Pharmo Flashcards

Question

How is bioavailability calculated?

Answer 1

For routes other than IV bolus (F= 100%) Compare amount reaching the body compartment with IV bioavailability F = AUC oral / AUC IV

Answer 2

Absorption- drug formulation, age, food (lipid sol > water sol), vomiting and malabsorption First pass metabolism - gut lumens, gut wall, liver

Answer 3

Any metabolism occurring before drug enters the systemic circulation IN gut lumen (gastric acid, proteolytic enzymes, grapefruit juice, insulin), gut wall (P glycoprotein efflux pumps drugs out of intestinal enterocytes and back into the lumen - ciclorporin) and liver (propranolol)

Answer 4

A drugs ability to dissolve in the body | 2 key factors- protein binding in systemic circulation and volume of distribution

Answer 5

Drugs bind to albumin (acidic drugs), globulins (hormones), lipoproteins (basic drugs), acid glycoproteins (basic drugs) Most drugs must be unbound/ free to have an effect Changes in protein binding causes changes in drug distribution - only important if: high protein binding, low Vd, narrow therapeutic ratio Drugs bound or unbound to proteins are still 'available'!!

Answer 6

Protein binding drug interactions - other drugs try to bind and displace drugs bound to proteins

Answer 7

Hypoalbuminaemia Pregnancy Renal failure Displacement by other drugs

Answer 8

Drugs that are not bound to plasma proteins are available for distribution to tissues of the body - tissue fluid, or extensively bound to body tissues Measure of how widely a drug is distributed in body tissues Hypothetical but useful with dosing regimens E.g. 100mg gentamicin dose --> peak plasma conc 5mg/ L has a Vd of 20L Vd = dose (mg) / peak plasma conc (mg/L) [DRUG]t0 Half life is proportional to Vd

Answer 9

``` Specific receptor sites in tissues Regional blood flow Lipid solubility Active transport Disease states Drug interactions ```

Answer 10

Phase 1 - make drug more reactive- oxidation, reduction, hydrolysis Phase 2 - make drug more soluble- conjugation with glucuronic acid, glutathione, sulphuric acid Either pharmacologically inactive --> active (PRODRUG) Or pharmacologically active (codeine) --> another active (morphine)

Answer 11

3A 2D6 2C9 2C19

Answer 12

In the liver (gut/lung)

Answer 13

``` Calcium channel blockers Benzodiazepines HIV protease inhibitors Most statins Cyclosporins ```

Answer 14

St. John's wort Phenytoin Rifampicin

Answer 15

Macrolides Cimetidine Grapefruit juice

Answer 16

Codeine B blockers Tricyclics

Answer 17

Fluoxetine Paroxetine Haloperidol

Answer 18

Most NSAIDs | Phenytoin

Answer 19

Fluconazole

Answer 20

Diazepam Phenytoin Omeprazole

Answer 21

Rifampicin

Answer 22

Omeprazole | Isoniazid

Answer 23

Mostly by kidney (also by lungs, breast milk, sweat, tears, bile) Elimination by the kidney is dependent on: glomerular filtration (affected by unbound drugs like gentamicin), passive tubular reabsorption (affected by urine flow rate and pH- aspirin), active tubular secretion (penicillin) 1st and 0 order kinetics Clearance

Answer 24

Rate of elimination of drug is proportional to drug level Constant fraction of drug eliminated in unit time Half life can be defined and so multiple dosing is acceptable

Answer 25

Rate of elimination is a constant Most drugs show this at high doses because receptors/ enzymes are saturated Zero order drugs are likely to show toxicity at high doses (fixed rate/unit time) and so small dose change may cause large increase in dose and toxicity No half life is calculable so will require TDM

Answer 26

Problems with the patient or population Problems with the doctor Problems with the pharmaceutical industry

Answer 27

ability of the body to excrete drug (=GFR) / rate of elimination Measure of hepatic, renal and other secondary forms of elimination such as sweating or biliary elimination Volume of plasma that is completely cleared of the drug per unit time Low GFR --> low clearance Half life is inversely proportional to clearance (so lower the clearance or GFR, the higher the half life)

Answer 28

Therapeutic drug monitoring | Important when- zero order kinetics, long half life, narrow therapeutic window, increased risk of drug-drug interaction

Answer 29

Repeated (first order) drug administration Reach a steady state (Cpss) in 3-5 half lives (irrespective of dose/ frequency) Require 4-5 half lived to completely eliminate most of a drug

Answer 30

HRH HEART- circulation/ cardiovascular factors affecting blood flow to main organs of elimination RENAL- factors affecting renal elimination (kidney failure, poor perfusion) HEPATIC- factors affecting hepatic eliminations (enzyme inducers and inhibitors)

Answer 31

Amount of time over which the concentration of a drug in plasma decreases to one half the concentration value that it had when it was first measured

Answer 32

Half life is directly proportional to volume of distribution Half life is inversely proportional to clearance Half life = (0.693 x volume of distribution) / clearance

Answer 33

Comparison of the concentration of drug with a therapeutic effect (minimal required concentration) to the concentration of drug with a toxic effect (maximal required concentration)

Answer 34

Repeated drug administration means that a new steady state can be achieved so that levels stay within the therapeutic window

