronism – causes hypertension Includes – conn’s syndrome and bilateral adrenal hyperplasia. Excess secretion of aldosterone, plasma rennin suppressed Rx. with aldosterone antagonists, Spironolactone, eplerenone Hypertensive emergencies Very high BP (often over 220/120 mmHg), associated with acute complications, pulmonary oedema, renal failure, aortic dissection etc. Need to reduce BP by 20% or to 100 mmHg diastolic within 1-2 hrs Sodium nitroprusside – mimics the action of endogenous NO on vascular SM, acting as a potent vasodilator. IV use with powerful rapid onset and offset. Breakdown to cyanide – caution in liver disease, but renal excretion. Avoid prolonged use (>72 hours)

Anti-coagulant and antiplatelet therapy Disorders of haemostasis are common these are thrombosis and embolism Arterial – white clot – CVA, MI: antiplatelets and thrombolysis Venous – red clot – DVT, PE. Anti-coagulation Other uses – pro thrombotic state and primary prevention

Basic pharmacology – ACAs – Warfarin – inhibits production of vitamin K dependent clotting factors Stops conversation to vit K to active reduced form. II (prothrombin), VII, IX, X – extrinsic pathway. Onset – days due to turnover of clotting factors (t1/2) Heparins Glycosaminoglycan – glucose backbone, one of 5 different groups on each glucose, some with sulphate, produced by mast cells. Unfractionated Vs low molecular weight, both activate anti-thrombin II via unique pentasaccharide sequence. Deactivates factor Xa, IIa, IXa

Warfarin PK – GI absorption, dose-dependent reduction in vit K dependent factors, many drug interactions, hepatic metabolism and slow onset of action • Give orally • Slow onset of action – heparin cover •

Slow offset – t1/2 48 hours but variable

•

Need to stop 3 days before surgery to give time to synthesise new clotting factors

•

Heavily protein bound – caution with drugs that displace it

PKs and clinical consequences: Hepatic metabolism – MFO p450 system – caution with liver disease, caution if used with drugs that affect p450 system Crosses placenta – do not give in 1st trimester – teratogenic, do not give in 3rd trimester either due to brain haemorrhage risk. Monitoring Warfarin – extrinsic pathway factors, prothrombin time citrated plasma clotting time after adding calcium and Thromboplastins INR – international normalised ration: • Allows a standard value between labs • Corrected for different lab Thromboplastins reagents

DRUG-DRUG INTERACTIONS WITH WARFARIN ARE HIGHLY SIGNIFICANT Effects on anticoagulation – majority ↑anticoagulant effect, but some ↓effect Drugs potentiating Warfarin 3 ways are clinically significant 1. Inhibit hepatic metabolism (P450) – Amiodarone, Quinolones, metronidazole, cimetidine, ingesting alcohol 2. Inhibit platelet function – aspirin 3. Reduce vitamin K from gut bacteria – cephalosporin antibiotics. Albumin displacement (NSAIDS & drugs that ↓GI absorption of vit K has lesser effect) INR will ↑if you start one de novo Drugs inhibiting Warfarin Antiepileptics, rifampicin, st. Johns wort all induce CYP450 thereby ↑metabolism of Warfarin  ↓INR Main uses of Warfarin Indication (duration)

INR range

DVT (3-6 months)

2.0-3.0

AF (until risk > benefit) Mechanical prosthetic valves (high risk)

2.5 - 4.5

Patients with recurrent thromboses on warfarin, thrombosis associated with inherited thrombophilia conditions Other uses – cardiac thrombus, CVA esp. With AF, cardiomyopathy Adverse effects – bleeding/bruising sites intracranial, epistaxis, injection, GI loss - Teratogenic - Reversal of therapy - parenteral vit K – slow takes 2-3 days -

Fresh frozen plasma – fast

Practical information Initiation 1. Indication 2. PMH e.g. PUB, SAH, bleeding disorder 3. Medication interactions

4. Age, mobility (blood tests and clinics) 5. Falls risk score 6. Review blood tests (LFTs, Plt, INR) 7. Consider loading dose and heparin cover 8. Prescribe (when to start) Discuss with patient the SE, and when to consult a doctor. Interactions with other medication and over the counter drugs, alcohol and cranberry/grapefruit juice, INR monitoring (1-4 weeks), give patient anticoagulant card Warfarin reversal - Common sense – stop Warfarin - Consider – bleeding, INR, indication, mechanical valve call cardiologist -

Agents o

IV vit K – poor-coagulant affects re-warfarinisation for 6 weeks

o

Prothrombin complex concentrate

o

Fresh frozen plasma

-

Source of bleeding (OGD, surgery)

-

Elective surgery

-

Heparin molecules

Unfractionated heparin (IV, continuous, occasional, subcut for prophylaxis) 20 kDa Mix of variable long length heparin chains Unique pentasaccharide sequence which binds to anti-thrombin II, this causes conformational change and

↑ AT II activity, AT III inactivation, thrombin (IIa),

and factor Xa, but also V, VII, IX, XI To catalyse inhibition of IIa b AT III, heparin needs to bind simultaneously to IIa and AT/ II. Unfractionated heparin is large enough for this, but not low MW heparin. Xa inhibition by AT II needs only heparin to bind to AT II, so both low and UH can act here. LMWH (subcut) 3-4kda have smaller chains that are < 18 saccharide units, absorbed more uniformly, high bioavailability (>90%), long t1/2. More predictable dose response than UH (does not bind to macrophages, endothelial cells, plasma proteins). Like UH, have unique sequence to bind to AT III, unlike UH, they do not inactivate thrombin. Affects factor Xa specifically. No monitoring required usually. Cleared by kidneys, care in renal failure, less likely to cause thrombocytopenia. Pharmacokinetics  given parenterally as poor GI absorption, rapid onset and offset of action

Dose- response

UFH

LMWH

Non-linearity

Predictable

Bio-availability

Variable

Predictable

Action

Variable monitor with APTT test

No monitoring – little affect on APTT

Administration

IV

SC

Initiation

Bolus then IVI

OD/BD

CHEAP

More expensive however, no monitoring

Uses of heparin Prevention of thromboembolism - Peri-operative – LMWH low dose - Immobility – CCF, frail or unwell patient Used to cover for risk of thrombosis around times of operation in those normally on Warfarin but who have stopped it for the surgery, as quick offset time allows its cessation if bleeding. -

