Pharmacy Flashcards
LO 1.1 Be aware of the major underlying causes of poor prescribing and see how these causes relate to each other
Deaths relating to prescribing rate is five times higher than it was ten years ago, perhaps due to increased reporting.
Prescribing Problems
o Prescribing errors are complex and multi factorial.
o poor communication in particular has been shown to be a major factor in both causing and compounding prescription error.
Patient and Population Related Problems
o Rapid patient turnover
o Sicker and older patients, more vulnerable to adverse effects
o Increased use of medicines generally (Multiple drugs)
o Increasing complexity of medical care (Co-morbidity)
Pharmaceutical Problems
o Vast numbers of new drugs
o Clinical evidence for new drugs is usually from selected, relatively healthier patients and/or young volunteers
o Some side effects only come to light after the drug comes to market
o Blind adherence to guidelines can lead to prescription where contraindications or serious interactions exists
Doctor related problems
o No room for error and expected to be perfect from day 1 after qualification
o Experience from medical school (level of teaching/examining)
o On call medicine (Sleep deprivation, exhaustion)
o Shift work (Lack of continuity of care, working alone more often)
LO 1.2 Recognise how problems in prescribing can compound prescription error giving the two models of error, and the types of error
Reason’s Model of Error Causation is a model of the general factors underlying error and accident causation in human systems. It is broken down into three components, Latent Conditions, Error Producing Conditions and Active Failures.
Swiss Cheese Model
In the Swiss cheese model, the layers represent defences on the path from hazard to accident. If weaknesses in the defences, either from inadequate design or error line up (‘holes in the cheese’), hazards may pass completely through all the layers to cause an adverse event.
Types of Error Skill based errors o Slips – Action based errors o Lapses – Memory based errors o Knowledge based mistakes o Violations - Knowingly disregard rules
LO 1.3 What are the requirements for a prescription. What should you confirm, legal requirements and a basic checklist.
Before writing a prescription confirm o Name of Drug(s) o Dose o Strength o Frequency o Duration of treatment o Allergies/adverse effects o Indication o Adherence
Legal Requirements o Written in indelible ink o Patient identification (name, address, hospital number) o Date of birth (if under 12) o Signed o Dated o Name and address of practitioner
Basic Check List for safe prescribing o The right drug o Drug distribution/elimination o Alternatives - Non prescription medications o Route o Dose o Frequency o Duration o Monitoring o Information o Special requirements
`What is the yellow card scheme
In Black Triangle Drugs (one being monitored, e.g. newly released, changed indication or formulation) and unlicensed herbal preparations you should report all suspected reactions, however trivial
In Established products and vaccines, report all suspected serious reactions, even if the reaction is well known and recognised, a serious reaction is any that results in or prolongs hospitalisation. Also ones that are fatal, life threatening, disabling or incapacitating. Also report paediatric cases
LO 1.6 Be familiar with a modern day formulary and give examples of formularies in everyday use
The British National Formulary is a comprehensive listing of all the drugs currently licensed in the UK. It is in widespread use throughout the NHS. It also includes some drugs that have traditionally been used but have now been identified as less suitable for prescribing, either because of lack of efficacy or increased toxicity.
LO 1.9 Identify the most important characteristics of a drug relevant to therapeutic use
Efficacy - How effective it is compared with similar drugs or a placebo
Safety - Major and minor adverse effects
Cost - But only if efficacy and safety of two drugs are equivalent
LO 1.10 Recognise the central role of the pharmacist in overviewing prescription and minimising the risk and consequences of prescription error to both patient and doctor
The pharmacist often has a deeper and broader understanding of pharmacology than most medics. They also occupy a pivotal position in the healthcare system in overseeing that prescriptions are correctly made out.
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.
Deifne Pharmacokinetics, Pharmacodynamics and Pharmacogenetics
Pharmacokinetics – What the body does to the drug
Pharmacodynamics – What the drug does to the body
Pharmacogenetics – The effect of genetic variations on pharmacokinetics/dynamics
What are the Key Pharmacokinetic Factors and understand the importance of pharmacokinetics applied to clinical practice
Absorption, Distribution, Metabolism, Elimination
Bio availability - leads to the correct formulation
Half-life - allows dosing regimens to be devised
Drug elimination
Intra-subject variability - allows appropriate dosing regimens for special patient groups, helps determine why a patient may fail to respond to a treatment or why a drug has caused toxicity
Drug-Drug interactions
LO 2.3 Recognise the main routes of drug administration in to the body
Enteral delivery includes drug routes via the GI tract:
o Oral
o Rectal
o Sublingual
Parental Delivery are the drug routes not via the GI tract: o Intramuscular o Intravenous / Intravenous Infusion o Intrathecal o Topical o Subcutaneous
LO 2.4 Understand the factors affecting drug Absorption
When drugs are given orally, both the rate of uptake of a drug and first pass metabolism can affect the peak plasma concentration of a drug and the time it spends in the body.
Passive Factors:
o Drug Liphophilicity.
o Molecular size
o pH changes
Active Factors:
o Presence of active transport systems
o Splanchnic blood flow (reduced in shock and heart failure)
o Drug destruction by gut and/or bacterial enzymes
LO 2.4 Understand the factors affecting drug Distribution and the factors affecting protein binding (what makes it worse, and what proteins bind to what)
The major factors affecting the distribution of a drug are:
o Lipophilicity / Hydrophobicity
o Tissue Protein Binding (e.g. muscle)
o The mass or volume of tissue and density of binding sites within that tissue - This can vary significantly between individuals, for example in a patient with a large muscle mass, Digoxin binding would be effected as it has a very high affinity to Na/K ATPase.
o Protein Binding -Once in the systemic circulation, many drugs are bound to circulating proteins. However, most drugs must be unbound (free) to have a pharmacological effect. Only the fraction of the drug that is not protein bound can bind to cellular receptors, pass across tissue membranes, gain access to cellular enzymes etc. Displacement of drugs from binding sites due to Protein Binding drug interactions raises the free concentration of the displaced drug. These changes in drug distribution are only important if three criteria are met:
High protein binding
Low volume of distribution
Drug has a narrow therapeutic ratio
Factors affecting protein binding include: Hypoalbuminaemia Pregnancy Renal failure Displacement by other drugs
Protein Binding o Albumin -Acidic drugs o Globulins - Hormones o Lipoproteins - Basic drugs o Acid Glycoproteins - Basic drugs
LO 2.5 Understand the factors affecting drug metabolism
Phase I
Most drug molecules are stable and relatively unreactive (pro-drugs) so in Phase I metabolism a reactive group is exposed on the parent molecule or added to the molecule via Oxidation, Reduction and Hydrolysis reactions. The process requires Cytochrome P450 and NADPH. These enzymes are both Inducible and Inhibitable, and are located on the external face of the endoplasmic reticulum in hepatocytes. A wide range of factors, including sex, age, genetics, cardiac output, and a disease state affects the metabolism of drugs. Some drugs already have a reactive group on their molecule so they can bypass Phase I. Morphine is a good example of this.
CYP Inducer Phenytoin Carbamazepine Barbituates Rifampicin Alcohol (Chronic) Sulphonylureas & St. John’s Wort
CYP Inhibitor Grapefruit Juice Omeprazole Disulfiram Erythromycin Valporate Isoniazid Cimetidine & Ciprofloxacin Ethanol (Acutely) Sulphonamides
Phase II
The reactive intermediate from Phase I is conjugated with a polar molecule to form a water-soluble complex. The process is also known as conjugation.
Glucoronic acid is the most common conjugate, as it’s an available by-product of cell metabolism. Drugs can also be conjugated with sulphate ions and glutathione. Phase II metabolism requires specific enzymes and a high-energy cofactor, uridine diphosphate glucuronic acid (UDPGA).
LO 2.5 How does drug excretion occur and understand the factors affecting excretion
Metabolism causes drugs to become more ionic, increasing the ability of the kidney to excrete them via passive glomerular filtration and active tubular secretion.
Excretion out of plasma is then offset by diffusion back across the tubule, especially for lipophilic drugs, which is why the liver goes to so much effort to make them more ionic in nature.
Organic Anion and Cation Transporters (OAT % OCT) are also responsible for transporting drugs across the tubule into the urine.
Factors affecting Renal Excretion
Balance between the above processes and the factors that affect them
o Renal Blood Flow
o Plasma Protein Binding
o Tubular Urinary pH (affects the proportion of weak acids/bases diffusing back into the blood)
LO 2.5 Understand the difference between linear and non-linear kinetics
First Order (Linear) Kinetics -Metabolism is Proportional to Drug Concentration. Give a straight line when a log scale is on the Y-axis versus time.
Half-life is the rate of decline of plasma drug level proportional to drug level.
Zero Order (Non-Linear) Kinetics: In a situation where drug is used at a concentration much greater than Km. The enzymes (e.g. CYP450s) are saturated. The rate of decline of plasma drug level is a constant, regardless of concentration. Because of this Zero Order drugs are more likely to result in toxicity. Zero order kinetics gives a straight line when normal (not log) plasma concentration (Y) is plotted against time (X).
During drug administration, a steady state will be reached within 5 half-lives of that drug. If an immediate effect is necessary, a Loading Dose is needed, bringing the concentration of the drug up to the level it wouldhave been after 5 doses.
LO 2.6 Appreciate how Steady State therapeutic levels in plasma (CpSS) are reached and how Loading Doses are employed to reach CpSS more rapidly
Reaching Steady State Concentration in Plasma (CpSS)
Infusion
With controlled, continuous infusion therapeutic levels are determined by dose rate and clearance.
Steady State Concentration in Plasma = (Dose Rate)/Clearance
Repeated Dosing
When, as in the majority of cases, drugs are given as repeated doses a steady is not obtained, instead the steady state will have peaks and troughs related to the dosing intervals. This is not strictly a ‘steady state’, but if the peaks and troughs are averaged out they are considered to be roughly therapeutically equivalent to the steady state.
Loading Dose
In repeated dosing the time then taken to reach a steady state concentration in plasma is 4-5 half-lives of the drug. If clinicians want to achieve a therapeutic concentration as quickly as possible without waiting for these 4-5 half-lives, they can use a loading dose. A loading dose aims to fill the compartments contributing to the drugs volume of distribution by using a larger than normal dose. The size of the loading dose is calculated using the known Vd of the drug and the desired therapeutic concentration. When using a high dose of a drug means the risk of toxic side effects is increased.
Loading Dose = Vd ×CpSS
LO 2.7 What is Pharmacodynamics, how do drugs exert their effects and what is the effect of concentration on this?
Pharmacodynamics – What the drug does to the body
Drug molecules bind to a range of biological receptor molecules. The four principle classes of receptor site are: o Receptors o Enzymes o Carriers/Transporters o Ion Channels
Drug Concentration
o The response to a drug is generally proportional to the number of receptor sites bound to by the drug.
However, as target receptors can exist at different tissues throughout the body, actual expression levels in different tissues may vary widely and the receptors in only one of these tissue types may actually serve as the desired site of action.
o Pharmodynamic response can be directly proportional to drug concentration.
o However, as the concentration of drug increases the number of sites generating a therapeutic response can become saturated. The Pharmodynamic response will then show a non-linear response to further increases in drug concentration.