Answer 35

Steady state (Cpss) = dose rate / clearance

Answer 36

When a clinician wants to achieve a steady state quickly within the therapeutic window they can give a loading dose Once the steady state is reached, it is maintained by the steady state equation: steady state = dose rate / clearance Loading dose = volume of distribution x steady state (Cpss)

Answer 37

``` Interactions with enzymes Transport systems Secondary messengers Hormones Ion channels ```

Answer 38

Pharmacodynamics is based around the concept of the receptor theory, whereby the drugs act on receptors to target the molecules.

Answer 39

``` Agonists (partial) Antagonists (competitive and non competitive) Specificity Selectivity Affinity Efficacy Potency Therapeutic index and window ```

Answer 40

An agonist will bind to the receptor and stabilise it (whilst bound) into its active state.

Answer 41

An antagonist will bind to the receptor and stabilise it (whilst bound) into its inactive state.

Answer 42

A partial agonist will bind to the receptor yet will not fit quite well as well and does not bring about the maximal response

Answer 43

Competitive antagonists bind to the site in which the natural ligand binds to and can completely remove all response from the receptor Competitive antagonism occurs where the antagonist can be “out-competed” for the receptor site by simply increasing the agonist concentration, shown on curves by a shift to the right.

Answer 44

Non-competitive antagonists bind to another site on the receptor (i.e. where the ligand does not bind) and will partially reduce the overall response of the receptor Non-competitive antagonism can be either irreversible binding to receptor site or reversible or irreversible binding to a separate site, which is represented by the EC50 staying the same yet a reduction in overall response

Answer 45

Specificity relates to the complementary drug and receptors (i.e. good specificity is only working on one receptor)

Answer 46

Selectivity relates to clinical effect of the drug and can be measured with specific therapeutic indices (i.e. good selectivity has minimal side effects)

Answer 47

Affinity defines the ability of a drug to bind to a specific receptor type. The terms used to define this are Kd for agonists and Ki for antagonists. These terms indicate the concentration at which half the receptors are occupied at

Answer 48

Efficacy defines the maximal effect of a drug when bound to a receptor. Agonists have 100% efficacy, partial agonists will have reduced affinity, efficacy, or both, and antagonists have affinity yet no efficacy.

Answer 49

Potency defines the overall response seen by the receptor once the ligand has bound. It is measured by the EC50 which is the concentration where 50% of the maximal response is obtained. EC50 is rarely equal to Kd values. Antagonist potency can also be measured, which can be defined as the concentration that reduces maximal activation of a receptor by 50%.

Answer 50

The therapeutic index is the relationship between concentrations causing adverse effects and concentrations causing desirable effects; it is calculated as LD50 / ED50 and a large therapeutic index is preferred.

Answer 51

The therapeutic window is the range of drug concentrations where they exert a clinically useful effect but without exerting toxic effects; it is the range between the lowest dose that has a positive effect and the highest dose before the negative effects outweigh the positive effects.

Answer 52

- Warfarin - Aminophylline - Digoxin - Aminoglycosides

Answer 53

Drug interactions with other drugs Drug interactions with food Drug interactions with diseases

Answer 54

Changes in gut motility can occur to affect absorption; for example, opiates and atrophine slow the gut down to increase Cmax and increase Tmax, whereas metoclopramide speeds the gut up to increase Cmax and decrease Tmax. Other drugs will interfere with absorption, such as calcium salts bind to tetracyclines and reduce their absorption or cholestyramine binds to Warfarin and digoxin to reduce their absorption.