DVT/PE and AF – administered prior to Warfarin – quick onset to cover patient whilst Warfarin loading is achieved o

LMWH often used unless fine control required

-

Acute coronary syndromes – ↓recurrence/extension of coronary artery thrombosis, and MI, unstable angina

-

Pregnancy – can be used cautiously in pregnancy in place of Warfarin

Adverse effects - Bruising/bleeding sites o Intracranial, injection sites, GI loss, epistaxis -

-

Thrombocytopenia (HIT) (heparin induced t) o

Autoimmune phenomenon (usually 1-2 weeks of Rx)

o

May bleed or get serious thromboses

o

Heparin and PF4 on platelet surface are immunogenic – immune complexes activate more platelets release more PF4, forms more IgG and complexes, leads to depletion of platelets and thrombosis

o

Platelets < 100 (or 5% reduction)

o

Lab assay for these antibodies

o

Stop heparin, add hirudin

Osteoporosis

Reversal of therapy – protamine sulphate, dissociates heparin for AT III, irreversible binding to heparin. Stop heparin, if actively bleeding give protamine, monitor APTT (activated partial thromboplastin time) if Unfractionated.

Anti-platelet drugs Thromboxanes A2 inhibition - Aspirin – COX-1 inhibition irreversible  Covalent acetylation of serine – hit and run drug -

Dipyridamole – phosphodiesterase inhibitors 

PGI2 ↑cAMP ↓aggregation



+ inotrope and vasodilatory (flushes and headaches), secondary prevention

Thromboxane A2 liberated from activated platelets- causes platelet aggregation/vasoconstriction Purpura is the appearance of red/purple discolorations on the skin due to small haemorrhage in the skin caused by various factors: blood disorders, vascular abnormalities, and trauma. It may be caused by aspirin as it infers with platelet adhesion and this factor potentiated by heparin as it ↑ the risk of haemorrhage. Platelet ADP receptor antagonists -

Clopidogrel – ADP antagonists 

Blocks platelet activation blocks PY2Y12 receptor ↓cAMP via Gi



Used with aspirin, more serious bleeds but same rate of life threatening, not for long term use if possible

Glycoprotein IIb/IIIa inhibitors Inhibit final common pathway of platelet aggregation - Abciximab, tirofibran, eptifibatide, ↓platelet cross linking by fibrinogen - Fibrinogen binds these receptors which cause platelet aggregation so good to block this final pathway. -

High risk ACS, post PCI (↑bleeding complications but ↓acute thrombosis and re-stenosis)

Session 10 – thrombolytic Drugs Fibrinolytic drugs make use of vascular intrinsic defence mechanism. Amplify the conversion of an inactive enzyme precursor plasminogen to active enzyme plasmin.

Plasminogen a single chain glycoprotein is 760 AA. Converted to plasmin by cleavage of ARG560-Val561 peptide band Plasmin is a serine protease with trypsin like activity. Attacks lysyl & arginyl bands of fibrin

Clinical uses of thrombolytics MI, PE, And ACUTE ISCHAEMIC STROKE 1st generation thrombolytics • Streptokinase – non enzymatic protein of beta- haemolytic streptococci. Activates fibrinolytic system by forming 1:1 stoichiometric complex with plasminogen converting to active enzyme plasmin. o Antigenic so only used once per patient SE – pyrexia, hypotension (if this occurs infusion is slowed), allergic reaction, very short T1/2 •

Urokinase (not licensed for use in MI) – trypsin – like serine protease of 2 polypeptide chains activates plasminogen directly converting it to plasmin binding activates SK active site by conformational change.

2nd generation thrombolytics APSAC acetylation of plasminogen T1/2 90 mins. Permit bolus dosing. Less bradykinin produced than with streptokinase (therefore less hypotension) 3rd generation thrombolytics Alteplase found to be same efficacy in acute MI than SK, but better in stroke Reteplase – recombinant plasminogen activator. T1/2 18 mins. 2 IV bolus injection 30 mins apart Tenecteplase – multipoint mutation of parent tPA Recombinant tPA’s (tissue plasminogen activators) – general points • Expensive but acceptable costs 10x more than SK • Lower risk of intracranial bleeds •

Works preferentially in the presence of fibrin therefore clot specific. SK causes systemic fibrinolytic activity. Practical difference is uncertain.

•

Possibly better efficacy

•

Efficacy preserved on repeated exposure non-antigenic

•

More rapid restoration of TIMI (thrombolysis in MI it is a grading scheme) – grade 3 flow great perfusion

•

Mechanism of action

Angioplasty the outcome is slightly better Administration of thrombolytic drugs. • IV bolus/infusion • No oral administration •

•

In acute MI: o

Aspirin ASAP prior to thrombolysis

o

IV heparin following administration of recombinant tPA’s

See if thrombolysis has worked check ECG if ST falls patient doesn’t need an angioplasty

Fibrinolytic therapy within the first 1-2 hours (up to 12) of onset of MI will prevent up to 60 deaths per 1000. Other uses: • Massive PE o Haemodynamic compromise

•

o

Good clinical evidence or positive CT pulmonary angiogram

o

Controversial benefit

o

Needs a clear diagnosis, evidence of significant haemodynamic compromise and absence of major contraindications are criteria for fibrinolytic therapy

Acute ischaemia CVA o

Within 3 hours of symptoms

o

Confirmed thrombotic CVA on CT

o

Specialised CVA units only

o

Contradictory evidence therefore not routine use

Less common uses include clearance of thromboses shunts and intraocular thromboses Time is of the essence. Longer time = more ischaemic death also thrombi become more resistant to lysis. Therefore benefit of Rx declines but the risks of Rx remain constant. MI: inclusion criteria