LO 2.8 Be able to describe the major types of drug-receptor interaction
Agonist – Bind to and stabilise receptor sites in the Active conformation
Antagonist – Bind to and stabilise receptor sites in the Inactive conformation
Partial Agonist/Antagonist – When drugs act as a mixture of both of the above, they are said to act as Partial Agonists or Partial Antagonists. The overall action of the drugs is dependent on the proportion of receptor sites it stabilises in the Active or Inactive confirmation.
LO 2.9 Define Affinity, Efficacy, Types of Agonmist and Potency and appreciate the idea of a Therapeutic Window and give the value they are each measured in.
Affinity – The tendency of a drug to bind to a specific receptor site.
Kd – Concentration at which half available agonist receptors are bound
Ki – Concentration at which half available antagonist receptors are bound
Efficacy – The maximal effect of a drug when bound to a receptor. Expressed in terms of percentage response, with 100% response when no increase in drug concentration brings about any further increase (non-linear response)
Agonists – Aim for 100% efficacy
Antagonists – Aim for 0% efficacy
Potency (Agonist) (EC50) – Concentration that produces 50% of maximal response
Potency (Antagonist) - Concentration that reduces maximal activation by 50%
Can only be measured in vitro
Competitive Antagonism
In competitive antagonism agonist efficacy can be restored, by increasing agonist concentration. This increases the competition for receptor sites.
In this case Potency (EC50) changes as more of the drug is needed to produce 50% of the maximal response, but the maximal effect stays the same.
Non-Competitive Antagonism
In non-competitive antagonism the antagonist can bind in two ways:
At the same site for the agonist binding irreversibly or unbinding very slowly
At a separate site to the agonist either reversibly or irreversibly
In this case, no matter how much agonist is added, the maximal effect will be depressed proportional to the degree of antagonist binding. However, because the agonist does not have to compete to occupy its binding site, the EC50 remains the same.
Therapeutic Window
The therapeutic window is the concentration of drug that is high enough to have a therapeutic effect, but not so high that is has a toxic effect.
Some drugs have extremely narrow therapeutic windows, e.g. Phenytoin meaning they have to be closely monitored.
Therapeutic Index
Therapeutic Index= (Toxic Dose in 50% of People (TD50))/(Effective Dose in 50% of People (ED50))
LO 2.10 Describe with examples pharmacokinetic and pharmacodynamic drug interactions
Pharmacokinetic Drug-Drug Interactions (ADME)
Absorption
Drugs given via the oral route can be affected by co-administration of other agents affecting gut motility and passive or active absorption by the gut.
o E.g. Metoclopramide acts as a dopamine antagonist. It is an antiemetic and gastroprokinetic. This will increase the rate of gastric emptying and can therefore increase the rate of uptake via the small intestine.
Distribution
The distribution phase can be affected by competition between drugs at protein/lipid binding sites. For the most part, drugs that exhibit linear kinetics and have a reasonable therapeutic window, these effects are offset by an increased clearance.
If the drug has non-linear (Zero Order) Pharmacokinetics and/or a narrow therapeutic window, e.g. Phenytoin, this can lead to serious toxicity.
Metabolism
Drugs can significantly affect metabolism of themselves or other drugs by two mechanisms – Induction and Inhibition of the CYP450 enzymes.
Elimination
The primary mechanisms affecting drug excretion include changes in:
o Protein Binding - Decreased binding increases the amount of free, unbound rug, accelerating its removal
o Tubular secretion - Inhibition of tubular secretion will result in increased plasma levels of drug. This can be used to improved therapeutic effect in some cases, if tubular secretion is very rapid
E.g. Probenecid was specifically developed to enhance the therapeutic action of Penicillin by reducing its renal excretion.
NSAIDs can also reduce tubular secretion.
o Urinary pH - Affects the proportion of weak acids/bases diffusing back into the blood.
Pharmacodynamic Drug-Drug Interactions
Pharmacodynamic Interactions involve a direct conflict between the effects of drugs. This conflict results in the effect of one of the two drugs being enhanced or reduced. For example:
o Propranolol, a non-selective β-Receptor Antagonist given for angina and hypertension will reduce the effect of Salbutamol, a β2-Receptor Agonist given for the treatment of asthma. The administration of β-blockers to asthmatics should, therefore, be avoided, or undertaken with caution.
Drug classes in which Drug-Drug Interactions Commonly Arise Anticonvulsants o Phenytoin o Carbamezepine Anticoagulants o Warfarin Antidepressants o Monoaimine Oxidases Antibiotics o Rifampicin o Macrolides o Quinolones Antiarrhythmics o Amiodarone
LO 2.11 Understand induction and inhibition of the Cytochrome P450 system
Induction of CYP450 Enzymes
o Individual members of the CYP450 enzyme family affected by increased transcription, translation or slower degradation.
o More rapid elimination.
o Induction typically occurs over 1-2 weeks and monitoring of drug levels/therapeutic effect needs to take this into account.
o Withdrawal of the inducing agent without a change in the therapeutic agent can lead to toxicity if dosing is not re-adjusted.
o Induction may lead to increased production of a toxic metabolite
Inhibition of CYP450 Enzymes
o Drug half-lives increasing and drug clearance decrease.
o Inhibition of CYP450s can either be competitive or non-competitive and usually takes place over a few days.
o Introduction of an inhibiting agent without a change in the therapeutic agent can lead to toxicity if dosing is not re-adjusted
o Withdrawal of an inhibiting agent without a change in the therapeutic agent can lead to concentrations falling to a sub-therapeutic level
Inducer Phenytoin Carbamazepine Barbituates Rifampicin Alcohol (Chronic) Sulphonylureas & St. John’s Wort
Inhibitor Grapefruit Juice Omeprazole Disulfiram Erythromycin Valporate Isoniazid Cimetidine & Ciprofloxacin Ethanol (Acutely) Sulphonamides
CYP450 Pharmacogenetics
Variation in CYP450 expression accounts for a large amount of inter-patient variability in drug response.
o Warfarin – CYP2C9
o Codeine – CYP2D6
LO 2.12 Outline how hepatic, renal and cardiac disease drug interaction occurs and the effect of certain foods
Drug Disease Interactions
Hepatic Disease
Reduced clearance of hepatic metabolised drugs
Reduced CYP450 activity
o This leads to drugs having much longer half-lives, which in turn leads to toxicity.
o E.g. Opiates in Cirrhosis – Small doses accumulate, leading to coma.
Hypoalbuminaemia (malnutrition, nephrotic syndrome)
o Less albumin for drugs to bind to, free drug plasma levels higher
Renal Disease
Falling GFR (acute or chronic)
Reduced clearance of renally excreted drugs (Digoxin, aminoglycosides)
Electrolyte disturbances may predispose to toxicity
Nephrotoxins
o E.g. Aminoglycosides are nephrotoxic, and can further enhance their own and other drug toxicities by reducing GFR
Cardiac Disease
Reduced Organ Perfusion
o Reduced hepatic and renal blood flow and clearance
Excessive response to hypotensive agents
Drug-Food Interactions
Grapefruit and Cranberry Juice can Inhibit CYP450 enzymes. This can reduce in significantly reduced clearance of a number of drugs, including Statins and Warfarin.
LO 2.13 Recognise the main ADR target types and give examples of these, which groups are most at trisk of ADR’s
On Target Adverse Drug Reactions
On Target ADRs are due to an exaggerated therapeutic effect of the drug, most likely due to increased dosing or another factor affecting the drugs pharmacokinetics or pharmacodynamics.
For example Hypertension treatment leading to hypotension and causing dizziness, unsteadiness, syncope
On Target ADRs often consist of effects on the same effector, but in different tissues. Like Antihistamine H1 receptor antagonists acting on Immune System H1 Receptors which also act on CNS H1 Receptors causing drowsiness
Off Target Adverse Drug Reactions
Off Target ADRs are interactions with other receptor types secondarily to the one intended for therapeutic effect. Virtually all drugs do this.
Off Target ADRs can also occur with metabolites that subsequently act as a toxin.
Paracetamol in overdose
o NAPQI
Groups Prone to Adverse Effects
Pregnant Women - Teratogenicity/Thalidomide
Breast Feeding Women - Many drugs can be passed on in the breast milk
Elderly - Polypharmacy/Reduced renal clearance/Nervous system is more sensitive to drugs
Patients with genetic enzyme defects - Glucose-6-Phosphate Dehydrogenase deficiency, resulting in haemolysis if an oxidant drug (e.g. aspirin) is taken
LO 2.14 Recognise circumstances in which drug interactions are most likely to occur
Polypharmacy
The risk of adverse drug reactions increases with every drug a patient takes. Hospital patients are often on a cocktail of 8 or more drugs, which takes the overall chance of an ADR to 80%.
LO 3.1 Understand the hormonal regulation of the female reproductive cycle
Beginning of Cycle
Oestrogen, Progesterone, Inhibin levels low
GnRH secretion due to lack of inhibition
LH and FSH rise, FSH more due to low Inhibin levels so less inhibition at the pituitary
FSH, followed by LH causes Follicles to Grow
Antral Phase
LH binds to Theca Interna in the ovaries - Producing androgens
FSH binds to Granulosa cells in the ovaries - Produce enzymes which convert Androgens -> Oestrogen
As the follicle grows, more oestrogen is produced for a given amount of LH and FSH
Pre-Ovulatory Phase
Follicle has grown, and is producing a high amount of Oestrogen
LH receptors develop in outer layers of Granulosa Cells
[High] Oestrogen positively feeds back
LH Surge produced ~12 – 14 days into the Cycle
o Timing may be influenced by environmental factors
o Stimulates ovulation
o Follicle size increases, collagenase activity
o FSH still being inhibited by Inhibin
Luteal Phase
Remains of follicle reorganise into Corpus Luteum
LH stimulates the Corpus Luteum
Produces Oestrogen and Progesterone
o Rising Oestrogen does not positively feedback on LH because Progesterone levels are also rising
o Prevents new follicles from developing (reduced FSH)
As the Corpus Luteum grows, more steroids are produced for a given LH level
Follicular Phase
Steadily rising titres of Oestrogen
Fallopian Tube - Increased Secretion, motility, cilia
Myometrium - Increased Growth, motility
Endometrium - Thickness, glandular invaginations, Secrete a watery fluid, conductive to sperm
Cervical Mucus - Thin, alkaline, conductive to sperm
Vaginal Epithelium - Increased Mitosis
Mildly anabolic
Effects on CVS
Luteal Phase
Action of Progesterone on Oestrogen-Primed Cells
Fallopian Tube - Reduced Motility, secretion, cilia
Myometrium - Further thickening, reduced Motility
Endometrium - Further thickening, increased secretion, Development of Spiral Arteries
Cervical Mucus - Thickening, acidification. Inhibits sperm transport
Mildly Catabolic
Elevates basal body temperature
Promotes change in Na+ and H2O excretion - With Oestrogen leads to net Na+ and H2O retention
14 Days after Ovulation
In the absence of pregnancy the Corpus Luteum regresses spontaneously
Progesterone and Oestrogen levels fall
Triggering a menstrual bleed
o The elaborate secretary epithelium of the endometrium collapses
o Apoptotic cell death
o Dead tissue shed as menstrual bleed.
o Spiral arteries contract to reduce bleeding.
