GPHC Exam - Preliminary Chapters

What is the main route of elimination of drugs by the body

Metabolism by the liver

At what stage does the liver need to be in for there to be a dose reduction

Severe liver impairment due to the liver reserve being large

In elderly patients what type of drug has reduced hepatic metabolism

Lipid soluble drugs due to the reduction in liver volume

Important for drugs with a narrow therapeutic window

What is one of the products the liver is responsible for synthesising

Blood proteins such as albumin (most abundant protein in blood)

Give examples of drugs which are highly protein bound

NSAIDs

Phenytoin

Warfarin

Prednisolone

Which types of drugs do not exert their therapeutic effect

drugs which are highly protein bound - as when they are bound to blood proteins they are not biologically active and do not exert therapeutic effect they are just carried along in the blood

When unbound they are free drugs which can act on target tissues to exert their therapeutic effect

How can liver impairment affect highly protein bound drugs

In severe liver impairment, low albumin levels is associated with reduced protein binding of drugs and therefore is a higher concentration of free drug in the blood causing toxicity in drugs which are highly protein bound

What is the liver responsible for synthesising in the blood

The liver is responsible for the synthesis of blood clotting factors

How does liver impairment affect the blood

In liver impairment there is a reduction in blood clotting factors resulting in blood taking a longer time to clot which increases the risk of bleeding - indicated by high INR and prolonged prothrombin time

Increases the sensitivity to oral anticoagulants e.g. warfarin or drugs that have a side effect of bleeding e.g. NSAIDs

Why is fat soluble vitamins affected by liver impairment

In liver impairment there is fat malabsorption (difficulting in digesting or absorbing). This includes malabsorption of fat soluble vitamins --> vitmain A, D, E and K

What is the name of the water soluble version on vitamin K and why may it be given

Menadiol - this can be given to prevent Vitamin K deficiency in malabsorption syndrome characterized by inability to absorb fatty substances

Why is Vitamin K so important and can happen if there is a deficiency

Vitamin K helps the blood to clot

deficiency is associated with an increased risk of bleeding

When can there be a reduction in bile excretion

In intra-hepatic or extra - hepatic obstructive jaundice.

What is obstructive jaundice

Where essential flow of the bile to the intestine is blocked

Which drugs are excreted in the bile

Fusidic acid and rifampicin - these can accumulate in liver impairment

How can severe liver disease cause hepatic encephalopathy

Certain drugs can further impair cerebral function and precipitate into a hepatic coma called hepatic encephalopathy

What type of drugs in severe liver impairment can cause hepatic encephalopathy

- Constipating drugs e.g. Opioids, TCAs

- drugs that cause drowsiness or sedation as a side effect e.g. opioid analgesics sedating antihistamines, benzodaizepines, Z-drugs

Drugs that cause hypOKalaemia as a side effect e.g. loop and thiazide diuretics

How is hepatic encephalopathy treated

Osmotic laxative - lactulose

How is chronic liver disease categorised

By fluid overload - presents as oedema ( build up of fluid in the body causing affected tissue to become swollen) - oedema commonly occurs in the lower body in the ankles and lower legs

or as ascites ( build up of fluid in the lining of the abdomen known as the peritoneal cavity) - causes a swollen abdomen

What drugs can worsen oedema and ascites (fluid overload)

Drugs that have fluid retention as a side effect e.g. NSAIDs, Corticosteroids

What are the common signs and symptoms of hepatotoxicity

Jaundice (yellow skin and eyes)

Abdominal pain (upper right)

Nausea and vomiting

Malaise (feeling unwell)

Pruritus (Itching)

Dark Urine

Pale or clay - coloured stools

Drowsiness, confusion

Lab results with an increase in liver enzymes

What are the common hepatotoxic drugs

Alcohol

Amiodarone

carbamazepine

Co-amoxiclav

Fluconazole

flucloxacillin

Isoniazid

Itraconazole

Ketoconazole

Labetalol

Methotrexate

Paracetamol

Phenothiazines

pioglitazone

Rifampicin

Statins

Tolcapone

Tetracyclines

Valproate

Concurrent use of two or more of these drugs can increase the risk of hepatotoxicity

What drugs are enzymes inhibitors

SICK FACES COM

Sodium valproate

Isoniazid

Cimetidine

Ketconazole

Fluconazole

Alcohol (binge)