Acute ST elevation/bundle branch block MI confirmed on ECG: onset 1 mins), >12 hours since onset Need to balance the risk of bleeding with the risk of leaving an MI untreated – can perform angioplasty if near appropriate centre, angioplasty also requires anticoagulants (though not thrombolytics) Informed consent – patients should give (at least) verbal consent to thrombolytic therapy – there needs to be adequate explanation of risks/benefits, assessment of risk based on inclusion and exclusion criteria, but decisions should be reached as quickly as possible. Haemorrhage: Rate per 10000 patients exposed to thrombolytics: •

Fatal stroke 2

•

Disabling stroke 1

•

Minor stroke 1

•

Bleeding (non-cerebral) major 7

Caused by lysis of physiological thrombi, lytic state due to systemic plasmin activation Acute side effects • Hypotension (transient, more with SK) • Allergic response (SK products only)

•

o

Anaphylaxis/allergy (rarely severe)

o

Reduced efficacy on re-exposure after antibody response

Reperfusion arrhythmias o

Transient, sometimes need treatment

o

Sinus bradycardia, idioventricular rhythm

o

Occasionally more severe: VT, VF

•

Any cerebrovascular event occurring after fibrinolytic therapy requires a CT or MRI diagnosis to establish where the cause is haemorrhagic (i.e. treatment related) or ischaemia (emboli from hear). The two are equally likely.

•

Serious bleeding after fibrinolytic treatment may require transfusion of blood or volume expanders, inhibition of further fibrinolysis with tranexamic acid or aprotinin, specific recombinant or pooled clotting factors.

Cancer Chemotherapy Cancer biology By the time a patient presents with symptomatic cancer already large no’s of tumour cells. An example: A tumour 1cm diameter has approx/ 109 cells A lethal tumour burden is 1012 cells Cell kill of a drug (90-99.9%) depends on both sensitivity of the cells to the drug and dose. 99.9% cell kill (999 to 1000) reduces tumour population 10 11 to 108. The aim of several courses of chemo is to kill several logs of tumour cells Technical inability to detect fewer than 10 3 to4 (minimal residual disease) explains recurrence after apparent complete remission. Cell cycle: variation in cycle is 9-43 hours between cancer cells. The growth fraction of a cancer represents the % of cells actively progressing through the cell cycle. Some drugs cause cytotoxicity when exposed to cancer cells at any stage of the cell cycle. Some drugs are phase-specific: Chemo drugs interfere with some essential steps required for cell growth or division, often with synthesis and replication of DNA. The damaged cancer cell will either repair the damage or initiate apoptosis. Apoptosis is initiated at G1s or G2M checkpoints, provided the mechanisms for apoptosis are in place – not the case in some cancers = e.g. p53 mutations or deletions Mechanisms of action • Anthracyclines – doxorubicin – topoisomerase – prevents the enzyme from religating cleaved DNA • Alkylating agents – cyclophosphamide – formation of DNA cross links – interferes with cellular replication

•

•

Antimetabolites – disrupt the synthesis of essential compounds required for cell synthesis o Methotrexate inhibit the enzyme required to convert folate to its active form o Cytarabine inhibits DNA synthesis (S-specific) o Vinca Alkaloids – vincristine – bind to tubili – prevent formation of the mitotic spindle (M specific) Synergism with some of these drug classes

The cancer cells may evade kill by the chemotherapy in many ways, such as: • ↓drug uptake – alteration of folate receptor – Methotrexate • ↑drug efflux – MDR – 1 gene  p-glycoprotein – many drugs • ↑DNA repair mechanisms • Mutations leading to alteration of drug target – topoisomerase II mutations – Anthracyclines • Upregulation of anti-apoptotic genes – proteins and pathways Prescribing – need specialist to prescribe drugs because: they have narrow therapeutic indices, significant SE profile Also dose needs to be altered for the individual based on their SA or BMI, their drug handling ability (eg. LFTs, renal function – dependent on the metabolism and excretion routes), general wellbeing Treatment phasing needs to take into account the balance between: growth fraction, the cell kill of each cycle of the chemo regimen, marrow and GIT recovery before next cycle, chose tolerable regimen – both short term organ toxicity and physical SE and long term damage causing late SE. Hence each patient dose is different and always remembers the aim of the Rx Clinical indication • Cancer… but varies • Predicted response is also different within the same cancer based on performance score, clinical stage, prognostic factors or score, molecular or cytogenetic markers • Side effects Vs anticipated or best outcome Neoadjuvant – given before surgery or radiotherapy for the primary cancer Adjuvant – given after surgery to excise the primary cancer, aiming to ↓relapse risk e.g. breast Ca Palliative – to treat current or anticipated symptoms without curative intent Primary – 1st line Rx of cancer in many haematological cancers this will be with curative intent initially aiming for remission Salvage – chemotherapy for relapsed disease For many types of cancer, chemotherapy regiment will consist of a number of different drugs – combination chemo – usually given an acronym. A drug may be given as a single agent. Routes of administration:

• IV is the most common – bolus, infusional bag, continuous pump infusion, • PO convenient, dependent on oral BA • SC convenient in community setting • Into a body cavity - bladder, pleural effusion • Intralesional – directly into a cancerous area – consider pH • Intrathecal – into the CSF – by lumbar puncture or ommaya reservoir • Topical – medication will be applied onto the skin • IM – rarely Chemotherapy Adverse effects – toxicity Need a balance between cancer cell kill and toxicity to normal cells undergoing cell division e.g. • Myelosuppression  ↓ Neutrophils (infection), anaemia and thrombocytopenia • GI effects – mucositis, diarrhoea • Temporary alopecia • Skin and nail changes • Cardiomyopathy or arrhythmia • Gonadal failure – temporary or permanent • Teratogenicity – must be advised to use contraception #Neurotoxicity – peripheral and central • Hepatocellular damage Adverse effects – those due to Rx on the tumour • ARF – often multifactorial – hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules • GI perforation at site of tumour – reported in lymphoma • Disseminated intravascular coagulopathy onset within a few hours of starting Rx for AML Properties of drug • Some IV chem. Drugs are vesicants – extravasation may lead to extensive skin and subcut tissue necrosis • Nausea – multifactorial but includes direct action of chemo drugs on the central chemoreceptor trigger zone. Beau’s lines are transverse depression in the nail plate caused by temporary cession of cell division in the proximal nail matrix. Drug interactions – other drugs may ↑plasma levels of the chemo drugs • Vincristine and intraconazole (anti-fungal) leads to more neuropathy • 6-mercaptopurine and allopurinol (commonly used to prevent gout and renal failure) the latter inhibits the breakdown of 6-MP • Methotrexate – caution with prescribing penicillin, NSAIDS Monitoring during Rx • Response of the cancer – reassessment of solid tumours by radiological imaging; leukaemias by BM examination after a predetermined no of cycles to ensure response • Drug levels e.g. Methotrexate drug assays taken on serial days to ensure CL from the blood after folate rescue • Checks for the organ damage – some regiments stipulate measurement of Creatinine clearance, ECG or LFTs