Relieves inhibition on GnRH, FSH and LH, triggering the development of new follicles and the beginning of a new cycle
Sudden Fall in Progesterone and Oestrogen Levels
If Conception has Occurred
The implanted embryo develops a placenta, which secretes Human Chorionic Gonadotrophin (hCG)
hCG prevents the regression of the Corpus Luteum
Continues to secrete Oestrogen and Progesterone
Supports early weeks of pregnancy (Until about 12-14 weeks)
Maintains suppression of the ovarian cycle
LO 3.2 Outline the general pharmacology of Oestrogens
Actions Mild anabolic Sodium and water retention** Raise HDL, Lower LDL Decrease Bone Resorption Impair Glucose Tolerance Increase Blood Coagulability
Side Effects Breast tenderness Nausea, vomiting Water retention Increased Coagulability Thromboembolism** Impaired glucose tolerance Endometrial hyperplasia & cancer
LO 3.2 Outline the general pharmacology of Progesterones
Actions Secretory endometrium Anabolic Increase bone mineral density Fluid retention Mood changes**
Side Effects Weight gain Fluid retention Anabolic Acne Nausea vomiting Irritability Depression Lack of concentration Pre-menstrual syndrome (marked exaggeration of mood changes)
LO 3.2 Outline the general pharmacology of Testosterones
Actions
Male secondary sex characteristics
Anabolic
Voice changes
Side Effects
Acne
Aggression
Metabolic adverse effect on lipids
LO 3.2 Outline in general how Sex Steroids are transported around the body, the site of metabolism and their mechanism of action.
Transported bound to Sex Hormone Binding Globulin (SHBG) (except progesterone) and albumin (mainly progesterone).
Metabolism is via the Liver, Progesterone is almost totally metabolised in one passage through the liver
Metabolites excreted in the Urine (as glucuronides and sulphates)
Mechanism of Action
Like all steroid hormones, sex steroids exert their effect via Nuclear Receptors. These receptors are found in the cytoplasm, complexed with heat shock proteins. Following the diffusion (or possibly transport) of their ligand into the cell and high-affinity binding, these receptors form a Homodimer with another ligand-receptor complex and translocate to the nucleus.
In the nucleus, the steroid-receptor complex homodimers can Transactivate or Transrepress genes by binding to Positive or Negative Hormone Response Elements. Large numbers of genes can be regulated in this way by a single ligand.
Steroids may also bind to receptors that are already present inside the nucleus, which will then bind to the HRE.
LO 3.3 Understand the differences in contraceptive mechanisms of COCP
Hormonal Contraception
Progesterone
Thick, ‘hostile’ cervical mucus plug
o Prevents sperm from entering uterus
o Main contraceptive action of progesterone
Negative feedback to hypothalamus / pituitary
o Decreases frequency of GnRH pulses
o Inhibits follicular development
Oestrogen
Oestrogen negatively feeds back on anterior pituitary
Loss of positive feedback mid-cycle so No LH surge
The COCP contains both an Oestrogen and a Progestogen (a Progesterone analogue). They work by mimicking the luteal phase of the menstrual cycle and suppress the release of gonadotrophins via negative feedback. As a result, follicular selection and maturation, the LH surge and consequently ovulation, do not take place. There is also an adverse effect on cervical mucus and the endometrium.
Route of Administration
Oral - One a day for 21 days, then break, placebo or iron pill for 7 days
Indications
Contraception and Menstrual Symptoms
Contraindications
Pregnancy, breast feeding, history or risk factors of heart disease, hypertension, hyperlipidaemia or any prothrombotic coagulation abnormality, diabetes mellitus, migraine, breast or genital tract carcinoma, liver disease
Adverse Effects
Venous thromboembolism, Hypertension, decreased glucose tolerance, headaches, mood swings, acne, flushing, nausea, vomiting, headache, amenorrhoea of variable duration on pill cessation
LO 3.3 Understand the differences in contraceptive mechanisms of the POP
The POP consists of low-dose Progestogen (a Progesterone analogue). This causes thickening of cervical mucus, preventing sperm penetration. It also has an adverse effect on the endometrium, affecting implantation. Contraception is less reliable than the COCP. It also causes suppression of gonadotrophin secretion, and occasionally ovulation, but the latter effect does not occur in the majority of women. During treatment with the POP ovulation still takes place and menstruation is normal.
Route of Administration
Oral - Daily, at the same time, starting at day 1 of menstrual cycle. If delay in taking the pill is greater than 3 hours, contraceptive effect may be lost
Indications
Contraception – More suitable for heavy smokers and patients with hypertension or heart disease, diabetes mellitus, or other contraindications for oestrogen therapy
Contraindications
Pregnancy, arterial disease, liver disease or breast or genital tract carcinoma
Adverse Effects
Menstrual irregularities, nausea, vomiting and headache, weight fain, breast tenderness
LO 3.4 Appreciate the main side effects and drug interactions of COCPs
COCP - Adverse Effects
Venous Thromboembolism (rare)
Hypertension
Amenorrhoea of variable duration on pill cessation
Flushing, headaches, nausea, acne, mood swings, weight gain (common)
COCP - Drug Interactions
Metabolism is by CYP450
o Therefore effected by inducers/inhibitors
o Enzyme inducers can lower levels of COCP causing contraception failure such as carbamezepine and phenytoin (anti-epileptics)
o Broad spectrum antibiotics (e.g. Amoxicillin)
Enterohepatic recirculation of oestrogen increases the efficacy of the COCP. If gut flora is killed by a broad spectrum antibiotic this is reduced and may cause contraception failure
LO 3.5 Understand differences in sex steroid PKs are related to administrative route
Oral
o Most common route (HRT, contraception, fertility)
Transdermal
o May reduce risk in turns of DVT, Thromboembolism by bypassing the Liver and giving smaller doses
o Important for people who complain of GI side Effects
o Slow, gradual release of steroid (Progestin)
Implants
o Slow, gradual release of steroid (Progestin)
Nasal
Vaginal
LO 3.6 Be aware of the clinical management options for other contraception and emergency contraception
Other Contraception
Depot progesterone
Intramuscular implant of progesterone, giving long term contraception
Same mechanism of action as POP
Emergency Contraception
‘Morning after pill’ – Up to 72hrs after sex
Very high oral doses of progesterone (1.5mg) alone, or a Progestogen with an oestrogen to prevent implantation of fertilised egg
o 75% effective
o Indications – Emergency Contraception after unprotected sex
o Contraindications – Oestrogen contraindications, need to ask about cycle and when they had sex to determine if the woman is already pregnant. If this is the case it would be illegal to prescribe (abortion).
Up to 120 hours after sex
o Progesterone receptor modulator – delays or inhibits ovulation
o Copper IUD
Describe the menopause and symptoms you get
The point where there is a cessation of menstrual cycles, usually from the age of 50 onwards. There are no more follicles which can be stimulated by GnRH. There is a dramatic decrease in oestrogen levels and FSH and LH levels will rise. The sudden rise in FSH is due to decrease amount of inhibin.
Changes that occur:
o Vascular changes - Transient rise in skin temperature and flushing
o Changes to oestrogen sensitive tissue - Shrinking of endometrium/cervix, Loss of vaginal rugae, Involution of breast tissue and Skin/Bladder changes
o Decreased bone mass - Oestrogen inhibit osteoclast function, therefore loss of oestrogen leads to osteoclast activity being greater than osteoblast activity. Leads to osteoporosis
LO 4.8 Understand the role of lipids in the pathophysiology of atherosclerosis
Atherosclerosis Pathophysiology
Endothelial injury due to o Raised LDL o ‘Toxins’ e.g. cigarette smoke o Hypertension o Haemodynamic stress
Endothelial injury causes
o Platelet adhesion, PDGF release, smooth muscle cell proliferation and migration
o Insudation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages
o Migration of monocytes into intima
Stimulated SMC produce matrix material
Foam cells secrete cytokines causing
o Further SMC stimulation
o Recruitment of other inflammatory cells
Pro-Atherogenic effects of Oxidated-LDL o Inhibits macrophage motility o Induces T-cell activation and vascular smooth muscle cell division/differentiation o Toxic to endothelial cells o Enhances platelet aggregation
LO 4.9 Recognise the potential for pharmacological manipulation of lipid metabolism and list the main lipid transporters
Studies have shown that both total and LDL cholesterol concentrations correlate with clinical coronary atherosclerosis. Importantly, increasing HDL levels reduces CHD risk.
Prevention of Atherosclerosis o Lifestyle changes (diet, exercise) can reduce LDL and increase HDL o Statins o Cholesterol absorption inhibitors o Fibrates o Niacin o Bile Acid Sequestrants
Lipoprotein Transporters
o Chylomicrons -Transport dietary triacylglycerols from the intestine to tissues such as adipose tissue.
o VLDL -Transport of triacylglycerols synthesised in the liver to adipose tissue for storage.
o LDL -Transport of cholesterol synthesised in the liver to tissues.
o HDL -Transport of excess tissue cholesterol to the liver for disposal as bile salts.
LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Statins
Examples
o Simvastatin - Short half life = 1-4 hours therefore is given at night
o Atorvastatin - Half life = 20 hours therefore can be given at any point in the day, has a superior efficacy
o Rostuvastatin - Contains sulphur, is more potent than simvastatin. Half life = 20 hours, so can be given at any time of the day
o Pravastatin
Route of Administration - Oral
Indications
Hyperlipidaemia which has not responded to changes in diet and exercise
Secondary prevention in patients with serum cholesterol greater than 5.5mmol/L (value varies depending on local policy)
Contraindications - Pregnancy, breastfeeding, liver disease
Mechanism of Action
o HMG-CoA Reductase inhibitor. Prevents cholesterol synthesis in the liver. Lower liver cholesterol concentration stimulates the production of LDL receptors, increasing the rate of LDL removal from plasma
Adverse Drug Reactions - Serious ADRs tend to be limited, even at the highest does of statin given.
o Increased transaminase levels - rapidly reversible, no evidence of chronic liver disease
o Myopathy - Diffuse muscle pain, primarily seen when used in combination with cyclosporine and occasionally erythromycin & niacin. Can test levels of creatinine kinase if symptomatic to confirm the presence of myopathy
o GI Disturbances
o Arthralgia
o Headaches
o Drug-Drug Interactions
o CYP450 inducers/inhibitors.
o Inhibitors significantly increase the risk of myopathies as the drugs spends more time in the plasma and therefore is more likely to interact with muscle tissue
LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Fibric Acid Derivatives (Fibrates)
Fibrates can be used in conjunction with statins, but typically are only used as first line choices in hypertriglyceridemias.
Examples
o Bezafibrate
o Ciprofibrate
o Gemfibrozil
Route of Administration - Oral
Indications - Hyperlipidaemia which does not respond to dietary control
Contraindications - Pregnancy, breast feeding, gall bladder disease, severe renal or hepatic impairment, Hypoalbuminaemia
Mechanism of Action
o Peroxisome Proliferator-Activated Receptor-α (PPAR-α) agonist
o LDL lowering (variable amount)
o HDL increases of 15-25% in hypertriglyceridemia
o Decreases Triglycerides 25-50%
Adverse Drug Reactions o Gastrointestinal disturbances o Dermatitis, pruritus, rash o Impotence o Headache, dizziness, blurred vision
Drug-Drug Interactions - Increased chance of myalgia and myopathies when taken with statins
LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Cholesterol Absorption Inhibitors
It is normally given as monotherapy in statin intolerant patients, however it will reduce LDL by a further 20% when given in combination with a statin. This is a better reduction than is gained by doubling statin dose and also reduces the risk of statin ADRs.