Chloramphenicol

Erthromycin

Sulphonamide

Ciprofloxacin

Omeprazole

Metronidazole

What drugs are enzymes Inducers

SCRAP GPS

Smoking

Carbamazepine

Rifampicin

Alcohol (chronic)

Phenytoin

St John's wort

Griseofulvin

Phenobarbital

Sulfonylurea

What effect does liver enzymes inhibitors have on metabolism

Drugs that are liver enzyme inhibitors decrease metabolism of other drugs which can increase plasma concentration of that drug leading to toxicity

What effect does liver enzymes inducers have on metabolism

Drugs that are liver enzymes inducers increase the metabolism of other drugs which can decrease the plasma concentration leading to sub-therapeutic effect

Why does grapefruit juice interact with drugs

Grapefruit juice contains CYP3A4 inhibitors which can increase the plasma concentration of drugs and cause possible toxicity

What are the common drugs that interact with grapefruit juice

CVS drugs - Amiodarone, dihydropyridine CCB, Statins, Verapamil, Dronedarone, Ranolazine

CNS drugs - Sertraline, Quetiapine

Immunosuppressants - Tacrolimus, Ciclosporin

Other drugs - Phosphodiesterase - type 5 inhibitors, Colchicine

What are the lab test results in liver impairment

ALT - High

AST - High

ALP - High

GGT - High

Bilirubin - High

Albumin - Low

Prothrombin time/INR - High

How are drugs excreted from the body

By the kidneys, via urine

For this to happen effectively, the kidneys needs efficient glomelur filtration

What is glomelur filtration

It is the first step in making urine - process used by the kidneys to filter excess fluids and waste products out of the blood and into the urine collecting tubules to allow for elimination from the body

Why does renal impairment increase the risk of drug toxicity

In renal impairment there is reduced renal excretion of a drug or its metabolites which can give rise to toxicity

What precautions should be taken when prescribing medications to patients with renal impairment

Depending on the severity of renal impairment, dose reductions may be required

Renal function test should be done before prescribing any drug that requires a dose reduction or modification in renal impairment if even mild renal impairment is suspected

How can the total maintenance doses be reduced in renal impairment

Maintenance doses can be reduced by either reducing the size of the individual dose OR by increasing the intervals between the doses

How should dosing in renal impairment be managed for narrow therapeutic index drugs

Recommended regimens should be regarded only as a guide to initial treatment, subsequent doses should be adjusted according to the clinical response and the monitoring of plasma drug concentration

List other problems that occur in renal impairment

Increased sensitivity to some drugs - even if elimination is not impaired

Many side effects are poorly tolerated

Some drugs are not effective when renal function is reduced e.g. thiazides - as they rely on efficient glomerular filtration

How can these problems that occur in renal impairment be solved

By either dose reductions

By using an alternative drug

Why might a loading dose be necessary for some drugs in patients with renal impairment, even if the maintenance dose is reduced

In some drugs, although the maintenance dose will be reduced it is important to give a loading dose if an immediate effect is required. This is because the plasma half life of drugs excreted by the kidneys is prolonged in renal impairment and take about FIVE times the normal half life of the normal drug to reach steady state plasma concentrations

What is a loading dose

Initial higher dose of a long acting drug which is given at the beginning of a course of treatment in order to quickly achieve therapeutic plasma concentration

How does renal function change with age?

Renal function declines with age.

What should be assumed when prescribing for the elderly?

At least some degree of mild renal impairment should be assumed.

The elderly excrete drugs slowly and are highly susceptible to nephrotoxic drugs

What is a significant risk factor for Acute Kidney Injury (AKI)

Dehydration

During intercurrent illness, what is there an increased risk of

During intercurrent illness there is an increased risk of AKI particularly in patient with an eGFR < 60ml/min

What should be considered for potentially nephrotoxic or renally excreted drugs in patients with renal impairment

Potentially nephrotoxic or renally excreted drugs may require a dose reduction or temporary discontinuation

What are the sick day rules in terms of drugs

They are a list of drugs that should be temporarily stopped during ANY illness that can result in dehydrations.