Treatment for non-Hodgkin’s lymphoma – R-CHOP which is Rituximab, Cyclophosphamide, doxorubicin hydrochloride, vincristine (AKA oncovin), prednisolone

Session 11- Drugs Treatment of Parkinson’s Disease Clinical features of Parkinsonism – Tremor (low Hz high amp), rigidity (cog-wheel, clasp knife), bradykinesia, postural instability Causes of Parkinsonism: • Idiopathic PD •

Other degenerative diseases – manifest with akinetic degenerative syndrome,

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Drug induced – anti-psychotic drugs ↓dopamine

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Neurotoxins

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Metabolic

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Vascular (pseudoparkinsonism)

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Toxins  CO, MN, MPTP

Pathophysiology of idiopathic Parkinson’s disease Degeneration of neurones in Substantia nigra (pars compacta), depletion of dopamine, symptoms appear with 50% neuronal loss. DA receptors in corpus striatum intact. Other NT also involved Pathology – neurodegenerative, Lewy body (at post mortem), loss of pigment on SN, ↓dopamine in that part of the brain. Clinical – progressive disease, motor symptoms improve with levodopa, however non motor manifestations... mood changes, pain, cognitive change, urinary symptoms, sleep disorder, sweating • 80% somnolence Prognosis in PD 15 year follow up: (sleepiness) • 94% dyskinesia • 50% swallowing difficulties • 81% falls •

84% cognitive decline (50% hallucinations)

Diagnosis of IPD – clinical features, exclusion of differentials, response to levodopa, structural neuro imaging is normal, functional neuro imaging – SPECT, PET DAT scan (like SPECT) – labelled tracer, presynaptic uptake, abnormal in PD, not diagnostic,

Rx of Parkinson’s Disease Drugs classes in IPD – Levodopa, DA receptor agonist, MAOI type B inhibitors, COMT, anticholinergics, Amantadine Phenylalanine Levodopa  dopamine then either MAO or COMT LEVO DOPA used in combination with peripheral decarboxylase inhibitor: e.g. carbidopa LEVO DOPA – tablet, standard dosages given with controlled release preparations. L. Dopa is toxic to neurones in cell culture; ↑ DA turnover may enhance oxidative stress. L. Dopa is not toxic to non PD patients. Long term usage – loss of efficacy, involuntary movements, motor fluctuations (on/off) Motor complications – wearing off, dyskinesias, dystonia, freezing, on/off flux LEVO dopa: • +’ves – highly efficacious, low SE • -‘ves – precursor (enzyme conversation), may be neurotoxic, long term failure of effect DA agonists (ERGOT derivatives pergolide, cabergoline, non ERGOT ropinirole, PATCH – rotigotine subcut - apomorphine) • Advantages - direct acting, no dyskinesias, possible neuroprotection • Disadvantages – SE, less efficacy than levo dopa, and expensive •

ERGOT cause fibrosis of: peritoneum, heart valve cavities and pleural cavity. Non-ERGOT don’t

Impulse control disorders with DA receptor agonists – pathological gambling, hypersexuality, compulsive shopping, desire to ↑dosage, punding Uses of DA agonists – de novo therapy, and add on therapy Anticholinergics – Ach may have antagonist effects to dopamine drugs, trihexyphenidyl, orphenadrine, procyclidine Advantages – treat tremor, not acting via DA systems Disadvantages – no effect on akinesia, SE! Mono amine oxidase inhibitors – non selective ‘cheese effect’ (e.g. selegiline, rasagiline) Selective type B – enhance dopamine. No therapeutic effect alone, prolong action of levo dopa and may be neuroprotective

Catechol-o-methyl transferase inhibitors – ↓peripheral breakdown of levo dopa, have levo dopa ‘sparing’ effect. Smoothes out motor response Surgery carried out stereotactically, of value in highly selected cases, controlled trails o

Lesion – thalamus for tremor, GPi for dyskinesias

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Deep brain stimulation – Subthalamic nucleus

Session 11- Anti-epileptic drugs Epilepsy = episodic discharge of abnormal high frequency electrical activity in brain leading to seizure. Diagnosis requires evidence of ‘recurrent’ seizures unprovoked by other identifiable causes Seizure – is the episodic discharge of high frequency impulses in the brain, or a part of it. Medical overview epilepsies should be viewed as a symptom of underlying neurological disorder and not a single disease entity. Common condition- 0.5-1% prevalence therefore 450000 in UK with some form of the disease, chronic epilepsy – 500 sudden deaths/year in UK, therapeutics currently effective for about 75%. 10% will still have frequent seizures Anti epileptic drugs – • ADRs – common some serious • DDIs – some positive combined with other AEDs often significant negative PK interactions Medic-social consequences of misdiagnosis – inappropriate labelling of epilepsy has serious implications such as social financial and medical there is a certain degree of difficulty in diagnosis Classification: Two main types: • Partial seizures (simple conscious normal) complex (consciousness effected) o Loss of local or local excitatory/inhibitory homeostasis, ↑ discharges in focal cortical area, 

Symptoms reflect area affected e.g. involuntary motor disturbance, behavioural change, impending focal spread accompanied by ‘aura’ e.g. unusual smell or taste



May become secondarily generalised

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Generalised seizures o

Generated centrally spread through both hemispheres with loss of consciousness (reticular system affected)

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Tonic-clonic seizures (grand mal) – 60% 

Tonic phase = patient falls unconscious with muscles in spasm and lack of respiratory movement leading to possible cyanosis

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Clonic phase – convulsive movements with possible biting of the tongue and urinary incontinence.