Examples - Ezetimibe
Route of Administration - Oral
Indications
o Hyperlipidaemia resistant to dietary control, in statin intolerant patients
o Given in combination with a statin
Contraindications - Breastfeeding
Mechanism of Action
o Blocks NPC1L1 in the intestinal brush border, inhibiting cholesterol absorption, increasing LDL receptor upregulation leading to further reducitons
o Reduce LDL levels by 15-20%
o Ezetimibe also undergoes enterohepatic circulation, increasing its half-life.
Adverse Drug Reactions
o Gastrointestinal disturbances (Diarrhoea, pain)
o Headache
LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Bile Acid Sequestrants
Examples
o Colestyramine
o Colestipol
Route of Administration - Oral
Indications - Elevated cholesterol resulting from a high LDL concentration
Contraindications - Biliary obstruction
Mechanism of Action
o Bile acids are produced from cholesterol. The bile acid sequestrants will bind to bile acids in the intestine. This prevents their reabsorption and further conversion of hepatic cholesterol into bile acids. Lower levels of hepatic cholesterol leads to increased LDL receptor expression and lowered plasma cholesterol concentration.
Adverse Drug Reactions
o GI disturbances – Nausea, vomiting, constipation, abdominal pain, flatulence, heart burn
o Very few systemic side effects as they are not absorbed
LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Niacin
Niacin
Used to increase HDL levels and is also found to decrease the risk of cardiovascular events. Inhibits lipoprotein-a synthesis
Side effects include
o Skin flushing and itching
o Dry skin
o Skin rashes -Eczema exacerbations or Acanthosis nigricans (thickened brown, leathery patches of skin)
LO 4.12 Appreciate differences in statin PKs and PDs and be able to relate this to Drug Interactions
There are considerable variations in pharmacokinetics and pharmacodynamics within the statin drug group
o Intestinal absorption varies between 30 – 85%
o Hepatic first pass uptake is extensive as it may occur either by diffusion or active transport by OATP2
o Systemic availability may fall to 5 – 30% of administered dose
o Hepatic elimination includes CYP3A4 for some statins, whilst others are only metabolised by Phase 2 pathways
o Exhibit Non-Linear Pharmacokinetics - Doubling of a dose results in ~6% reduction in LDL
Short Acting Statins
o Simvastatin - Half-life 1-4hrs, given at night to coincide with peak cholesterol in early morning
Long Acting Statins
Atorvastatin - Half-life ~20 hours. Given any time of day.
Rostuvastatin - Half-life ~20 hours. Given any time of day.
LO 4.3 Understand the general pharmacology of the major groups of oral hypoglycaemics and differentiate their main side effects with regards to therapeutic use -Sulphonylureas
Sulphonylureas (Insulin Release Stimulants)
Examples o Tolbutamide (t½ ~ 4hrs, duration of action 6-12hrs) o Glibencamide (t½ ~ 10hrs, duration of action 18-24hrs) o Glipizide (t½ ~ 7hrs, duration of action 16-24hrs)
Indications - Diabetes mellitus, in patients with residual β-cell activity
Contraindications - Breastfeeding women, elderly, renal and hepatic insufficiency
Route of Administration - Oral
Mechanism of Action
o Sulphonylureas antagonise β-cell K+/ATP activity, resulting in depolarisation. Voltage gated Ca2+ channels open, Ca2+ entry causes insulin vesicle fusion with cell membrane
Adverse Drug Reactions
o Hypoglycaemia
o GI disturbance
o Weight gain
Drug-Drug Interactions
o Highly protein bound (90-99%)
LO 4.3 Understand the general pharmacology of the major groups of oral hypoglycaemics and differentiate their main side effects with regards to therapeutic use - Biguanides
Biguanides (Insulin Sensitisers)
Examples - Metformin
Indications- Type II diabetes – Endogenous insulin presence required
Contraindications
o Compromised HRH function
o In respiratory disease
Mechanism of Action
o Unknown
o Increases insulin receptor sensitivity, enhancing skeletal and adipose glucose uptake
o Inhibits hepatic gluconeogenesis
o Reduces hyperglycemia, but does not induce hypoglycemia
o Tends to be give 2-3 times a day prior to meals to provide acute negative feedback on top of a basal endogenous insulin signal
Adverse Drug Reactions
o GI disturbances – ameliorated by slow dose titration
o Lactic Acidosis
LO 4.3 Understand the general pharmacology of the major groups of oral hypoglycaemics and differentiate their main side effects with regards to therapeutic use - Thiazolineinediones
Examples
o Rosiglitazone
o Pioglitazone
Indications - Uncontrolled non insulin dependant diabetes
Contraindications
o Compromised HRH function
o Especially heart failure – can cause oedema
Mechanism of Action
o PPAR-γ agonist. Agonistically bind to a nuclear hormone receptor site.
o Reduction in gluconeogenesis and an increased glucose uptake into muscles
Adverse Drug Reactions
o GI disturbance
o Weight gain
Drug-Drug Interactions - Very heavily protein bound (~99%)
LO 4.3 Understand the general pharmacology of the major groups of oral hypoglycaemics and differentiate their main side effects with regards to therapeutic use - Meglitidines
Examples
o Repaglinide
o Nateglinide
Indications - Uncontrolled non insulin dependant diabetes
Mechanism of action
o K+/ATP channel antagonists on β-cells, resulting in depolarisation, calcium entry and fusion of insulin containing vesicles with membrane
Adverse Drug Reactions
o Relatively lower risk of hypoglycaemia than Sulphonylureas
o Not associated with weight gain – useful in treating obese patients
Which hypoglycaemic agents would you give first?
Metformin is the first hypoglycaemic drug that you would use. If the patient is intolerant to Metformin, or is not overweight then Gliclazide (sulphonylurea) would be a better option as the first line of treatment.
Pioglitazone is the second line treatment, which is added to Metformin or a sulphonylurea. This happens if:
- Metformin and a sulphonylurea are not tolerated
- Metformin or sulphonylureas are contraindicated.
LO 4.4 Understand the use of the main categories of Insulin analogues and how they are used in Type I and II diabetes
Insulin analogues are manufactured on a large scale, using recombinant DNA technologies. There aqre many variations meaning that different formulations of insulin can be prepared, so the rate of uptake following sub-cutaneous injection can be varied. A mixture of these different insulins can be used together in a mix to give the best control.
Ultra Rapid
3 – 4 Duration
Meals/Acute hyperglycaemia
Short Acting
2 – 5 Duration
Meals/Acute Hyperglycaemia
Intermediate
4 – 10 Duration
Basal Insulin/Overnight control
Intermediate/Long Acting
8 – 30 Duration
Basal Insulin/Overnight Control
Due to the absence of properly functioning control systems, the best way to mimic the optimal actions of insulins is to utilise mixtures of analogues. There are two main mixtures used:
o Basal Bolus Regimen involves utilising a long acting insulin as background and then a fast acting insulin with meals. This involves injecting around 5 times a day yet does provide good flexibility.
o Pre-mixed Insulin Regime involves administration of both fast and slow acting insulin twice a day. Whilst this does not provide optimised glycaemic control, it involves less injecting for the patient.
LO 4.5 Describe the main steps used in Type II combination therapy
o Begin with no pharmacological intervention, therapy starting with Diet, Exercise and Lifestyle changes
o A Biguanide (Metformin) started when necessary
o Over time if HbA1c levels go above 7%, a Sulphonylurea (e.g. Tolbutamide) is added to therapy
o Over time if HbA1c levels go about 7.5% a Thiazolidinedione (e.g. Rosiglitazone) may be added, or a newer hypoglycaemic, or start insulin therapy
o If on this regime if HbA1c levels go above 7.5%, doses will be titrated upwards to regain adequate glycaemic control
LO 4.6 The crucial role played by patient and clinical monitoring in acute and chronic treatment
Monitoring in Acute Treatment
In patients with advanced diabetes, monitoring several times a day is required to determine dosing level with insulin. The regime in non-insulin therapies is frequently determined by dietary habit. With careful monitoring and control of their diet, patients can stay within normal glucose ranges.
Monitoring in Chronic Treatment
Glycosylated Haemoglobin - Glucose in the blood will react with the terminal valine of the haemoglobin molecule to produce glycosylated haemoglobin (HbA1c). The percentage of HBA1c is a good indicator of how effective blood glucose control has been. As RBCs normally spend ~3 months in the circulation the %HbA1c is related to the average blood glucose concentration over the preceding 2-3 months. Poorly controlled diabetics can have a HbA1c value above 10%.
LO 4.7 Recognise the main types of anti-obesity agents
Orlistat
Mechanism of Action
o Gastric and pancreatic lipase inhibitor, reducing the conversion of up to 30% of dietary fat to fatty acids and glycerol
Adverse Drug Reactions
o Broad GI disturbances
o (Soft fatty stools, flatus, faecal discharge/incontinence)
Sibutramine Mechanism of Action o Noradrenaline and serotonin re-uptake inhibitor leading to appetite suppression, increased thermogenesis Adverse Drug Reactions Increased heart rate and blood pressure
Rimonabant
Mechanism of Action - Endocannabinoid antagonist
Adverse Drug Reactions - Depression – currently withdrawn in the UK by NICE
LO 5.1 Generally overview factors in antibiotic use
Bacteria are prokaryotic organisms. The chemotherapy of infections aims to selectively target the invading bacterial while having minimal effect upon the host. This is achieved by exploiting the differences that exist between the structure and physiology of the prokaryotic bacterial cells and the host eukaryotic cells.
Antibacterial agents can be considered as bacteriostatic (inhibit bacterial growth, but do not kill them), or bactericidal (kill the bacteria).
LO 5.2 Understand the selective targeting of microbial biochemistry that underlies their use
Site - Peptidoglycan cell wall Reason - Peptidoglycan cell wall only present in prokaryotic cell. Antibacterial Drugs: o Penicillins o Cephalosporins o Glycopeptides
Nucleic Acids Bacterial genome is a single, circular strand of DNA unenclosed by a nuclear envelope, in contrast to eukaryotic chromosomal arrangement within the nucleus Antibacterial Drugs: o Antifolates o Quinolones o Rifampicin
Protein Synthesis Bacterial ribosome (50s+30s subunits) is different to the mammalian ribosome (60s+40s subunits) Antibacterial Drugs: o Aminoglycosides o Tetraclyclines o Macrolides o Chloramphenicol o Fusidic acid
Cytoplasmic Membrane
Bacterial plasma membrane does not contain any sterols, unlike mammalian.