List the drugs that should be stopped due to sick day rules

DAMN

DIURETICS (exacerbates dehydration; electrolyte imbalance)

ACE INHIBITORs/ARBs (nephrotoxic and reduces eGFR)

METFORMIN (increased risk of lactic acidosis in RI)

NSAIDs (nephrotoxic and reduces eGFR)

When should DAMN drugs usually be restarted

Restarted 24-48 hours after normal eating and drinking

According to NHS scotland cards, when do sick day rules apply

When you are unwell with any of the following:

- Vomiting or diarrhoea (unless only minor)

-Fevers, sweats and shaking

What are the signs and symptoms of AKI

Reduced Urine output

Nausea and vomiting

Confusion and drowsiness

Abdominal pain

Fatigue

Lab results: Reduced eGFR and CrCl

Increase in serum creatinine

List the Common Nephrotoxic drugs

ACEi/ARBs

Aciclovir

Aminoglycosides

Aminosalicylates

Amphotericin

Ciclosporin

Cyclophosphamide

Glycopeptides

Lithium

Methotrexate

NSAIDs

Tacrolimus

Trimethoprim

Why should nephrotoxic drugs be avoided in patients with renal disease

Nephrotoxic drugs should be, if possible, avoided in patients with renal disease as the consequences of nephrotoxicity are likely to be more serious when renal reserve is already reduced

What is the MHRA/CHM advice given in 2019 for renal function test

Use the appropriate estimate of renal function to avoid the risk of adverse drug reactions

What is the prefered formular for renal function test

COCKCROFT-GAULT FORMULA

((140-age) x constant x weight)/serum creatine

constant: Male 1.23 female 1.04

When should the ideal body weight be used to calculate the creatinine clearance

where fat is likely to be the major contributor to body mass

BMI >40

Why is creatinine used to estimate renal function

Creatinine is a substance used by the body at a fairly constant rate.

It is excreted unchanged by the kidneys via glomerular filtration

How does serum creatinine indicates renal function

If filtration in the kidney is deficient, serum creatinine rises

Higher the serum creatinine is the greater the degree of renal impairment

The greater the volume of creatinine cleared per minute the better kidney function

How is Chronic kidney disease categorised

Using a combination of GFR and albumin:creatinine ratio (ACR)

What is the significance of decreased GFR and increased ACR in assessing kidney function.

Decreased GFR and an Increased ACR is associated with an increased risk of adverse outcomes.

E.g. if a patient has an eGFR of 14 ml/min and an ACR of 15 mg/mol the patient has a CKD classification of G4 A2 which is severe renal impairment

What is the cautionary and advisory label for drugs that colour Urine

'This medicine may colour your urine. This is harmless

What drugs colour your urine RED

Dantron e.g. Co-danthrusate

Doxorubicin

Levodopa (dark - red bodily secretions)

What drugs colour your urine YELLOW - BROWN

Nitrofurantoin

Senna

What drugs colour your urine PINK/ORANGE

Phenindione

What drugs colour your urine BLUE

Triamterene

What drugs colour your urine ORANGE

Rifampicin (also colour bodily secretion such as tears which can stain contact lenses)

Sulfasalazine (bodily secretion - same as above)

What can prostaglandin analogues cause

Irreversible brown pigmentation of the iris

What can happen to stool when taking Iron

Colour the stools a tarry colour

What is the pain management oral drug of choice

Morphine (CD 2)

(Morphine with an oral strength below 13mg/5ml is a CD 5)

Alternative choice: Oxycodone

What is the typical dose of oral morphine in pain management

Immediate - release: 30mg 4 hourly

Modified release: 100mg 12 hourly, 24 hourly

(when pain is stable: switch from immediate - release <4 hours of last dose)

What is the max dose increments of morphine

1/3 or 1/2 of total daily dose every 24 hours

When is parenteral opioids given

When the patient is unable to take opioids by mouth

e.g. Difficulty swallowing, Severely weak, experience severe N&V or in a coma

What is the parental dose of morphine

Morphine (IV, IM, SC) - 1/2 oral dose

Diamorphine (IV, IM, SC) = 1/3 oral dose - more soluble so larger dose given in smaller volume - this avoids fluid overloading the patient - preferred way

What is the recommended concentration for SC Diamorphine, and why should saline be used instead of water for injection above 40mg/ml?