Answer 55

``` Class I (object) drugs are administered at a dose where the number of molecules of that drug is much lower than the number of binding sites available for that drug whereas class II (precipitant) drugs are used at much higher numbers than the number of binding sites available so displace the class I drugs. Administering a precipitant drug can cause free object drug concentrations to rise to toxic levels, pushing levels out of the therapeutic window. This can however be met with an increased clearance to achieve a similar steady state. ```

Answer 56

Drugs can affect the metabolism of themselves or other drugs by two mechanisms of either induction or inhibition (described in previous lecture).

Answer 57

The primary mechanism affecting drug excretion includes changes in protein binding, inhibition of tubular secretion, and changes to urine flow / pH. Decreased protein binding increases the amount of free unbound drug which accelerates its removal, and inhibition of tubular secretion will result in increased plasma levels of the drug (NSAIDs can act to reduce tubular secretions).

Answer 58

Interactions will either enhance or reduce therapeutic outcomes through actions on the receptor, and these drug interactions can occur via different receptors or different tissues. This can have several categories. For example, opiate analgesics and naloxone act antagonistically whereas digoxin toxicity is enhanced by hypokalaemia caused by loop diuretics (e.g. Furosemide). Even using aspirin with Warfarin will cause levels of unbound Warfarin to increase.

Answer 59

* Anticonvulsants * Anticoagulants * Antidepressants * Antibiotics * Antiarrhythmics

Answer 60

The effects of hepatic, renal, or cardiac deficit on both PK and PD are common loci for drug-disease interaction. These drug-disease interactions often lead to exacerbation of systemic toxicity due to their close interdependence. Renal Disease- Falling GFR will cause a reduced clearance of renally excreted drugs, e.g. digoxin or aminoglycoside antibiotics. Further reduction in GFR can be seen in patients on NSAIDs or ACEis, causing AKI and are considered to be nephrotoxic. Hepatic Disease- Hepatic disease would cause reduced clearance of hepatically metabolised drugs by a reduced CYP 450 activity. This results in much longer half-lives of drugs resulting in toxicity. Good examples include opiates in cirrhosis, with small doses even resulting in accumulation causing coma. Cardiac Disease- a falling cardiac output can cause reduced organ perfusion, resulting in both reduced hepatic blood flow and renal blood flow, reducing drug clearance. Many drugs are bound to albumin, so any hypoalbuminaemia caused by liver failure, malnutrition, nephrotic syndrome, plus many more, higher free drug levels will be seen. This would affect PD and PK significantly.

Answer 61

- Cranberry juice can be used therapeutically in UTI treatment, yet also acts to inhibit CYP2C9 so reduce clearance of Warfarin to cause raised INR and increased risk of haemorrhage. - Grapefruit juice inhibits several CYP450 isoenzymes, so can reduce clearance of many drugs (e.g. simvastatin)

Answer 62

In pharmacology, any unexpected or dangerous reaction to a drug. An unwanted effect caused by the administration of a drug. The onset of the adverse reaction may be sudden or develop over time.

Answer 63

On target ADRs OR Off target ADRs

Answer 64

‘On target’ ADRs which are due to exaggerated therapeutic effect of the drug, most likely due to increased dosing or due to factors affecting the PK or PD. A simple example would be use of a certain drug to treat hypertension which could result in dizziness or syncope. Many ‘on target’ ADRs include effects on the same receptor type but found on other tissues.

Answer 65

‘Off target’ ADRs involves interaction of other receptor subtypes secondarily to the one intended for the therapeutic effect, which can also occur with metabolites that can subsequently act as a toxin. Inappropriate immune responses also constitute off target ADRs.

Answer 66

Use of polypharmacy increases the risk of ADRs, due to effects of drug-drug interactions.

Answer 67

Receptors Ion channels Enzymes Transporters

Answer 68

Receptors are the sensing elements in the system of chemical communication that coordinates the function of all the different cells in the body. Drugs can act by being agonists, partial agonists, or antagonists for known endogenous mediators.

Answer 69

Some ion channels incorporate a receptor and open only when the receptor is occupied by an agonist. Thus drugs can act on ion channels indirectly (via G-protein coupled receptors) or directly (drug binds directly to ion channel) to alter its function.

Answer 70

Drugs can target certain enzymes to act as a competitive or non-competitive inhibitor of the enzyme, which can be reversible and irreversible. They can also act as false substrates, whereby drug molecules undergo chemical transformation to form an abnormal product that subverts the normal metabolic pathway. It should be mentioned that drugs may require enzymatic degradation to convert them from an inactive form (the prodrug) to their active form.

Answer 71

Transport of some ions and molecules requires carrier proteins, allowing for facilitated diffusion. Drugs can act to block these transporters, preventing these substances entering the cells.

Answer 72

Changes in gut motility can occur to affect absorption; for example, opiates and atrophine slow the gut down to increase Cmax and increase Tmax, whereas metoclopramide speeds the gut up to increase Cmax and decrease Tmax. Other drugs will interfere with absorption, such as calcium salts bind to tetracyclines and reduce their absorption or cholestyramine binds to Warfarin and digoxin to reduce their absorption.

Answer 73

``` Class I (object) drugs are administered at a dose where the number of molecules of that drug is much lower than the number of binding sites available for that drug whereas class II (precipitant) drugs are used at much higher numbers than the number of binding sites available so displace the class I drugs. Administering a precipitant drug can cause free object drug concentrations to rise to toxic levels, pushing levels out of the therapeutic window. This can however be met with an increased clearance to achieve a similar steady state. ```

Answer 74

Drugs can affect the metabolism of themselves or other drugs by two mechanisms of either induction or inhibition (described in previous lecture).

Answer 75

The primary mechanism affecting drug excretion includes changes in protein binding, inhibition of tubular secretion, and changes to urine flow / pH. Decreased protein binding increases the amount of free unbound drug which accelerates its removal, and inhibition of tubular secretion will result in increased plasma levels of the drug (NSAIDs can act to reduce tubular secretions).

Answer 76

Interactions will either enhance or reduce therapeutic outcomes through actions on the receptor, and these drug interactions can occur via different receptors or different tissues. This can have several categories. For example, opiate analgesics and naloxone act antagonistically whereas digoxin toxicity is enhanced by hypokalaemia caused by loop diuretics (e.g. Furosemide). Even using aspirin with Warfarin will cause levels of unbound Warfarin to increase.