Antibacterial Drugs:
o Polymyxins
LO 5.3 Recall the major sites of action of antibiotics
DNA, Protein, Cell Wall Synthesis
LO 5.4 Primary therapeutic reasons for use of antibiotics
Prophylaxis of Bacterial Infections
Prophylactic antibiotics are given to people who are at an increased risk of infection.
o Peri-operative (Prevention of surgical site infections)
o Short term - e.g. Meningitis contacts
o Long term - e.g Asplenia (encapsulated bacteria) or Immunodeficiency
Treatment of Significant Bacterial Infections
o Treatment of cultured, proven infection
o Empirical treatment of suspected infection
LO 5.5 Understand the factors governing antibiotic choice accounting for likely infectious agent AND patient
The ideal antibiotic therapy is one that gives:
o Clean killing of infecting bacteria with minimal impact on non-target commensal organisms and leaves no resistance in any surviving pathogens
o No adverse effects on patient
Factors to help determine the likely infectious agent o Anatomical Site o Duration of illness o Past medical history o Occupational history o Travel history o Time of year o Age o Personal background
Factors determining which antibiotics are likely to be effective
o Community or healthcare onset?
o Severity of infection
o Baseline rate of resistance
o Immune status of patient - Immunocompromised patients will need IV Antibiotics immediately
Which antibiotic is the best choice? Considerations o Efficacy o Cost o Administration Route o Safety o Patient age o Patient organ function o Patient Allergies o Toxicity and Drug Interactions o Pregnancy, breast feeding
LO 5.7 Understand the main genetic mechanism underlying antimicrobial resistance
Chromosomal Gene Mutation
o Chromosomal gene mutates in one bacteria in a population, conferring a resistance to antibiotic
o Antibiotic kills all other bacteria, acting as a selection pressure, giving resistant bacteria an advantage
o Population of antibiotic resistant bacteria daughter cells
Horizontal Gene Transfer
o Transformation
Bacteria with antibiotic resistance gene releases DNA
Uptake of DNA by recipient cell, conferring antibiotic resistance
o Transduction
Phage infected, antibiotic resistant Bacterial donor cell Phage passes the DNA conferring resistance to recipient cell
o Conjugation
Connection is made between antibiotic resistant donor cell, and recipient cell
Plasmid containing resistance gene is replicated and passes from donor cell to recipient cell
Plasmid may even become incorporated into recipient cell DNA
LO 5.8 Briefly describe biochemical mechanisms of antibiotic resistance
Antibiotic Inactivation -Production of enzyme that inactivate the drug
E.g. β-lactamase which inactivates Penicillins
Alteration of Drug Binding Site - so drugs no longer have affinity for them
E.g. Bacterial ribosome alteration, meaning Aminoglycosides and Erythromycin cannot bind
Alteration of Metabolic Pathways - Development of altered metabolic pathways
E.g. bacteria can become resistant to Trimethoprim due to acquired changes in their Dihydrofolate Redctase enzyme, which gives it very little affinity for the drug
Reduced Intracellular Antibiotic Concentration
o Active Efflux Mechanisms
E.g. Active transport mechanisms used (e.g. p-glycoprotein) to pump a drug out of the bacterial cell because it accumulates to an effective level
o Decreased permeability
E.g. Some bacteria become resistant to Tetracycline because they alter their cell membrane to make it impermeable to the drug
LO 5.9 Be aware of scale of emergent patterns of antibiotic resistance and name the main organisms e.g. MRSA
Patterns of Emergence of Antibiotic Resistance
o Local selection (e.g. in a hospital)
o Clonal dissemination (e.g. around the country)
o Global spread
Main Antibiotic Resistant Organisms
o Methicillin Resistant Staphylococcus Aureus (MRSA)
o Glycopeptide Intermediate susceptibility Staphylococcus Aureus (GISA)
o Glycopeptide Resistant Enterococci (GRE)
o Extended Spectrum Beta Lactamase enterobacteriaceae (ESBLs)
o Extensively Drug Resistant Klebsiella Pneumoniae (XDR-KP)
LO 5.10 List the main steps to avoid spread of resistance
Antimicrobial Stewardship o Right antibiotic o Right time o Right dose, frequency and duration o Right route
Infection Control
Prevent the spread of recognised resistant bacteria
o Isolation or cohorting
o Hand hygiene
o Decolonisation of patients
Prevent bacterial exposure to antibiotics
o Minimise risk of infection
o Monitor and control antibiotic prescribing
LO 5.11 What are the methods of adminitration and elimination of antibiotcs. Define MIC, time dependent and concentration dependent killing
Administration - Oral or Intravenous (Required for Immunocompromised patients)
Metabolism/Elimination - Renal or Hepatic
o Time dependent killing
Prolonged antibiotic presence at the site of infection, but not high concentration
o Concentration dependent killing
High antibiotic concentration at the site of infection, but short duration
Minimum Inhibitory Concentration – MIC
The MIC is the lowest concentration of an antibiotic that will inhibit the visible growth of a microorganism after overnight incubation. A MIC is generally regarded as the most basic laboratory measurement of the activity of a microbial agent against an organism.
LO 5.12 Understand the process of viral replication and describe the main steps involved use example of infleunza
- Influenza virus binds to cell via Hemagglutinin onto sialic acid sugars on the surface of epithelial cells.
- Entry of virus into cell via endocytosis
- ATP driven proton entry into the endosome, allowing fusion of the viral membrane with the internal endosomal membrane
- Entry of protons into the virus itself via the viral M2 Ion Channel. Low pH inside the virus results in breakdown in the viral coat of the nucleocapsid core. This releases viral RNA into the host cytoplasm
- Virus replicates using host cell machinery
- Viral protein assembly
- New virus buds off the cell membrane, but many remain attached by re-attaching to the sialic acid on the cell surface
- Viral Neuramidase enzyme breaks this bond, allowing viral release
LO 5.13 Recognise the main classes of Influenza Virus
Influenza A o Multiple host species which are able to infect humans o Antigenic drift and shift - Drift = different each year - Shift = leads to an epidemic
Influenza B
o No animal reservoir
o Lower mortality than influenza A
Influenza C
o Common cold like
LO 5.14 Describe the general pharmacology of M2 ion channel blockers and the main ADRs associated with M2 Ion Channel Blockers
Examples
o Amantadine
o Rimantadine
Route of Administration - Oral
Indications
o Prophylaxis and treatment of acute Influenza A in groups at risk.
Mechanism of Action
o Inhibits the un-coating of a virus, therefore preventing it from being able to infiltrate into the cell. This occurs by the action of:
o Inhibits H+ influx into the cell, therefore preventing the change in pH which stimulates the viral un-coating.
o Blocks M2 Ion Channel, preventing breakdown of viral coat and release of viral RNA into host cell.
Adverse Drug Reactions
o Amantadine has more marked ADR risk than Rimantadine of ~5-10%, therefore Rimantadine is usually preferred
o Dizziness
o Hypotension
o GI disturbance
o Confusion, insomnia and hallucination can be problematic in the elderly (CNS)
o Is nephrotoxic in high doses
Therapeutic Notes
o Limited to Influenza group A, ineffective against group B
o Rapid emergence of M2 mutations in H5N1 viruses
o Resistance can develop quickly as only a single point mutation is needed in order to change the shape. This causes the binding site to move away from the channel, so that when the drug binds it will no longer block the channel E.g. amantadine in chicken feed leading to resistance
LO 5.15 Describe the general pharmacology of Neuramidase Inhibitors and the main ADRs
Examples
o Zanamivir
o Oseltamivir
Route of Administration
o Zanamivir – Inhaled
o Oseltamivir – Oral (80% bioavailability)
Indications
o Treatment of Influenza A or B virus within 48 hours after onset of symptoms when influenza is endemic in the community
Contraindications - Breast feeding
Mechanism of Action
o Inhibits neuraminidase enzyme which cleaves the virus from receptors on the membrane, once the virus has been produced. It causes aggregation of the virus at the cell surface, therefore preventing the virus from spreading throughout the body and therefore to other people also.
o Sialic acid analogues, with very high binding affinities for Neuramidase.
o The receptor is not involved with antigenic shift or drift
Adverse Drug Reactions o Headache o Nose bleed o Respiratory depression (rarely) o Bronchospasm o GI disturbances
Therapeutic Notes
o Zanamivir has low bioavailability therefore is given as a dry powder inhalant. It is not used for prophylaxis.
o Oseltamivir is a pro-drug and by contrast is well absorbed, with 80% bioavailability. This enables it to be given orally for both treatment and prophylaxis.
o Gives rise to:
• 35-38% reduction in severity
• 25-36% reduction in duration when given as soon after infection as possible
LO 5.16 Explain the results arising from the clinical trials with Neuramidase Inhibitors and appreciate how these have informed dosing strategy
Initiation of Treatment
The earlier treatment is started after symptom onset, the shorter the duration of symptoms. The time window for significant reduction goes up to 48 hours, little benefit accrues after this time.
Mortality
Oseltamivir could offer ~70% reduction in risk of mortality according to one Canadian study. This was achieved when dosing was delayed as long as 64 hours after symptom onset.
Prophylaxis
Treatment for six weeks with 75mg significantly reduced incidence of flu in both healthy adults and frail elderly subjects.
LO 5.17 Appreciate how emergence of resistance of different viral strains to Neuramidase Inhibitors will affect therapy
Some resistance has been reported to Oseltamivir in H1N1 viral strains. Virus still remains sensitive to Zanamivir.
LO 6.1 Review relevant previous module material on respiration and asthma, epidemiology, symptoms, examinations
Asthma is a chronic disorder characterised by Airway Wall Inflammation and Re-modelling. It is a Reversible Airflow Obstruction (greater than 12% reversibility with salbutamol). Airways in asthma have thickened smooth muscle and basement membranes (collagen deposition in BM). Triggers cause the airway smooth muscle to contract, reducing airway radius, increasing resistance and reducing airflow.
Asthma is increasing in prevalence, more common in the developed world and increasing in populations who move from developing -> developed countries
o 5.4 million people in the UK current receive treatment
o Genetic risk
o Sensitisation to airborne allergens such as House Dust Mite, Pollens, Air pollution and tobacco smoke (Pre-/post natal exposure, active)
o Hygiene hypothesis
The diagnosis of asthma is a clinical one. There is no standard definition of the type, severity or frequency of symptoms, nor of the findings on investigation. Asthma is defined as more than one of the following recurring symptoms:
o Wheeze - High pitched, expiratory sound, Polyphonic
o Dry cough - Often worse at night (Lack of sleep, poor performance at school) - Exercise induced
o Breathlessness - With exercise
o Chest Tightness
o Variable Airflow Obstruction
Examination
Inspection
o Chest - Scars, deformities, Hyper-expansion (Barrel Chest)
o General health - Eczema, hay-fever, Lethargy, speaking?
o Percussion - Hyper-resonant
o Auscultation - Polyphonic wheeze
Spirometry – Flow Volume Loop
o Low PEFR
o Low FEV1/FVC Ratio
o >12% increase in FEV1 following salbutamol
Allergy Testing
o Skin prick to aero-allergens, e.g. cat, dog, HDM
o Blood IgE levels to specific aero-allergens
Chest X-Rays
o Performed to exclude other diseases/inhalation of foreign body/pneumothorax
LO 6.2 Understand autonomic innervation pharmacology of bronchial smooth muscle
Sympathetic Innervation
Sympathetic activity results in Bronchodilation, with nerves innervating bronchial blood vessels and glands, but not bronchial smooth muscle. However, β-adrenoreceptors are abundantly expressed on airway smooth muscle, epithelium, glands and mast cells (especially β2). Binding at these sites of β-agonists results in bronchodilation, reduced histamine release and increased mucociliary clearance.