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Absence seizures (petit mal) – 5%

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Many other types recognised

Complications Status epilepticus – most seizures are short lived ( 30 mins or convulsions occurring back to back with no recovery between them. NOTE any convulsion lasting >5mins or two convulsions without recovery should receive emergency Rx. Uncontrolled convulsions can lead to hypoxia and irreversible brain damage and death. Adult mortality = 20% risk ↑with length of episode Priorities are ABC, exclude hypoG, hypoventilation may result with high AED doses, ITU for paralysis and ventilation if failing Rx – BZD e.g. Lorazepam (0.1 mg/kg) preferred as longer t1/2 than diazepam. IV route (rectal if difficult IV access) AND phenytoin (zero order kinetics (1520mg/kg), rapidly reaches therapeutic levels IV  cardiac monitoring – arrhythmias + hypotension Other drugs – midazolam, pentobarbital propofol VERY BASIC RULE OF THUMB

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Valproate sodium as 1st line for primary generalised seizures Carbamezepine for partial seizures (or generalised seizures)

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Lamotrigine can be used in either circumstances, and is probably the drug of choice for ♀of child bearing age

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Benzodiazepines and phenytoin are 1st line for acute life threatening status epilepticus.

Drugs used in psychiatric Disease Contemporary knowledge of CNS disorders is largely predicated on knowing how drugs act on disease systems and then inferring the pathophysiology of the disorder. Therefore pathophysiology is inferred rather than proved since we do not yet know the primary enzyme, receptor or genetic deficiency in any given psychiatric disorder Virtually all effective psychopharmacological drugs discovered to date were found by good luck, or by empiricism, that is, by probing disease mechanisms with a drug of known action but no prior proof that such actions would necessarily be therapeutic. Action of CNS Drugs As agonists/antagonists of NT receptors. Some drugs may compete with the NT for its own binding site attempting to mimic the NT or to block the NT. Less commonly act as inhibitors of regulatory enzymes – the enzymes most important in the NT processes are those that make or destroy NT. Key transmission and modulatory pathways in CNS • Noradrenergic pathways • Dopaminergic pathways • Serotonergic (5HT pathways) • GABA-ergic pathways • Cholinergic pathways • Glutamate pathways Formulation of psychiatric disorders Genetic vulnerability to the expression of the disease. Life events that come the individual’s way. Individual’s personality, coping skills, social support. Other environmental influences e.g. viruses, toxins other disease. BIOPSYCHOSOCIAL MODEL Depression Key Sx – low mood, guilt, loss of concentration, ↓energy, ↓↓appetite, sleep, pessimism disturbance, physical aches and pains, irritability, self harm, suicidal ideas/acts, psychotic Sx Unipolar depression is where the mood swing is always in the same direction. The majority of cases are due to external triggers such as difficult life events (reactive depression). However about 25% of patients seems to have

endogenous depression where no such relationship can be seen. This is often familial. Pathophysiology: Theory 1 Monoamine hypothesis - depression due to a deficiency of monoamine NT – NA and serotonin – certain drugs that depleted these could induce depression reserpine. E.g. monoamine oxidase inhibitors (MAOIs) – block enzyme from destroying NT NT receptor hypothesis – an abnormality in the receptors for monoamine transmission leads to depression. Depletion of NT causes compensatory up regulation of post synaptic receptors, altered balance of various NT systems, long term adaptive responses e.g. altered gene expression – some post mortem evidence HOWEVER = no clear and convincing evidence that monoamine deficiency accounts for depression or that receptor change accounts for depression. Growing evidence that despite apparently normal levels of monoamines and receptors that these systems do not respond normally Theory 3 – the monoamine hypothesis of gene expression - deficiency in molecular functioning hypothesised problem within the molecular events distal to the receptor. Monamine oxidase inhibitors With additonal actions(TCAs) Pure(SNRIs) Non- selective noradrenalin and serotonin Noradrenaline (NARIs) Serotonin( SSRIs) Selective noradrenaline or serotonin Monoamine uptake inhibiotrs Other drugs (e.g. mirtazepine) Antidepressants

Theory 4 – “neurokinin hypothesis of emotional dysfunction”. Observation that substance P – an antagonist to neurokinins may have an antidepressant action

Selective serotonin reuptake inhibitors – First line nowadays due to improved safety profile First line treatment for moderate to severe depression Fluoxetine, citalopram, paroxetine Citalopram most selective, paroxetine most potent may interact with extrapyramidal dopaminergic system. PK - almost completely absorbed from gut. Long elimination T1/2 metabolised in liver. Side effects and toxicity Common – anorexia, nausea, diarrhoea Rare – precipitation mania, ↑ suicidal ideation and neurological SE such as tremor, extrapyramidal syndromes NB – safe in overdose if taken on own Tricyclic antidepressants First generation antidepressants. Still used amitryptiline, imipramine, clomipramine Block re-uptake of serotonin, NA Other effects 1. Inhibition of NA uptake, enhancing NA Neurotransmission (sympathomimetic effect) 2. Muscarinic cholinoceptor blockade – ↓cholinergic neurotransmission (anticholinergic effect) 3. Alpha 1- adrenoceptor blockade – suppression of NA neurotransmission (sympatholytic effect) PK – lipid soluble, absorbed from gut, long half lives, metabolised in liver SE and toxicity = CNS – sedation and impairment of psychomotor performance, lowering of seizure threshold. ANS, reduction in glandular secretions, eye accommodation block. CVS – tachycardia, postural hypotension, impaired myocardial contractility GI – constipation Overdose ‘PURE’ non-selective monoamine uptake inhibitors

Developed as SSRIS with property of NA uptake inhibition grafted on. E.g. venlafaxine a second line drug. Dose dependent – lower doses serotonin action, higher doses NA SE and toxicity- as with SSRIs, also sleep disturbance, ↑BP, dry mouth, hyponatraemia, relatively short T1/2 therefore may be a withdrawal syndrome on discontinuation