Answer 77

* Anticonvulsants * Anticoagulants * Antidepressants * Antibiotics * Antiarrhythmics

Answer 78

The effects of hepatic, renal, or cardiac deficit on both PK and PD are common loci for drug-disease interaction. These drug-disease interactions often lead to exacerbation of systemic toxicity due to their close interdependence. Renal Disease- Falling GFR will cause a reduced clearance of renally excreted drugs, e.g. digoxin or aminoglycoside antibiotics. Further reduction in GFR can be seen in patients on NSAIDs or ACEis, causing AKI and are considered to be nephrotoxic. Hepatic Disease- Hepatic disease would cause reduced clearance of hepatically metabolised drugs by a reduced CYP 450 activity. This results in much longer half-lives if drugs resulting in toxicity. Good examples include opiates in cirrhosis, with small doses even resulting in accumulation causing coma. Cardiac Disease- a falling cardiac output can cause reduced organ perfusion, resulting in both reduced hepatic blood flow and renal blood flow, reducing drug clearance. Many drugs are bound to albumin, so any hypoalbuminaemia caused by liver failure, malnutrition, nephrotic syndrome, plus many more, higher free drug levels will be seen. This would affect PD and PK significantly.

Answer 79

- Cranberry juice can be used therapeutically in UTI treatment, yet also acts to inhibit CYP2C9 so reduce clearance of Warfarin to cause raised INR and increased risk of haemorrhage. - Grapefruit juice inhibits several CYP450 isoenzymes, so can reduce clearance of many drugs (e.g. simvastatin)

Answer 80

In pharmacology, any unexpected or dangerous reaction to a drug. An unwanted effect caused by the administration of a drug. The onset of the adverse reaction may be sudden or develop over time.

Answer 81

On target ADRs OR Off target ADRs

Answer 82

‘On target’ ADRs which are due to exaggerated therapeutic effect of the drug, most likely due to increased dosing or due to factors affecting the PK or PD. A simple example would be use of a certain drug to treat hypertension which could result in dizziness or syncope. Many ‘on target’ ADRs include effects on the same receptor type but found on other tissues.

Answer 83

‘Off target’ ADRs involves interaction of other receptor subtypes secondarily to the one intended for the therapeutic effect, which can also occur with metabolites that can subsequently act as a toxin. Inappropriate immune responses also constitute off target ADRs.

Answer 84

Use of polypharmacy increases the risk of ADRs, due to effects of drug-drug interactions.

Answer 85

Receptors Ion channels Enzymes Transporters

Answer 86

Receptors are the sensing elements in the system of chemical communication that coordinates the function of all the different cells in the body. Drugs can act by being agonists, partial agonists, or antagonists for known endogenous mediators.

Answer 87

Some ion channels incorporate a receptor and open only when the receptor is occupied by an agonist. Thus drugs can act on ion channels indirectly (via G-protein coupled receptors) or directly (drug binds directly to ion channel) to alter its function.

Answer 88

Drugs can target certain enzymes to act as a competitive or non-competitive inhibitor of the enzyme, which can be reversible and irreversible. They can also act as false substrates, whereby drug molecules undergo chemical transformation to form an abnormal product that subverts the normal metabolic pathway. It should be mentioned that drugs may require enzymatic degradation to convert them from an inactive form (the prodrug) to their active form.

Answer 89

Transport of some ions and molecules requires carrier proteins, allowing for facilitated diffusion. Drugs can act to block these transporters, preventing these substances entering the cells.

Answer 90

Progesterone only pills (POP) | Combined oral contraceptive pill (COCP)

Answer 91

Low-dose Progestogen (Progesterone analogue). It causes thickening of cervical mucus to inhibit sperm transport. It inhibits endometrial implantation and causes suppression of gonadotropin secretion

Answer 92

Oral – daily at the same time each day, starting at day 1 of the menstrual cycle. (If delay >3hours, contraceptive effect may be lost)

Answer 93

Contraception – more suitable for heavy smokers & HTN/Heart Disease, DM patients or other contraindications of oestrogen therapy

Answer 94

Pregnancy, arterial disease, liver disease, carcinoma of breast or genital tract

Answer 95

Menstrual irregularities & poor cycle control, NV, headaches, weight gain, breast tenderness

Answer 96

Metabolised by CYP450 so affected by inhibitors & inducers. Inducers can lead to contraception failure

Answer 97

It contains both an Oestrogen (usually Ethinylestradiol, 20-50mg) and a Progestogen (a Progesterone analogue). It mimics the luteal phase of the menstrual cycle and suppress gonadotropin release by negative feedback (inhibits follicular maturation and ovulation)

Answer 98

Oral - One a day for 21 days, then break, placebo or iron pill for 7 days

Answer 99

Patients wanting Contraception & | Patients with menstrual symptoms- Uterine bleeding

Answer 100

Pregnancy, breast feeding, Hx or Heart Disease risk factors, HTN, hyperlipidaemia, any prothrombotic coagulation abnormality, DM, liver disease, carcinoma of breast of genital tract

Answer 101

Venous Thrombo-embolism, HTN, decreased glucose tolerance, mood swings, acne, NV, amenorrhoea of variable duration on pill cessation Weight gain

Answer 102

Metabolised by CYP450 so affected by inhibitors & inducers. Inducers can lead to contraception failure e.g. carbamezepine and phenytoin (anti-epileptics). Broad spectrum antibiotics (e.g. Amoxicillin) :Enterohepatic recirculation of oestrogen increases the efficacy of the COCP. If gut flora is killed by a broad spectrum antibiotic this is reduced and may cause contraception failure

Answer 103

Depot progesterone Morning after pill Progesterone receptor modulators Copper IUD