Parasympathetic Innervation
Parasympathetic activity is normally dominant in maintaining smooth muscle tone in the airways. Muscarinic Receptors are present on airway and vascular smooth muscle and glands. The M3 Receptor is pharmacologically the most important.
LO 6.4 Know in detail the action of different bronchodilators and when they are used, namely: short and long acting B2 agonists
Mechanism of Action - β2 agonists act on the β2 receptors found on bronchial smooth muscle. The receptors are coupled to Gs Proteins, which cause an increase in cAMP and consequent decrease in intracellular [Ca2+]. This reduces the binding of Ca2+ by light myosin, causing smooth muscle dilation. Additionally, the decrease in intracellular Ca2+ will also increase Ca2+ activated K+ currents, thus hyperpolarising muscle cells further and augmenting bronchodilation.
Pharmacokinetics of β2 Agonists
β2 Agonists are administered by inhalation in aerosol, powder or nebulised form and can also be administered intravenously. Deposition within the pulmonary tract is related to particle size, with 1-5microns being optimal.
However, the majority of the drug (up to 90% depending on the inhaler device) is deposited in the upper airway and/or swallowed before being removed by the liver.
Fast Acting β2 Agonists
o Immediate Action
o Salbutamol – Duration of action 3-5hrs
o Terbutaline – Duration of action 3-5hrs
Long Lasting β2 Agonists
o Often given in adjunct with anti-inflammatories
o Formoterol – Duration of action 13hrs
o Salmeterol – Slower onset
Adverse Drug Reactions
o Inhaled high doses can cause skeletal muscle tremor (β2 activity)
o Even though β2 agonists are very selective, they can still antagonise cardiac β1 receptors enough to induce tachycardia and dysrhythmia
Drug-Drug Interactions
o β-blockers such as Propranolol, which bind to both β1 and β2 receptors
LO 6.5 Understand the broad mechanism of anti-inflammatory action of the corticosteroids. How long do they take to occur? And the pharmokinetics relating to ashtma.
Acts like normal steroid hormones, entering nucleus and binding to HRE. Therapeutic effects of changes in gene expression may only be apparent some hours after administration. Steroids may also bind to receptors that are already present inside the nucleus, which will then bind to the HRE.
Anti-inflammatory Effects
Reduced production of acute inflammatory mediators, especially eicosanoids (prostaglandins, leukotrienes), due to the production of Lipocortin, an enzyme that inhibits Phospholipase A2, preventing the formation of Arachidonic Acid and its metabolites.
Glucocorticoids also reduce the number of circulating immunocompetent cells (neutrophils and macrophages) and decrease the activity of cells involved in the chronic stages on inflammation (macrophages, fibroblasts), decreasing inflammation and decreasing healing.
Use of Glucocorticoids in Asthma
They have both an anti-inflammatory action and increase the expression of β2 Receptors. Optimal effects are seen after weeks/months of therapy.
Pharmacokinetics
10-50% of an inhaled dose is delivered to the lungs, depending on the inhaler device. A major proportion of the drug is deposited in the upper airway and/or swallowed and metabolised by the liver. Newer drugs are designed to undergo hepatic first pass metabolism to reduce ADR risk.
LO 6.6 Be able to outline the general steps in the management of asthma
Step 1
Mild Intermittent Asthma
Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Step 2
Introduction of regular preventer therapy
Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Regular preventer therapy – corticosteroid (e.g. Beclometasone)
Step 3
Add on therapy
Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Regular preventer therapy – corticosteroid (e.g. Beclometasone)
Regular long acting β2 Agonist (E.g. Salmeterol)
Step 4
Trial additional therapy Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Regular preventer therapy – corticosteroid (e.g. Beclometasone)
Trial of additional therapy, such as Muscarinic Antagonist (e.g. Ipratropium Bromide), Leukotriene Receptor Antagonist, Methylxantine (e.g. Theophylline)
Step 5
Continuous or frequent use of oral steroids (e.g. Prednisolone)
LO 6.7 Describe the steps in management of severe acute asthma and describe its features
Severe Acute Asthma – Status Asthmaticus
Severe Acute Asthma/Status Asthmaticus is defined as any one of: o Unable to complete sentences o Pulse ≥ 110 bpm o Respiration ≥ 25 per minute o Peak expiratory flow 33-50% of best or predicted Life Threatening features include: o Peak expiratory flow < 33% o PaO2 < 8kPa o PaCO2 > 4.5kPa o Silent chest o Cyanosis o Feeble respiratory effort o Hypotension, bradycardia, arrhythmia o Exhaustion, confusion, coma Severe, acute asthma is near fatal if PaCO2 is > 6kPa. Mechanical ventilation is required.
Management of Severe Acute Asthma (Status Asthmaticus)
o Oxygen – High flow, aim to keep O2 94-98% saturation
o Nebulised Salbutamol, continuous if necessary
o Intravenous Hydrocortisone
o Oral Prednisolone - ~40mg daily for 10-14 days
If no response to above treatment, add:
o Add nebulised Ipratropium Bromide
o Consider IV Magnesium Sulphate 1.2-2g over 20 minutes
o Consider IV Aminophylline if no improvement and life threatening features not responding to above treatment
Beware if taking oral Theophylline
LO 6.9 Appreciate the general mechanisms underlying autoimmune disease, particularly Rheumatoid Arthritis (RA)
Autoimmunity is the state that is present when an individual has made an immune response to self-antigens. In many cases the presence of autoantibodies in serum provides evidence for autoimmunity, and these may be helpful in diagnosing and monitoring autoimmune diseases.
Autoimmune Disease
Autoimmune disease is the term applied to a disease in which autoimmunity is thought to play a significant pathogenic role. (I.e. where the tissue damage results from the autoimmune response). Autoimmune disease can be classified as being organ specific. i.e. the target antigen is located in one organ or non-organ specific, i.e. the target antigen is located on many different tissues/organs.
Organ – Specific
- Hashimoto’s
- Thyrotoxicosis
- Primary myxoedema
- Chronic atrophic gastritis
- Pernicious anaemia
- Addison’s Disease
- Myasthenia gravis
- Diabetes mellitus (type 1)
- Premature ovarian failure
- Male infertility
Intermediate / Mixed
- Goodpasture’s syndrome
- Primary biliary cirrhosis
- Autoimmune haemolytic disease
- Ulcerative colitis
Non-Organ specific
- Systemic Lupus Erythematosus
- Rheumatoid arthritis
- Sjogren’s syndrome
- Progressive systemic sclerosis
LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Glucocorticoids
Examples o Prednisolone (Oral) o Beclometasone (Topical/Inhaled) o Hydrocortisone (Cortisol) (Oral for replacement, IV for status asthmaticus and anaphylactic shock)
Indications
o Immunosuppression
o Anti-inflammatory therapy
o Replacement of endogenous corticosteroids
Contraindications - Systemic infection
Mechanism of Action
o Diffuse into cytoplasm and bind receptor. Complex moves to nucleus and binds Hormone Response Element (HRE). Inducers/Inhibits transcription.
Adverse Drug Reactions o Cushingoid effects o Suppression of HPA axis o Osteoporosis o Suppression of growth in children o Mineralocorticoid effects if the glucocorticoid also has those actions
Therapeutic Notes - Long term therapy must be withdrawn slowly, due to HPA suppression
LO 6.12 Appreciate the pharmacological rationale for using Immunosuppressants in treating certain cancers
Some immunosuppressants work by inhibiting the division of cells - E.g. Azathioprine, Methotrexate, Cyclophosphamide, Cyclosporin
Some cancers are the uncontrolled division of immune cells and therefore immunosuppressants will work to suppress the cancer
LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Azathioprine
Indications
o Rheumatoid Arthritis, Inflammatory Bowel Disease
o Prevention of graft and transplant rejection
o Autoimmune conditions where corticosteroid therapy o alone inadequate
o Leukaemia
Route of Administration - Oral / IV
Mechanism of Action
o Azathioprine is a pro-drug, which is converted into 6-Mercaptopurine in the liver
o 6-Mercaptopurine is a fraudulent purine nucleotide that impairs DNA synthesis and has a cytotoxic action on dividing cells
Adverse Drug Reactions
o Myelosuppression -> Leukopenia, thrombocytopenia, anaemia
o Increased infection susceptibility
o GI disturbances (nausea, vomiting, diarrhoea)
o Drug-Drug Interactions
o Interacts with Allopurinol (treats gout), necessitates lowering of dose
Therapeutic Notes
6-Mercaptopurine is eliminated by the enzyme TPMT, which is subject to a high rate of genetic polymorphism. High levels of TPMT expression will lead to under-treatment, low levels of TPMT expression gives toxicity.
LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Cytotoxic Alkylating Agents
Examples - Cyclophosphamide
Indications - Immunosuppression/Cancer chemotherapy
Contraindications - Pregnancy
Mechanism of Action
o Pro-drug, that is activated by CYP450s.
o Alkylating agent, which creates cross-links in DNA so that it cannot replicate. Therefore it selectively acts on cells with a higher mitotic rate.
Adverse Drug Reactions
o Induction of bladder cancer (urine concentration of acrolein metabolite)
o Lymphoma and Leukaemia
o Infertility & Teratogenesis
Drug-Drug Interactions - Pro-drug is activated by CYP450s (inducers/inhibitors)
LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) -
Calcineurin Inhibitors
Examples
Cyclosporin (Binds Cyclophilin)
Tacrolimus (Binds Tacrolimus-Binding-Protein)
Indications
o Prevention of graft and transplant rejection
o Prevention of graft vs. host disease
o Atopic dermatitis, psoriasis
Route of Administration - Oral, intravenous
Mechanism of Action
o Reduction in IL-2 synthesis and release, via Calcineurin inhibition suppressing both cell-mediated and antibody-specific adaptive immune responses. Active against T helper cells.
o Ciclosporin binds to Cyclophilin and Tacrolimus binds to Tacrolimus-Binding-Protein
o Drug/Protein complexes bind to and inhibit Calcineurin, which normally has a phosphatase activity on the Txn factor for IL-2. Therefore, inhibition of Calcineurin reduces IL-2
Adverse Drug Reactions
o Nephrotoxic (proximal tubule), renal damage almost always occurs
o Hypertension in 50% of people
o GI disturbances
Drug-Drug Interactions
o Metabolism is by CYP450, so is affected by inducers/inhibitors
Therapeutic Notes
Unlike most immunosuppression agents, Cyclosporin does not cause myelosuppression
LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Methotrexate
Antirheumatic Drugs (DMARDs) (DRUGS SLOW DOWN DISEASE PROGRESSION, DOESN'T JUST TREAT INFLAMMATION)
Indications - Immunosuppression and Cancer chemotherapy
Contraindications - Pregnancy
Route of Administration - Orally, intravenously, intramuscularly, intrathecally
Mechanism of Action
o Antifolate
o Competitively antagonises Dihydrofolate Reductase (DHFR), preventing the regeneration of intermediates (tetrahydrofolate) essential for the synthesis of purines and thymidine, thus inhibiting DNA synthesis.