Schizophrenia – Psychosis Schizophrenia is an example of a mental illness with psychotic symptoms. 1% of UK population Other illnesses are mania, psychotic depression, and organic syndromes Symptoms of schizophrenia • Positive symptoms: hallucinations, delusions, thought disorders, abnormal behaviour • Negative symptoms – blunted affect, social withdrawal, poverty of thought and speech • Cognitive symptoms – selective attention, poor memory reduced abstract thought • Affective symptoms – anxiety and depression Schizophrenia – its symptoms are numerous, its presentations are diverse, its cause is unknown and its response to treatment is unsatisfactory Genetic (strong familial component) + biological (e.g. maternal gestational hypertension) + upbringing  schizophrenia Dopamine theory of schizophrenia Amphetamine causes symptoms very similar to positive symptoms of schizophrenia. Dopamine antagonists are the best treatment for schizophrenia. Some evidence of ↑ dopamine function in schizophrenics But amphetamine does not cause negative symptoms. Dopamine antagonists do not treat negative symptoms; changes in dopamine function may be a response to long term drug treatment Main dopamine pathways • Mesolimbic – important in emotional response and behaviour, and connect to the hippocampal and amygdala areas. • Meso-cortical – important in arousal and mood • Nigrostriatal – 75% of brain dopaminergic pathways. Neurones span from the substantia nigra to the corpus striatum and is the key pathway damaged in Parkinson’s disease. Dopamine antagonism can thus induce ‘extra-pyramidal’ movement disorders and are relevant to SE of antipsychotic drugs key pathway damaged in Parkinson’s disease • Tuber-hypophyseal in hypothalamus and pituitary gland Is schizophrenia associated with ↑ 5HT FUNCTION?

5HT has been implicated in a number of behaviours which are disturbed in schizophrenia (e.g. perception, attention, mood, aggression, sexual drive, appetite, motor behaviour, sleep) Many of the most effective antipsychotic drugs are antagonists at 5HT-2A receptors Lysergic acid diethylamine (LSD), a 5HT-2A agonist is psychotogenic. Precursors of 5HT exacerbate schizophrenia. Chronic Fluoxetine (Prozac) ↑ 5HT activity and ↑ both +ve & –ve symptoms BUT LSD produces mainly visual hallucinations: other psychotic symptoms (conceptual disorganisation and cognitive impairments) are generally absent No strong evidence for changes in 5HT function Is schizophrenia associated with ↓cortical glutamate function? Glutamate is the predominant excitatory NT in the brain Phencyclidine (PCP: non-competitive antagonist at NMDA-type glutamate receptors) induces symptoms very similar to schizophrenia Post mortem studies have shown: • ↑ cortical glutamate receptors • ↑ binding of glutamate receptor ligands in cortex, basal ganglia and hippocampal formation • BUT both ↑ and ↓ in glutamate binding in temporal lobe have been reported • Glutamate systems are important, mechanism unclear

DRUGS First generation typical antipsychotics  haloperidol, chlorpromazine (increased dopamine antagonism) Atypical antipsychotics  olanzapine, risperidone, quetiapine, Clozapine (most effective but serious ADRs) Action of all antipsychotics • • • • •

Sedation – within hours Tranquilisation – within hours Antipsychotic – several days or weeks Activating effect within weeks – negative symptoms Production of extrapyramidal side effects – hours or days advantage of atypical Atypical advantages Less SE so more acceptable to patient, different preparations e.g. dissolvable some once daily dosage. Differing SE profiles can be matched to patient characteristics, 1st line treatment in schizophrenia Typical antipsychotics

Haloperidol safe in emergencies, more sedating, well known SE Wide range of pharmacological action, DA receptor blockade, anticholinergic effects, α-adrenergic blockade, antihistamine effect, allergic reactions SE – extrapyramidal SE – Parkinsonism, acute dystonia, akathisia (inner restlessness), tardive dyskinesia Neuroleptic malignant syndrome - severe rigidity, hyperthermia, ↑ CPK, autonomic lability Postural hypotension, weight gain, endocrine changes e.g prolactinaemia, pigmentation Toxicity – CNS depression, cardiac toxicity, risk of sudden death with high dose

Anxiety Fears out of proportion to situation  avoidance  fear of dying, going crazy Physical symptoms – light headedness, SOB, hot and cold flushes, palpitations, numbness Treatment – non-pharmacological approaches first line. Treat any coexistent disorder Drugs – antidepressants, anxiolytics, occasionally antipsychotics Principle NT systems – GABA, 5-HT, NA, many of drugs prescribed however have very specific pharmacological effects Benzodiazepines e.g. diazepam, lorazepam Exerts effects through structure known as GABA-BDZ receptor complex. BDZ only bind to BDZ receptor of which there are 2 main groups – high and low affinity High affinity group – important in anxiolytic, hypnotic and anticonvulsant effects of BDZ. Inhibitory effects in brain They act as full agonist at these receptor sites, lead to enhancement of GABA. BA following oral admin – almost complete-maximum concentration 30-90 mins, highly lipid soluble – CNS diffusion rapid. Renal excretion, long t1/2 Tolerance can occur; dependence-on discontinuation of Rx can get withdrawal effects such as insomnia, agitation, anxiety SE – • Common – drowsiness, dizziness, psychomotor impairment • Occasional – dry mouth, blurred vision, GI upset, ataxia, headache, ↓BP • Rare – amnesia, restlessness, skin rash Toxicity – cleft lip and palate if used in pregnancy. If taken late in pregnancy may cause resp depression and feeding difficulties in baby Treatment of overdose – deaths are rare – support

Flumazenil and antagonist/partial inverse agonist at BDZ receptors may be useful in reversing effects