Answer 104

Same as POP

Answer 105

IM implant of progesterone

Answer 106

Patients wanting long term contraception

Answer 107

Very high oral dose of progesterone (1.5mg) alone or a Progestogen with an oestrogen to prevent implantation

Answer 108

Oral up to 72hrs after sex

Answer 109

Emergency contraception after unprotected sex

Answer 110

COCP contraindications | Need to ask about cycle and when they had sex to determine if woman’s already pregnant- illegal (abortion)

Answer 111

delays or inhibits ovulation- emergency contraception 120 hours after sex

Answer 112

Stops or kills sperm- emergency contraception 120 hours after sex

Answer 113

Oestrogen and Progesterone given to replace lost hormones

Answer 114

Orally or topically (patch/gel)

Answer 115

Menopause | Control well being

Answer 116

Don’t give oestrogen alone unless patient has had a hysterectomy- would cause endometrial hyperplasia and cancer

Answer 117

Adverse effect on lipid and thrombophilia profile Risks: Unopposed oestrogens- endometrial and ovarian cancers Increase risk of breast cancer, IHD, stroke thromboembolism, uterine bleeding

Answer 118

Decreased risk of colorectal cancer, increased sexual function, small reduction in bone loss

Answer 119

Combined HRT- patient given same dose of oestrogen and progesterone for 28 days continuously; woman has no withdrawal bleed, woman does have risk of endometrial hyperplasia- so only given when woman has had a hysterectomy

Answer 120

Sequential HRT- patient given oestrogen only up to day 14-16 and then progesterone added; will stimulate withdrawal bleed; reduced risk of endometrial cancer as endometrial hyperplasia does not occur; can be given to patients who haven’t had a hysterectomy

Answer 121

Opposes oestrogen receptors

Answer 122

Fertility problems- Chlomiphene Breast cancer and ovulation induction- Tamoxifen

Answer 123

Anti oestrogen used for fertility problems

Answer 124

Induces ovulation by inhibiting binding of oestrogen and thus causing an increase in GnRH, LH and FSH

Answer 125

Breast cancer and ovulation induction

Answer 126

- Reduces oestrogen binding- limiting progress/ recurrence of breast cancer

Answer 127

Antagonises effects of progesterone Sensitises uterus to prostaglandins Partial agonist for progesterone receptors and inhibits action of progesterone

Answer 128

Medical termination of pregnancy and inducing labour (not in UK)

Answer 129

Weak progesterogenic effect by competing with dihydrotestosterone

Answer 130

Hisuitism- Cyproterone

Answer 131

Act of oestrogen receptors | Have different actions depending on where the receptor is found

Answer 132

Osteoporosis in post menopausal women- Raloxifene

Answer 133

No proliferative effects on endometrium, oestrogenic effects on bone, lipid metabolism, blood coagulation, reduced risk of invasive breast cancer, increased hot flushes

Answer 134

``` Statins Fibrin acid derivatives Cholesterol absorption inhibitors Bile acid sequestrants Niacin ```

Answer 135

``` Simvastatin (short HL 1-4hrs) Atorvastatin (HL = 20 hours) Rostuvastatin (HL = 20hours) Pravastatin ```

Answer 136

Simvastatin 1-4 hours

Answer 137

HMG-CoA Reductase inhibitor. Prevents cholesterol synthesis in the liver. Lower liver cholesterol concentration stimulates the production of LDL receptors, increasing LDL removal from the plasma

Answer 138

Hyperlipidaemia which has not responded to changes in diet & exercise Secondary prevention in patients with serum cholesterol >5.5mmol/L

Answer 139

Pregnancy, breast feeding, liver disease

Answer 140

Serious ADRs tend to be limited even at the highest doses of statin given. Myalgia, myopathy & rhabdomyolysis, increased transaminase levels, GI disturbances, arthralgia, headache

Answer 141

CYP450 inducers & inhibitors. Inhibitors increase risk of myopathies as drug spends more time in the plasma & can interact with muscle

Answer 142

Bezafibrate Ciprofibrate Gemfibrozil

Answer 143

Agonist at Peroxisome Proliferator-Activated Receptor- α. This causes LDL decrease, HDL increase, TAG decrease

Answer 144

Hyperlipidaemia which doesn’t respond to dietary control

Answer 145

Pregnancy, breast feeding, gall bladder disease, severe renal or hepatic impairment, Hypoalbuminaemia

Answer 146

GI disturbances, dermatitis, pruritis, rash, impotence, headaches, dizziness, blurred vision

Answer 147

Increased chance of myalgia & myopathies when taken with statins

Answer 148

Blocks NPC1L1 in the intestinal brush border to inhibit cholesterol absorption. Increases hepatic LDL receptors

Answer 149

Hyperlipidaemia resistant to dietary control in statin intolerant patient

Answer 150

Breast feeding

Answer 151

GI disturbances, headache

Answer 152

Colestipol | Colestyramine

Answer 153

They bind to bile acids in the intestine to prevent reabsorption and conversion to cholesterol in to bile acids in the liver.