Adverse Drug Reactions o Mucositis o Myelosuppression o Hepatitis, cirrhosis o Increased infection risk o Teratogenesis
Drug-Drug Interactions
o Adverse DDIs with drugs affecting renal blood flow and renal elimination, e.g. NSAIDs
Therapeutic Notes
o Essential to carry out clinical monitoring
o Baseline chest X-ray, FBC, LFT, U+E + Creatinine
o Monthly FBC, LFT, U+E + Creatinine
o Oral bioavailability is dose dependent, so usually given IV
o Plasma protein binding ~50% - NSAIDs displace, raising plasma concentration
90% renal elimination – glomerular active and tubular secretion
o Intracellular/hepatic metabolism to polyglutamates. These polyglutamates accumulate in cells and also bind very strongly to DHFR. Polyglutamates can be retained in cells for weeks to months
o Weekly, not daily dosing
LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Aminosalicylates
Antirheumatic Drugs (DMARDs) (DRUGS SLOW DOWN DISEASE PROGRESSION, DON’T JUST TREAT INFLAMMATION)
Examples - Sulfasalazine
Indications
o Rheumatoid arthritis
o Inflammatory bowel conditions
Contraindication
o Renal impairment
o Hypersensitivity
Mechanism of Action
o Sulfasalazine is broken down in the gut to the active component 5-aminosalicylate (5-ASA) and sulfapyridine, which acts as a vehicle to transport the drug to the colon.
o Inhibition of T-cell proliferation and IL-2 production. Reduced Neutrophil chemotaxis and degranulation.
Adverse Drug Reactions
o Mostly due to sulfapyridine (10-45% of patients)
o Myelosuppression
o Hepatitis
o Rash
o GI disturbances (Nausea, vomiting, abdominal pain)
Therapeutic Notes
o Few ADRs/DDIs seen in Pregnancy
o Treating Rheumatoid Arthritis
o Only 30-40% 5-ASA is absorbed
o Molecular mechanism does not involve COX inhibition
o Inhibit T-cell proliferation and IL-2 Production, reduced neutrophil chemotaxis and degranulation
o Treating Inflammatory Bowel Disease
o 5-ASA reaches the colon in large quantities, but acts via an unknown mechanism (again not COX inhibition)
LO 7.1 Appreciate the main features of Gate Theory
Pain Perception
Activation of Nociceptors
Noxious thermal, chemical or mechanical stimuli can trigger firing of primary afferent fibres, through the activation of Nociceptors in the peripheral tissues. (Sharp Stabbing Pain - Alpha/Delta Fibres, Dull Nagging Pain C-Fibres)
Transmission of Pain Information
Transmission of pain information from the periphery to the dorsal horn of the spinal cord is inhibited or amplified by a combination of local (spinal) neuronal circuits and descending tracts from high brain centres. This constitutes the ‘Gate-Control Mechanism’.
In the Gate-Control Mechanism:
o Primary afferent fibres synapse in Lamina I, II and V of spinal cord dorsal horn
o Transmitter peptides are involved in ascending pain pathways - Substance P, Calcitonin, Bradykinin, Glutamate, Nitric Oxide
o The activity of the dorsal horn relay neurons is modulated by several inhibitory inputs. These include:
- Local inhibitory interneurons, which release opioid peptides
- Descending inhibitory noradrenergic fibres from the locus ceruleus area of the brainstem
- Activated by opioid peptides
- Descending inhibitory serotonergic fibres from the Nucleus Raphe Magnus and Periadueductal grey areas of the brainstem
- Activated by opioid peptides
Onward Passage of Pain Information
The onward passage of pain information is via the Spinothalamic Tract, to the higher centres of the brain. Here, there is coordination of the cognitive and emotional aspects of pain and control of appropriate reactions.
Opioid peptide release in both the spinal cord and brainstem can reduce the activity of the dorsal horn relay neurons and cause analgesia, known as ‘shutting the gate’.
LO 7.3 Understand the general Pharmacology of NSAID action on COX-1 and COX-2 and the 3 main types of inhibitor for it
The main action of all the NSAIDs is inhibition of the enzyme Cyclooxygenase (COX). This enzyme is involved in the metabolism of Arachidonic Acid to form Prostanoids, i.e. the ‘classic prostaglandins’, Prostacyclin and Thromboxane A2.
Inhibition of cyclooxygenase can occur by several mechanisms:
Irreversible inhibition
E.g. Aspirin causes acetylation of the active site. This is the basis for Aspirin’s effect on platelets
Competitive inhibition
E.g. Ibuprofen acts as a competitive substrate
Reversible, non-competitive inhibition
E.g. Paracetamol has a free-radical trapping action that interferes with the production of hydroperoxidases, which are believed to have essential role in cyclooxygenase activity.
LO 7.4 Understand therapeutics/ADRs in terms of action on COX-1 and COX-2
Cyclooxygenase exists in two enzyme isoforms. Generally, NSAID action on COX-1 is rapid and competitive, on COX-2 is slower and often irreversible.
COX-1
Expressed in most tissues, especially platelets, gastric mucosa and renal vasculature
Involved in physiological cell signalling
Most adverse effects of NSAIDs are caused by COX-1 Inhibition
COX-2
Induced at sites of inflammation and produces the Prostanoids involved in inflammatory responses
Analgesic and Anti-inflammatory effects of NSAIDs are largely a result of inhibition of COX-2
LO 7.5 Appreciate the use of NSAIDs as Analgesics, Anti-inflammatories and Anti-pyretics
NSAIDs as Analgesics
NSAIDs act as analgesics by reducing synthesis of Prostaglandins that sensitise Nociceptors to inflammatory mediators.
Thought to reduce headache pain by cerebral vasodilation mediated by prostaglandins.
May also have a secondary effect on prostaglandin facilitation of afferent pain signal in spinal cord dorsal horn neurones.
Anti-Inflammation
Along with Prostaglandins, there are a number of other mediators involved in the inflammatory response. Therefore NSAIDs will have an effect proportionate to prostaglandin involvement.
Primarily reduce erythema, swelling and pain response associated with swelling.
Antipyresis
Fever due to bacterial endotoxins trigger macrophage release of endogenous pyrogen IL-1. This stimulates hypothalamic production of Prostaglandin E that elevates the set point on central ‘thermostat’. NSAIDs reduce PG-E synthesis.
LO 7.6 Recognise the differences in NSAID pharmacokinetics specifically aspirin pharmacokinetics
NSAIDs are typically given orally, but there are also many topical preparations for local delivery to injured soft tissue.
Most NSAIDS generally show First Order Elimination Kinetics
Many heavily bound to plasma protein 90-99%
Some NSAIDs have short half-lives (< 6 hours)
o Ibuprofen – t½ = 2hrs
Some NSAIDs have long half lives (> 10 hours)
o Naproxen – t ½ = 14hrs
Aspirin Pharmacokinetics
o Low doses - First Order Elimination Kinetics (Dose dependant)
o High doses (>12 300mg tablets) - Zero Order Elimination Kinetics
LO 7.7 Describe the major ADRs / Drug Interactions associated with NSAIDs
NSAID GI ADRs
NSAID group ADRs at therapeutic levels are mainly due to COX-1 Inhibition.
o PGE2 is involved in protection of gastric mucosa
o Inhibition of PGE2 increases mucosal permeability and decreases mucosal blood flow and protection
o NSAIDs can cause damage to stomach directly on ingestion
o Ulceration, haemorrhage and even perforation seen with long term high dose elderly users
o GI ADRs can be offset (long term) with PPIs or Misoprostol (synthetic prostaglandins)
NSAID Renal ADRs
Renal ADRs can occur in susceptible individuals, although therapeutic dosage in otherwise healthy patients does not cause problems. Neonates, the elderly and patients with compromised HRH function or reduced blood volume are particularly at risk.
o Prostaglandins responsible for vasodilation of afferent arteriole
o Reversible reduction in GFR occurs as a result of PGE2 and PGI2 inhibition
Other ADRs
o Skin reactions (15% for some NSAIDs)
o Asthmatic bronchospasm (10% incidence)
o Allergic response
o Prolongation of bleeding time (platelet inhibition)
o Aspirin is associated with risk of the post-viral Reye’s Syndrome in children
Selective COX-2 Inhibitors
Since most NSAID ADRs are due to COX-1 inhibition, drugs have been developed that only inhibit COX-2. Unfortunately their use was associated with an increased risk of hypertension and cardiac and renal failure.
NSAID Drug-Drug Interactions
Due to their wide availability some patients may already be self-medicating with NSAIDs. It is therefore appropriate to question patients prior to prescription to name other drugs they may be taking.
o Aspirin is highly plasma protein bound and can displace other drugs, increasing their active free concentration. Competitive displacement of these drugs may require dose adjustment to avoid changes in PK and PDs.
Warfarin - Increased Concentration -> More Bleeding
Methotrexate - Increased Concentration -> Wide ranging, serious ADRs
Sulphonylureas - Increased Concentration -> Hypoglycaemia
NSAIDs can interact with ACE inhibitors and attenuate their action, blocking the production of vasodilating prostaglandins
LO 7.8 Understand the mode of action of NSAIDs on platelet function exemplified by Aspirin and its role in cancer prophylaxis
Aspirin is used as the reference NSAID for efficacy and ADR severity. It is the only NSAID to irreversibly inhibit COX enzymes, via acetylation. It also has a unique pharmacokinetic profile, as its t½ is less than 30 minutes – it is rapidly hydrolysed in plasma to salicylate, which has it’s own t½ of ~4 hours.
Atherothrombotic Disease
The use of low dose (75mg) Aspirin in reducing platelet aggregation is very widespread in treating a range of conditions with a vascular component. Aspirin irreversibly inhibits COX-1 activity that drives pro-aggregative activity in both platelets and vessel walls to reduce the likelihood of thrombotic formation.
GI Cancer Prophylaxis
There is evidence that aspirin may reduce the risk of GI cancer of the colon, rectum and possibly upper GI. This is because these cancers synthesise PGE2, which promotes tumour growth. Clinical trials are on going.
LO 7.9 Appreciate the special case of Paracetamol as an Analgesic/Antipyretic
Paracetamol is a unique ‘non-NSAID’, as it has virtually no anti-inflammatory action. It is very effective for mild/moderate analgesia and fever.
At therapeutic doses (8x500mg tablets a day) is has a much better ADR than other NSAIDs, making it the agent of choice. Its pharmacokinetics is first order in a healthy patient, with a t½ of 2-4hrs.
Paracetamol’s mechanism of action is currently unknown. It is possibly a weak COX-1/COX-2 inhibitor, but may also act in the CNS, possibly on a COX-3 isoform.
LO 7.10 Recognise the main features of Paracetamol overdose and toxicity and its treatment
At therapeutic levels, Paracetamol has Linear Pharmacokinetics, and is conjugated with Glucuronide (60%) or Sulphate (30%) in Phase II Drug Metabolism. A small amount also undergoes Phase 1 Oxidation, to produce the toxic metabolite N-acetyl-p-benzo-quinone imine (NAPQI).