Bipolar disorder Depression and hypomania/mania Feeling unusually excited, happy, optimistic or feeling irritable Overactive – poor concentration and short attention span, poor sleep, rapid speech, jump from one idea to another, poor judgement, ↑interest in sex Psychotic symptoms – hallucinations, grandiose delusions Mood stabilisers – Lithium, sodium valproate, carbamazepine, olanzapine Lithium Theories 1. Electrolytes and channels – may compete with Mg and Ca ions 2. NT – acute Li ↑5HT, chronic Li may ↓5-HT receptor sites 3. Second messenger systems – Li attenuates the effects of certain NT on their receptors without altering receptor density Clinical pharmacology – renal excretion, slow release preparations can be given once daily. Li levels need to be monitored (at least 3 monthly) and taken 12 hours after last oral dose. Need to check renal function and thyroid function before starting Side effects: • Memory problems – 52% • Thirst – 42% • Polyuria – 38% • Tremor – 34% • Drowsiness – 24% • Weight gain – 18% Other effects – kidneys, hypothyroidism, hair loss, rashes Toxic effects – need to monitor  V&D, coarse tremor, Dysarthria, cognitive impairment, restlessness, agitation Rx of toxicity – supportive measure, anticonvulsants, ↑fluid intake, haemodialysis may be necessary

Session 13: Drugs Affecting Acid Secretion The parietal cell: mechanism of acid secretion When stimulated, parietal cells secrete HCl at a concentration of roughly 160mM (pH 0.8). The acid is secreted into large cannaliculi which are continuous with the lumen of the stomach. Cytoplasmic tubulovesicular membranes are abundant in the resting cell and virtually disappear in concert with a large increase in the cannalicular membrane. It appears that the proton pump as well as the K and Cl

conductance channels initially reside on intracellular membranes and are transported to and fused into the cannalicular membrane just prior to acid secretion. Mechanism of acid secretion The [H+] in parietal cell secretions is roughly 3 million fold higher than in blood, and chloride is secreted against both a conc grad and electric grad. This, the ability of the parietal cell to secrete acid is dependent on active transport. H +/K+ ATPase or the proton pump located in the cannalicular membrane. Current model: H+ are generated within the parietal cell from dissociation of water. The OH- in this process rapidly combine with CO 2  HCO3- by a carbonic anhydrase. The HCO3- is transported out of the Basolateral membrane in exchange for chloride. The HCO3- into the blood is known as the alkaline tide. This process serves to maintain intracellular pH in the parietal cell. Cl and K are transported into the lumen of the canaliculus by conductance channels, and such is necessary for secretion of H +. H+ pumped out of the cell by the proton pump; K is thus effectively recycled. Accumulation of osmotically-active H+ in the canaliculus generates an osmotic gradient across the membrane that results in outward diffusion of water – the resulting gastric jucice is 155mM HCl and 15 mM KCl with some NaCl Control of Acid secretion Parietal cells bear receptors for three stimulators of acid secretion: • Ach • Gastrin •

Histamine (H2 type receptor)

Extracellular Ca is also necessary for acid secretion. Binding of Ach and gastrin result in elevation of [Ca]i while histamine’s effect is to activated adenylate thus ↑[cAMP]. Histamine from enterochromafin-like cells may be the primary modulator, but the magnitude of the stimulus appears to result from a complex additive of multiplicative interaction of signals of each type. Pharmacologic antagonists of each of these molecules can block acid secretion Drug therapy for suppressing secretions of Gastric acid 1. Antacids – neutralise if given sufficiently large volumes can heal ulcers 2. Promoting gastric emptying and so removing acid – metoclopramide efficacy limited 3. H2 blockade a. H1 receptor drugs have no effect b. H2 blocking drugs – cimetidine, ranitidine, famotidine, nizatidine

4. Proton pump inhibitors a. Blocks H+ K+ ATPase, non-competitive bind and inactivate the ATPase. i. Omeprazole, lanzoprazole, esomeprazole H. pylori – Rx. Lanzoprazole, clarithromycin and amoxicillin. Bacteria causes ulcers, especially duodenal ulcers =. Urea breath test used for diagnosis

Drugs affecting gut Motility Myogenic control of the gut. Rhythmic contraction creates slow waves of depolarisation throughout the smooth muscle. Passive current spread through gap junctions. Interstitial cells of cajal act as pacemaker to drive electrical activity. Neural control – intrinsic and extrinsic control, stimulation of the post-ganglionic cholinergic enteric nerves ↑force of contraction of gut. Stimulation of nonadrenergic inhibitory nerves inhibits contractions. Gastric motility – a complex neuronal network •

Local nerves – enteric nervous system – autonomous collection of nerves within gut wall

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Auerbach’s plexus – between circular and longitudinal muscle layers

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Meissner’s plexus – submucosa

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Henle’s plexus in circular muscle adjacent to submucosa

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Cajal’s plexus in circular muscle adjacent to longitudinal muscle.

Extrinsic nerves Intestino-intestinal inhibitory reflex – distension of one intestinal segment causes complete intestinal inhibition Anointestinal inhibitory reflex – distension of the anus causes intestinal inhibition Gastrocolic and duodenocolic reflexes – stimulates motility after material has entered the stomach or duodenum . Neurotransmitters – all endocrine hormones in the GIT are peptides produced in the endocrine cells of mucosa •

Gastrin promotes acid secretion

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Secretin – duodenum

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Cholecyskinin – small intestine

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Motilin – small intestine

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Paracrine transmitters – histamine, somatostatin, prostaglandins

Nausea and Vomiting Emesis – the pyloric sphincter closes while the cardia and oesophagus relax. Gastric contents propelled by contraction of abdominal wall and diaphragm. Glottis closes with elevation of the soft palate preventing entry of vomitus into the trachea and nasopharynx.