Answer 154

Elevated cholesterol resulting from a high LDL concentration

Answer 155

Biliary obstruction

Answer 156

GI disturbances, very few systemic side effects as they are not absorbed

Answer 157

Inhibits lipoprotein-a synthesis

Answer 158

Skin flushing & itching, dry skin, skin rashes

Answer 159

Vascular disease leading to small and large vessel damage in which there's premature death from cardiovascular disease

Answer 160

Insulin deficiency

Answer 161

Insulin resistance (decreased insulin sensitivity) and eventually insulin deficiency

Answer 162

Diet and lifestyle changes- no pharmacological intervention Drugs- beta cell stimulators and insulin sensitisers (GLP-1) Insulin

Answer 163

Lose weight by limiting fat intake whilst increasing proportionate calories of complex carbohydrates - helps keep HbA1c levels stable Reduction in alcohol Stop smoking Increasing exercise Some clinicians give anti obesity drugs to obese patients before diabetic medication

Answer 164

Sulphonylureas | Meglitidines

Answer 165

Tolbutamide (t1/2= 4 hrs, acts upto 6-12 hrs) Glibencamide (t1/2= 10 hrs, acts upto 18-24 hrs) Glipizide (t1/2= 7 hrs, acts upto 16-24 hrs)

Answer 166

They antagonise B cell K+/ATP channel activity; decrease in K+ current causes depolarisation; Ca2+ influx and insulin release

Answer 167

Reduces HbA1c between 1-2%

Answer 168

Oral | 1/day

Answer 169

Diabetes mellitus, in patients with residual β-cell activity

Answer 170

Breastfeeding women, elderly, renal and hepatic insufficiency Obese people as it can cause weight gain

Answer 171

Hypoglycaemia (esp in elderly, with missed meals or excess alcohol) GI disturbances Weight gain (not helpful in obese patients) Highly protein bound

Answer 172

Repaglinide Nateglinide (t1/2 = 1-3 hrs)

Answer 173

They antagonise B cell K+/ATP channel activity decrease in K+ current; causes depolarisation; Ca2+ influx and insulin release

Answer 174

Meglitidines work faster than sulphonylureas Meglitidines have a relatively lower risk of hypoglycaemia than sulphonylureas Meglitidines not associated with weight gain (useful for OBESE patients)

Answer 175

Reduces HbA1c by 1%

Answer 176

Oral | 1/day

Answer 177

Uncontrolled non-insulin dependent diabetes

Answer 178

Biguanides | Thiazolineinediones

Answer 179

Metformin (t1/2 = 2/3 hrs)

Answer 180

Increases insulin receptor sensitivity (skeletal and adipose) Inhibits hepatic gluconeogenesis Reduces hyperglycaemia but doesn’t cause hypoglycaemia

Answer 181

Reduces HbA1c by upto 2%

Answer 182

Oral | 2,3 / day

Answer 183

T2DM – endogenous insulin presence required | First line of treatment always/ for overweight patients (NICE)

Answer 184

Compromised HR (CKD

Answer 185

``` GI disturbances (thus give slow dose titrations)- wind, loose stools etc. Lactic acidosis Vitamin B12 deficiency ```

Answer 186

Does not induce hypoglycaemia when reducing hyperglycaemia Also reduces LDLs and VLDLs Weight neutral- used for overweight patients Reduced risk of cancer (bowel etc.)

Answer 187

Rosiglitazone Piogliatazone (t1/2 = 7 hrs but metabolites have prolonged t1/2 upto 150 hrs)

Answer 188

Reduction in gluconeogenesis and increased glucose uptake (peak effects after 1-2 months) PPAR-gamma agonist (receptor found on adipose tissue) – stimulates uptake of fatty acids, making cells more dependent on glucose remaining in blood- uptake of glucose (provided endogenous insulin). By reducing circulating fatty acid concentrations and lipid availability in liver and muscle, the drug improves patient’s sensitivity to insulin.

Answer 189

Reduce HbA1c by 1-1.5%

Answer 190

Oral | 1/day

Answer 191

Uncontrolled non-insulin dependent diabetes

Answer 192

Compromised HRH function (especially heart failure, can cause oedema)

Answer 193

``` Highly protein bound Oedema Increases in LDL GI disturbance Weight gain Fractures in post menopausal women – inhibits osteoblast function Bladder cancer ```

Answer 194

Don’t induce hypoglycaemia | Increases in HDL

Answer 195

Glucagon like peptide 1 analogues Dipeptidyl peptidase 4 inhibitors Alpha gluosidase inhibitors Sodium glucose Cotransporter 2 inhibitors

Answer 196

GLP normally secreted from L cells in small intestine upon the ingestion of food Pancreas- Beta cell- enhances glucose dependent insulin secretion; Alpha cell- suppresses post prandial glucagon secretion Liver- reduces hepatic glucose output Stomach- slows rate of gastric emptying Brain- promotes satiety and reduces appetite Muscle- increased uptake of glucose

Answer 197

SC injection – 1,2 / day

Answer 198

Used after Drugs before Insulin, only if: HbA1c has reduced by 1% in last 6 months AND Weight has decreased by 3 % in last 6 months

Answer 199

Nausea and other GI symptoms

Answer 200

Promotes Weight loss by promoting satiety and reducing appetite

Answer 201

Sitagliptin

Answer 202

Inhibits DPP enzyme that breaks down GLP-1, therefore increasing GLP and decreasing blood glucose levels