SC Diamorphine can be given up to a strength of 250mg/ml with physiological saline or water for injection

Above 40mg/ml water for injection should only be used as saline can cause precipitation

Which opioids can be given rectally

Morphine

Oxycodone

Why are transdermal opioids given

Chronic Pain stabilised on an immediate release opioid dose

What are the two transdermal preparation of opioids

Fentanyl Patches (72 - hourly)

Buprenorphine patch (72 hourly, 4 - day/7 day)

Not suitable for people in acute pain or rapid changing pain levels

When aren't transdermal patches suitable

Transdermal patches are slow release preparations which take a long time to reach steady state plasma level. This means they do not provide fast pain relief and doses CAN NOT be rapidly titrated to match rapidly changing pain levels

When can immediate release morphine be given with transdermal patches

As breakthrough pain

When switching a patient to opioid patches due to possible opioid-induced hyperalgesia, how should the equivalent dose of the new opioid be adjusted

The equivalent dose of the new opioid is reduced by 1/4 to 1/2.

What is opioid induced hyperalgesia

Condition where long term opioid use can cause the patient to become more sensitive to pain

What is breakthrough pain

Pain that occurs between regular doses of a strong opioid such as morphine is known as breakthrough pain

What are rescue doses

When breakthrough pain occurs, additional doses known as 'rescue doses' of IMMEDIATE RELEASE preparation is given

What are the common opioids used for breakthrough pain and why

Oral morphine solution or oxycodone oral solution is given as they are more flexible in providing various fractions of doses as opposed to a fixed dose tablet or capsule

What medication is unlicensed to use for breakthrough pain

Fentanyl - Buccal, sublingual or nasal preparations can be given as unlicensed rescue doses for breakthrough pain

How long before a painful activity should rescue doses be given and give an example of such activity

30 MINUTES before e.g wound dressing

What is the standard dose for breakthrough pain

1/10th - 1/6th of the total daily dose every 2 - 4 hours as required

Can be up to hourly if pain is severe or in the last days of life

When does pain management need to be reviewed

If a patient is taking breakthrough doses frequently - twice daily or more - their pain management needs to be reviewed

What is a one of the most common side effect of opioids

Opioid - induced Constipation

What is the treatment for opioid induced constipation

Treated with a fecal soften laxative and a peristaltic stimulant laxative

Lactulose + senna

Give another example of a laxative that can be used in opioid induced constipation and explain why it is used only in terminally ill patients

Co-danthramer OR Co-danthrusate - contain a combination of a fecal soften and a stimulant laxative dantrone

dantrone is carcinogenic so reserved only to be used in terminal ill patients

What is Methylnaltrexone used for in the context of opioid-induced constipation

Methylnaltrexone is an opioid receptor antagonist which is licensed to be used in opioid induced constipation if other laxatives are inadequate

When does the opioid induced side effect nausea and vomiting occur

Usually at the start of therapy of strong opioids however most patients build a tolerance to it

What drug treatment can be given for opioid induced N&V side effect and for how long

Prokinetic anti-emetic can be co-prescribed for initial opioid induced N&V treatment for 4-5 days. e.g. metoclopramide

Alternatively the antipsychotics Haloperidol can be given

What is another common side effect of opioids

Dry Mouth

How can you counsel a patient who is experiencing dry mouth due to opioids

Maintain good oral hygiene

Can suck on ice cubes or pineapple chunks, chew sugar free gum can help moisten the mouth or use artificial saliva

What can dry mouth be associated with

Oral candidiasis

This can be treated with Antifungal treatment - nystatin, miconazole, fluconazole

According to the WHO analgesic ladder, what can be used for pain due to bone metastases

radiotherapy, bisphosphonates and strontium

What drug treatment can be given to patients with Neuropathic pain

A trial of tricyclic antidepressant such as amitriptyline.

Anti-epileptics can be added or substituted if pain persists - gabapentin and pregabalin are licensed for neuropathic pain

Ketamine can be used under specialist supervision if poor response to opioids

What drug treatment can be given to pain due to nerve compression e.g. by a tumour pressing on a nerve

Treated by a corticosteroid e.g. Dexamethasone which via its anti inflammatory action reduces the oedema around the tumour thus reducing compression

At age are patients considered to be elderly

Aged 65 and over

When prescribing in the elderly what should be considered

Dosage should be substantially lower compared to younger patient

Common to start with about 50% of the adult dose

Some drugs should be avoided all together - long acting sulfonylurea and benzodiazepines