Anti-emesis drugs Dopamine D2 receptor antagonists –, metoclopramide, Domperidone (D 2 antagonist) (spiel below) Acts – postrema on the floor of the 4th ventricle and to ↑rate of gastric emptying Indicated in acute nausea/vomiting (esp. Induced by L-dopa or dopamine agonists Route – oral or PR (extensive FPM) but does not cross blood-brain barrier. ADR – stimulates prolactin release (galactorrhoea) but rare dystonia Ondansetron (5-HT3 receptor antagonist) 5-HT released into the gut causes vagal stimulation. Therefore Ondansetron is effective: •

postrema on the floor of the 4th ventricle

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Against vagal afferent nerves in GI

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Indicated – in high doses in radiation sickness and chemo Rx/ postoperative

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Route – IV, IM or orally

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The anti-emetic effect can be enhanced by single dose of a corticosteroid

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ADRs; headaches; constipation; flushing (IV

Metoclopramide In addition to D2 antagonism anti-cholinergic effects (GI) and blocks vagal afferent 5-HT3R (GI Indications are GI cause for N&V; migraine; post-op Routes – oral; IM; IV

Short T1/2 – 4 hours

ADRs – extra-pyramidal reactions (dystonia) occur in 1% - therefore avoid in PD; galactorrhoea Hyoscine (Ach antagonist) – direct antagonist of muscarinic receptors, it is used to treat motion sickness – oral or patch. Effects usually short lived ADRs – systemic anti-cholinergic effects; bradycardia Cyclizine (H1 antagonist) – has additional anti-muscarinic effects used in acute N&V. Can be given oral, IV or IM but can cause QT prolongation and therefore Cl in myocardial ischaemia etc. Crosses the BBB – sedative effect Other H1 antagonists include promethazine; phenothiazine may suppress nausea following surgery or gastric irritation/opioid induced nausea and useful if sedation required. • Other agents o Cannabinoids – nabilone o

Benzodiazapines –lorazapam

Constipation Laxatives treatments • non-pharmacological o Consider underlying medical cause – diabetes, PD, dehydration, pregnancy, mechanical obstruction, or cancer o

↑fluid intake

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High fibre diet

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Exercise

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Bulk – fybogel

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Faecal softeners – glycerol (Also acts as a stimulant

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Osmotic – lactulose/macrogols/phosphate enemas

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Irritant/stimulants – castor oil, senna, sodium picosulfate

Drugs causing constipation – anticholinergics, aluminium antacids, antidepressants (TCA, SSRIs), antiepileptics (carbamazepine), antipsychotics (Clozapine, quetiapine), antispasmodics (dicycloverine, hyoscine), calcium supplements, diuretics (inadapamide), iron supplemenets, opioids (codeine, Buprenorphine), verapamil. Bulk laxatives 

Vegetable fibre – resistant to digestive enzymes, take a few days to work, attempt to re-establish normal bowel habit (chronic or simple constipation related to IBS, pregnancy etc.) normal fluid intake essential. ADR – flatulence. Cl – adhesions/ulceration – may cause intestinal obstruction. Ideally patients should ↑fibre in their diet. Faecal softeners Arachis oil (enema) and glycerol (supplement) act by lubricating and softening stool, safe but not always effective. Indicated as per bulk laxatives but also: adhesions etc. As no risk of obstruction and anal fissures and haemorrhoids Osmotically active laxatives mg and Na salts. Mg and Na salts (saline purgatives = phosphate enema) cause water retention in small/large bowel to ↑peristalsis act quickly and are severe, usually PR, reserve for resistant constipation. Lactulose – disaccharide (galactose/fructose) cannot be hydrolyzed by digestive enzymes. Fermentation of lactulose by colon bacteria leads to acetic and lactic acid (osmotic effect). Oral takes 48 hours to work thus used in Liver Failure – reduced production of ammonia. Movicol (polyethylene glycol) – powder dissolved in fluid, may prevent dehydration, initial effects within hours, takes 2-4 to get full relief. Like all osmotic laxatives – caution required to prevent intestinal obstruction . Irritant/stimulant laxative Excitation of sensory nerve endings leads to water and electrolyte retention and thus peristalsis. Used for rapid treatment e.g. faecal impaction or surgical prep. Can act 6-8 hours (orally) so bedtime Rx. Repeated use – colonic atony and hypokalaemia Anthraquinones – Danthron, senna plant, rhubarb roots. Most frequently used senna and codanthramer. Danthron plus faecal softener e.g. docusate sodium. Some derivatives are absorbed in small intestine and excreted into colon along with those that have escaped absorption. Similar to the other laxatives – can cause abdominal cramps – don’t use in intestinal obstruction

Abuse – melanosis coli. What Type of Laxative If history and/or examination reveals soft faeces stimulant laxatives (e.g. senna, bisacondyl glycerol) If history and DRE reveals hard faeces: osmotic laxatives (e.g. movicol), bulkforming laxatives (e.g. ispaghula) Constipation hypokalaemia feedback

Diarrhoea Think cause – may represent overflow to constipation, anti-diarrhoeal drugs treat symptoms not the cause. Appropriate fluid/electrolyte management is important: anti-motility, bulk forming – fluid absorbents, and fluid absorbents. Anti motility drugs – Opiate analgesics (codeine), Opiate analogue – loperamide – 40 times more potent than morphine as antidiarrheal agent and penetrates CNS poorly. Act via opioid receptors in bowel: •

↓bowel motility - ↑ time for fluid to reabsorb

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↑ anal tone and ↓ sensory defecation reflex

Good for chronic diarrhoea. Avoid in IBD as causes toxic megacolon Bulk forming – a relatively small amount of faecal fluid (10-20ml) influences composition drugs such as ispaghula act via water absorption. Particularly useful for patients with ICS (constipation and diarrhoea) and those with ileostomy. Fluid absorbents a relatively small amount of faecal fluid (10-20ml) influences composition. Kaelin acts as a fluid absorbent, therefore producing a more formed stool, very little use Cholestyramine is a bile acid sequestrant and used for bile salt induced diarrhoea (crohn’s/post-vagotomy) Pancreatic enzymes help with diarrhoea due to pancreatic malabsorption

Irritable Bowel Syndrome A heterogenous group of abdominal symptoms for which no organic cause can be found – 3 common patient profiles 1. Diarrhoea predominant

2. Constipation predominant 3. Altering symptoms Symptoms – diarrhoea occurring mainly in the morning, colicky lower abdominal pain, stability of weight. Abdominal pain/discomfort relieved by defecation or associated with altered bowel frequency” Others. Altered stool passage, abdominal bloating, distension or hardness, symptoms made worse by eating, passage of mucus Mebeverine – reserpine derivative IT has direct effects on colonic hypermotility. It relieves spasm of intestinal muscle. It does not have troublesome systemic anti-muscarininc SE. Useful when combined with bulk forming agent (fybogel meberverine) other smooth muscle relaxants include peppermint oil and alverine.