Answer 203

Inhibits SGLUT2 in PCT and therefore encourages glucose secretion via kidneys

Answer 204

Flatulence and diarrhoea | High doses associated with elevation of ALT

Answer 205

Thrush / UTIs | Polyuria and Thirst

Answer 206

Ultra Rapid : Onset = 0.2 – 0.5 ; Peak = 1 ; Duration = 3 – 4 Short Acting : Onset = 0.5 – 1 ; Peak = 2 – 5 ; Duration = 6 - 12 Intermediate : Onset = 1.5 – 3 ; Peak = 4 – 10 ; Duration = 16 – 24 Long Acting Onset = 4 – 6 ; Peak = 8 – 30 ; Duration = 18 – 36

Answer 207

FIRST LINE TREATMENT Always give Biguanide (metformin), UNLESS - Patient is intolerant to Biguanide (metformin) - Patient is not overweight --> In which case give Sulphonylurea (Tolbutamide) SECOND LINE TREATMENT - Over time if HbA1c rises >7%- add a Sulphonylurea (Tolbutamide) - Over time if HbA1c rises >7.5%- add a Thiazolineinediones (Pioglitazone), or start insulin therapy If on this regime, HbA1c levels rise higher than 7.5%, doses will be titrated upwards to regain adequate glycaemic control

Answer 208

In patients with advanced diabetes, monitoring several times a day is required to determine dosing level with insulin 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

Answer 209

Glucose in the blood will react with the terminal valine of the Hb molecule to produce glycosylated Hb (HbA1c) % HbA1c is a good indicator of how effective blood glucose control has been As RBCs spend ~3 months in circulation the %HbA1c is related to average blood glucose concentration over previous 2-3 months Poorly controlled diabetics have a HbA1c >10% In combination therapy, new medications are added at HbA1c values of 7 or 7.5%

Answer 210

2 x intermediate dosages of insulin OR 1 x long acting dosage of insulin + 2 x short acting dosages of insulin (with meals)

Answer 211

Local reactions Hypoglycaemia (coma) – overdose Rarely- immune resistance

Answer 212

Orlistat Sibutramine Rimonabant

Answer 213

Bariatric surgery

Answer 214

Gastric and pancreatic lipase inhibitor | Reduces the conversion of up to 30% dietary fat to fatty acids and glycerol

Answer 215

Broad GI disturbances | Soft fatty stools, flatus, faecal discharge/ incontinence

Answer 216

NA and serotonin reuptake inhibitor Appetite suppression Increased thermogenesis

Answer 217

Increased heart rate and blood pressure

Answer 218

Endocannabinoid antagonist

Answer 219

Depression- currently withdrawn in UK by NICE

Answer 220

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

Answer 221

``` o Influenza A • Most dangerous • Multiple host species which are able to infect humans- e.g. bird flu and swine flu • Exhibits antigenic drift and shift • Drift = different each year • Shift = leads to an epidemic • New vaccine development is necessary to treat the pre-absorbed virion when it is vulnerable to the pre-vaccinated immune system o Influenza B • No animal reservoir • Lower mortality than influenza A o Influenza C • Common cold like ```

Answer 222

M2 ion channel blockers- developed from tricyclics amines | Neuraminidase inhibitors

Answer 223

o Amantadine | o Rimantadine- preferred as amantadine has a 5-10% higher risk of ADRs

Answer 224

Inhibits the un-coating of a virus, therefore preventing it from being able to infiltrate into the cell. This occurs by the action of: • Inhibiting H+ influx into the virus cell itself by blocking the M2 Ion channel., therefore preventing the change in pH which normally stimulates the viral un-coating • So viral RNA not released into host cell

Answer 225

Prophylaxis and treatment of acute Influenza A in groups at risk.

Answer 226

Ineffective against group B Rapid emergence of M2 mutations in H5N1 viruses Resistance can develop quickly as only a single point mutation is needed in order to change the shape. This causes the binding site to move away from the channel, so that when the drug binds it will no longer block the channel E.g. amantadine in chicken feed leading to resistance

Answer 227

Amantadine has more marked ADR risk than Rimantadine of ~5-10%, therefore Rimantadine is usually preferred Dizziness Hypotension GI disturbance Confusion, insomnia and hallucination can be problematic in the elderly (CNS) Is nephrotoxic in high doses

Answer 228

o Zanamivir | o Oseltamivir

Answer 229

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. Sialic acid analogues, with very high binding affinities (Ki ~ 0.1nM) and potency ( ED50 ≈ 30nM) for Neuramidase. The receptor is not involved with antigenic shift or drift

Answer 230

Zanamivir- inhaled Oseltamivir- Oral (80% Bioavailability)

Answer 231

Treatment of Influenza A or B virus within 48 hours after onset of symptoms when influenza is endemic in the community

Answer 232

Breast feeding Zanamivir has low bioavailability therefore is given as a dry powder inhalant. It is not used for prophylaxis. 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. Gives rise to: 35-38% reduction in severity

Answer 233

``` Headache Nose bleed Respiratory depression (rarely) Bronchospasm GI disturbances ```

Answer 234

Phase III Clinical Trials have directly informed therapeutic strategy. Trial outcomes are discussed with respect to: • Severity of symptom related to dose o Reduction in symptom severity in Placebo: 75mg:150mg treatment groups showed no difference in outcome between the two active groups with decrease in symptoms score of about 40% vs. Placebo. • Timing of initiation of treatment and illness duration o 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 past this time. • Mortality o It appears that Oseltamivir could offer ≈ 70% reduction in risk of mortality in one Canadian study. Importantly, this was achieved even when dosing as delayed as long as 64 hours after symptom onset. • Prophylaxis o Treatment for six weeks with 75 mg significantly reduced incidence of flu in both healthy adults and frail elderly subjects.