If a toxic dose of Paracetamol is taken the Phase II pathways quickly become saturated and much more Paracetamol undergoes Phase I metabolism (Zero Order Kinetics), producing more NAPQI. Not only is NAPQI toxic to hepatocytes but it also undergoes Phase II conjugation with Glutathione, which is an important anti-oxidant, resulting in further damage from reactive oxygen species. Liver failure occurs over a period of several days.
Unconjugated NAPQI is highly is highly reactive and binds with cellular macromolecules/mitochondria. Precipitous loss of function primarily leads to necrotic hepatic cell death. A single dose of over 10g (20 tablets) is potentially fatal.
Treatment of a Paracetamol Overdose
Paracetamol overdose must be treated as soon as possible and guided by blood levels of the drug. Treatment is time dependent, as delayed hepatotoxic effects peak at 72-96 hours post ingestion.
Within 0-4 hours treat with Activated Charcoal orally which reduces uptake by 50-90%
Within 0-36 hrs Start N-Acetylcysteine or Methionine by mouth if N-Acetylcysteine cannot be given promptly
LO 7.12 Know the general classification of endogenous and exogenous opioids
Endogenous opioids are found distributed in specific parts of the CNS and peripheral nervous system, that play important roles in processing pain signals – The limbic system, thalamus, spinal cord and primary afferent peripheral terminals.
Endogenous opioids are peptides derived from precursor proteins. There are three different forms, however the first four amino acids of all the endogenous opioids are conserved.
o Enkephalins -Precursor: Proenkephalin
o Endorphins - Precursor: Pro-opiomelanocortin (POMC)
o Dynorphins - Precursor: Prodynorphin
Exogenous Opioids
Exogenous opioids include the natural, semi-synthetic and synthetic agents with actions on endogenous opioid receptors. These are chemically distinct from the endogenous opioids.
LO 7.13 Appreciate the different classes of Opioid Receptors
Three major types of opioid receptors have been identified. They are expressed in the CNS both pre and post-synaptically.
o Mu (μ) (MOP) - Evidence for supraspinal analgesia in the CNS
o Kappa (κ) (KOP) - Evidence for analgesia in the spinal cord
o Delta (δ) (DOP) - Enkephalins. Widely distributed.
Binding to μ or δ receptors causes hyperpolarisation of the neuron by opening potassium channels, decreasing excitability. They also inhibit voltage gated calcium channels and subsequently the release of Substance P.
Binding to κ receptors inhibits voltage gated calcium channels and subsequently the release of Substance P.
All opioid receptors are G-protein coupled receptors. They all have Gi mediated action, reducing cAMP levels.
LO 7.14 Understand the basic pharmacology of Opiates in reducing pain
Exogenous opiates work the same way as endogenous opiates. The majority of therapeutic effects are mediated by the μ receptor (MOP). Binding of an Opioid to the μ receptor causes hyperpolarisation of the neurone by opening of potassium channels and inhibition of voltage gated calcium channels. This reduces neuronal excitability and decreases the amount of Substance P neurotransmitter release. This inhibits the pain transmission pathway, reducing the feeling of pain.
Exogenous Opioids – Agonists, Partial Agonists and Antagonists
Full Opioid Agonists
o Higher affinity for μ receptor
o Morphine, Codeine, Methadone (Codeine and Methadone are relatively weak agonists compared to Morphine and lack dependence )
Partial Opioid Agonist
o Developed to have mixed effects at all three receptors
o Can provide excellent analgesia without euphoria
o Nalbuphine - Mixed agonist/antagonist effects at μ, Partial agonist at κ, Weak against δ
Full Opioid Antagonists
o Bind predominantly to μ receptors and used to reverse potentially fatal agonist effects (Respiratory Depression)
o Naloxone
LO 7.15 Recognise the key importance of Opiate pharmacokinetics in therapeutic/toxic balance including route of admin
Route of Administration
o Oral (70% removed by first pass metabolism, necessitating larger doses)
o Rectal
o Intravenous - Most rapid response, avoids first pass metabolism, so often used for severe pain, with patient controlling the level of analgesia
o Intramuscular
o Intrathecally
Dose adjustment necessary for Oral preparations. Normally the t½ of Morphine is about 2 hours. However, one of its metabolites Morphine-6-Glucoronide is at least pharmacologically equivalent to Morphine with a t½ of 4-5 hours. This extends the period of effective analgesia.
Hepatic and Renal failure can increase half lives up to 50 hours, thus is a serious factor to consider in palliative care patients.
Methadone has an oral bioavailability of ~90%. It also has a t½ of about 24 hours, making it more suitable for treating chronic pain.
Codeine Pharmacokinetics
Codeine is an important opiate, which is given orally. It needs to be metabolised by CYP2D6 into Morphine to become pharmacologically active.
CYP2D6 is subject to Genetic Polymorphism, so that 10% of the Caucasian population cannot effectively convert Codeine to Morphine. Another polymorphism seen in Chinese people means codeine is less effectively converted to Morphine and dose may need to be adjusted upwards in this ethnic group.
LO 7.16 Describe major therapeutic uses of opiates
Strong Opioids are used in the treatment of moderate to severe pain, particularly: o Visceral o Postoperative o Cancer-related o Myocardial infarction o Pulmonary Oedema o Peri-operative analgesia
Weak Opioids are used in the relief of mild to moderate pain, and as antidiarrhoeals:
LO 7.17 Recognise side effects of Opiods group and factors that predispose to ADRs
Respiratory Depression
The most serious opioid ADR is Respiratory Depression, and is the single greatest cause of death following opiate overdose. This is due to a μ receptor mediated action of opiates on CO2 sensitivity. Normally therapeutic levels do not cause excessive depression, but when combined with sleep, pulmonary deficit or other depressant drugs such as anaesthetics, alcohol or sedatives the risk of death can be much greater.
Other Opiate ADRs o Miosis (Important overdose sign) o Euphoria o Confusion o Psychosis o Coma o Tolerance and dependence o GI disturbances (nausea, vomiting, constipation) o Rarely anaphylactic responses, due to non-opiate receptor effects on mast cells, causing the release of histamine, leading to bronchoconstriction & hypotension
LO 7.18 Management of intentional or accidental opiate overdose
Treat with Naloxone, which is an antagonist of the μ receptor, rapidly reversing adverse agonistic effects, such as respiratory depression. Naloxone has a short t ½ (1 hour) therefore repeated doses may be needed.
LO 7.19 Cover the medico-legal aspects of opiate prescription
Some opioid analgesics are controlled drugs
o Misuse of Drugs Act 1971
o Misuse of Drugs Regulations 2001
Schedule 2 (controlled drugs) o Diamorphine (heroin) o Morphine o Remifentanil o Pethidine
Schedule 5 (controlled drug – invoice) o Includes preparations of certain controlled drugs (e.g. Codeine)
LO 2.4 Understand the factors affecting drug Bio availability, what is oral bio availability, how do you measure it and what is first pass metabolism.
Bioavailability is the fraction of a dose that finds its way into a body compartment, usually the blood. For an IV bolus, bioavailability is 100%. Factors affecting bioavailability include:
o Drug formulation
o Age
o Food (water soluble drugs are less likely to be affected by food)
o Vomiting
o Malabsorption
o First pass metabolism.
Oral Bioavailability is the proportion of a dose given orally (Or by any other route other than intravenous) that reaches the systemic circulation in an unchanged form. Bioavailability can be expressed as amount or rate.
Amount – Measured by are under curve of blood drug level vs. time
Rate – Measured by peak height and rate of rise of drug level in blood
Oral Bioavailability(F)=(AUC oral)/(AUC IV) × 100
First Pass Metabolism
Any metabolism occurring before the drug enters the systemic circulation is referred to as the first pass effect. This can occur in:
o The Gut Lumen -Gastric acid, proteolytic enzymes, grapefruit juice
o The Gut Wall - P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen, e.g. cicosporin
o The Liver - Substances absorbed in the ileum enter the portal circulation and are taken to the liver, where enzyme systems metabolise them
E.g. only 90% of an oral dose of paracetamol reaches systemic circulation
E.g. Popranolol is extensively metabolised
LO 2.4 Understand the factors affecting the Volume of Distribution of a drug, what is the equation of VoD and at what volume is each compartment indicated.
The Volume of Distribution is a measure of how widely a drug is distributed in body tissues. It is a calculated pharmacokinetic space into which a drug is distributed.
Volume of Distribution (Vd)= (Total Amount of Drug in Body)/(Plasma Concentration of Drug at Time Zero)
Vd values that amount to less than that of a certain body compartment volume indicate that the drug is contained within that compartment.
o When the volume of distribution is less than 5 Litres, it is likely that the drug is restricted to the vasculature.
o If it is less than 15 Litres, this implies that the drug is restricted to the extracellular fluid
o Greater than 15 Litres suggests distribution within the total body fluid.
Some drugs (usually basic) have a volume of distribution that exceeds body weight, in which case tissue binding is occurring. These drugs tend to be contained outside the circulation and may accumulate in certain tissues. For example, very lipid-soluble drugs, such as general anaesthetics (e.g. Thiopental), can build up in fat, meaning the drug has a much longer half-life in an obese patient.
LO 2.4 What is Clearance of a drug and Understand the factors affecting it, how its calculated. What is half life and how is it calculated.
The volume of plasma that is completed cleared of drug per unit time
Hepatic, renal and other secondary forms of elimination such as sweating or biliary elimination are measured in terms of Clearance. Hepatic and Renal Clearance are simply added together when calculating removal, so that:
Total Clearance = Hepatic Clearance + Renal Clearance
Calculating Renal Clearance
The renal artery is the input to the kidney and the kidney has two possible outputs, the renal vein and the ureter. Therefore, if a substance is not metabolised or synthesised, an equal amount must leave in the urine and the renal venous blood. Renal clearance can be calculated with the equation:
Clearance=(Amount in urine × Urine flow rate)/(Arterial Plasma Concentration)
E.g. Substance X is present in the urine at a concentration of 100mg/ml. The urine flow rate is 1ml/min. The excretion rate of substance X is therefore:
Excretion rate = 100mg/ml x 1ml/min = 100mg/min
If Substance X was present in the plasma at a concentration of 1mg/ml then its clearance would be:
Clearance=100/1=100 ml per min
100ml of plasma would be completely cleared of substance X per minute.
Factors Affecting Clearance
Heart – CVS/Circulatory factors affecting blood flow to the main organs of elimination
Renal – Factors affecting Renal elimination
Hepatic – Factors affecting Hepatic elimination
Half-Life (t½)
The half-life of a drug is the amount of time over which the concentration of a drug in plasma decreases to one half of the concentration value it had when it was first measured.
Half Life= (0.693 × Volume of Distribution)/Clearance
LO 8.1 Recognise the names of example inhalational and IV anaesthetics
Inhalational (Volatile) Agents o Nitrous Oxide (N2O) o Isoflurane o Desflurane o Sevoflurane
Intravenous Agents
o Propofol
o Ketamine
LO 8.2 Know the range of effects on the CNS produced during general anaesthesia
o Reticular Formation (Reticular Activating System) Depressed (Hindbrain, midbrain, thalamus)
o Thalamus - Transmits and modified sensory information
o Hippocampus depressed - Memory
o Brainstem depressed - Respiratory and some CVS
o Spinal cord
- Dorsal horn (analgesia )
- Motor neuronal activity (MAC)