Answer 235

* The Neuramidase Enzyme also appears to be evolutionary conservative, which is a great advantage for any antimicrobial therapeutic although reports of resistance in various HA and NA surface glycoprotein antigens subtypes have been reported. * In the small number of those treated for H5N1 bird flu resistance appears to be high. For other types highly variable values have been reported for H1N1. However the same degree of resistance to zanamivir is not apparent.

Answer 236

Treatment aims to selectively target the invading bacteria with minimal effect upon the host o Achieved by exploiting the differences that exist between the structure and physiology of the prokaryotic bacterial cells and the host eukaryotic cells

Answer 237

Peptidoglycan cell wall- Peptidoglycan cell wall only present in prokaryotic cell 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 Protein synthesis- Bacterial ribosome (50s+30s subunits) is different to the mammalian ribosome (60s+40s subunits) Cytoplasmic membrane- Bacterial plasma membrane does not contain any sterols, unlike mammalian

Answer 238

Penicillin Cephalosporin Glycopeptides

Answer 239

Antifolates Quinolones Rifampicin

Answer 240

``` Aminoglycosides Tetraclyclines Macrolides Chloramphenicol Fusidic acid ```

Answer 241

Polymixins

Answer 242

Prophylaxis- given to people who are at increased risk of infection • Peri-operative- prevention of surgical site infections • Short term- Meningitis contact • Long term- Asplenia (encapsulated bacteria), immunodeficiency Significant bacterial infection- given go people with a cultured, proven infection • Empirical treatment

Answer 243

Bacteriostatic (inhibit bacterial growth, but do not kill them) OR Bactericidal (kill the bacteria)

Answer 244

o Clean killing of infecting bacteria • Minimal impact on non-target commensal organisms • No resistance in any surviving pathogens o No adverse effects on patient

Answer 245

``` 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 ```

Answer 246

``` 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 ```

Answer 247

o Efficacy- maximal o Cost- minimal o Administration Route- oral, IV, SC etc. o Safety- patient age, toxicity, drug interactions, allergies, pregnancy/breast feeding, organ function

Answer 248

* Pharmacological- toxicities, drug interactions * Allergic reactions * Impact on normal flora- Clostridium Difficile infection

Answer 249

* To ensure- adequate and non-toxic dose * Used for drugs with Zero order kinetics (where half life cannot be determined) * Used with: aminoglycosides (inc. gentamicin), vancomycin

Answer 250

Chromosomal gene mutation | Horizontal gene transfer

Answer 251

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

Answer 252

Transformation o Bacteria with antibiotic resistance gene releases DNA o Uptake of DNA by recipient cell, conferring antibiotic resistance Transduction o Phage infected, antibiotic resistant Bacterial donor cell o Phage passes the DNA conferring resistance to recipient cell Conjugation o Connection is made between antibiotic resistant donor cell, and recipient cell o Plasmid containing resistance gene is replicated and passes from donor cell to recipient cell o Plasmid may even become incorporated into recipient cell DNA

Answer 253

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

Answer 254

1. Local selection (e.g. in a hospital) 2. Clonal dissemination (e.g. around the country) 3. Global spread

Answer 255

o Methicillin Resistant Staphylococcus Aureus (MRSA) o Glycopeptide Intermediate susceptibility Staphylococcus Aureus (GISA) o Glycopeptide Resistant Enterococci (GRE) o Extended Spectrum Beta Lactamase enterobacteriaceae (ESBLs) o Extensively Drug Resistant Klebsiella Pneumoniae (XDR-KP)

Answer 256

Antimicrobial Stewardship- measures to ensure appropriate usage of antibiotic o Right antibiotic o Right time o Right dose, frequency and duration (Pharmacokinetics – ADME) o Right route Infection Control o Prevent the spread of recognised resistant bacteria • Isolation or cohorting • Hand hygiene • Decolonisation of patients o Prevent bacterial exposure to antibiotics • Minimise risk of infection • Monitor and control antibiotic prescribing

Answer 257

o Administration- Oral or IV (immunocompromised) o Distribution o Metabolism/Elimination- Renal or Hepatic

Answer 258

Time dependent killing- B lactams- e.g. Vancomycin o Works by having a prolonged presence at site of infection o But antibiotics not at high concentration Concentration dependent killing – Aminoglycosides o Works by having a high antibiotic concentration at the site of infection, thus eradicating microorganisms o But short duration

Answer 259

Minimum Inhibitory Concentration – MIC 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 Related to pharmacodynamics of antibacterials