CSB601 Medications

Medications from CSB601. RA= Rheumatoid Arthritis NSAIDs= Non Steroidal Anti Inflammatory Drugs MOA= Mechanism of Action ADR= adverse reactions OA= Osteoarthritis N/ V/ D= nausea, vomiting, and diarrhea.

Paracetamol- mechanism of action

Not fully determined.

However, mechanisms involved in analgesic effect may include:

• Inhibition of central prostaglandin synthesis and

• Possible effect on serotonergic pain pathways

Paracetamol- Practice Points

• Very effective anti-pyretic, effective analgesic

• Not very effective for inflammation

• Works best when taken REGULARLY, and at MAXIMUM RECOMMENDED DOSES – especially for chronic pain

• Safe for children from approximately 4 weeks of age (need liver functioning well to process paracetamol)

• Safe for breastfeeding and Pregnant mothers (Category A)

• Usually very well tolerated, and allergy is rare

• VERY dangerous in a large overdose! Liver failure= death

Paracetamol- Indications

Nociceptive pain

Examples of NSAIDS

• aspirin

• ibuprofen

• diclofenac

• naproxen

• indomethacin

Properties of NSAIDS

• Analgesic

• Antipyretic

• Anti-inflammatory

NSAID- mechanism of action

inhibit the synthesis of prostaglandins by inhibiting cyclo-oxygenase (COX)-1 and COX-2

NSAID- contraindications

• Asthma (may worsen)

• Cardiovascular risk patients (↑ MI and stroke risk)

• Therapy with anticoagulants (↑ bleeding risk)

• Renal impairment

• Dehydration (further impairs kidneys)

• PUD/GORD/GIT complications*

• Elderly

• Pregnancy (↑ risk of miscarriage, foetal renal or cardiac impairment)

• Impending surgery

Effective for Nociceptive Pain

Analgesics: Paracetamol, NSAID

Opioids

May be effective for Neuropathic Pain

Antidepressants: Amitriptyline

Antiepileptics: Carbamazepine, gabapentin

Opioids

Medication that interact with NSAIDS

• warfarin

• ACE inhibitors

• diurectics

• Sartans

• lithium

• MTX

• corticosteroids

Triple Whammy

Diuretics, ACE inhibitor and NSAIDs

First line treatment for RA

csDMARDs: conventional synthetic disease-modifying antirheumatic drugs

CsDMARD examples

• MTX

• leflunomide

• sulfasalazine

• hydroxychloroquine

Methotrexate (MTX) MOA

folic acid antagonist: stops the conversion of inactive folic acid to the active form, folinic acid by antagonising the enzyme DHFR. By reducing folinic acid, it inhibits DNA synthesis

MTX Indications

Rheumatoid Arthritis

MTX Practice points

ONLY TAKEN ONE DAY PER WEEK

It is cytotoxic, immunosuppresive and anti-inflammatory

It is an oral tablet

It is hepatotoxic and teratogenic

MTX contraindications

Contraindicated in hepatic impairment due to hepatotoxicity

Can be used in children for juvenile RA under a specialist

Avoid in Pregnancy and Breastfeeding

Contraindicated in mod-severe renal impairment

Avoid in those with immunodeficiency, GI ulcers, UC, active infections

MTX ADRs

• Nausea/vomiting

• Blurred vision

• Oral mucositis

• Pulmonary toxicity

• Dyspnoea, chest pain, cough, fever

• Hepatoxicity

• Rash/itch/photosensitivity

• Neurotoxicity

• Myelosuppression

• Immunosuppression – infections such as meningitis

RA second line treatment

bMARDs: biological disease-modifying antirheumatic drugs

bMARDs examples

• abatacept

• adalimumab

• certolizumab

• Etanercept

• infliximab

Infliximab MOA

TNF-alpha antagonist: by blocking the cytokine, stops the inflammatory and immune response.

Infliximab Practice Points

• Usually used WITH MTX

• Only available as IV

• Lots of ADRs, usually given with antihistamine/corticosteroid to reduce severity

• Can take up to 12 weeks to see effect

• Given every 6-8 weeks once they reach maintenance dose

Infliximab Indications

Rheumatoid Arthritis

Infliximab Contraindications

• Avoid in hepatic impairment

• Avoid in pregnancy

• Seek specialist advice for breastfeeding use

• Not used for juvenile RA

• Cannot be given with several vaccines

• Contraindicated if there has been a malignancy in the past 5 years, active infection, blood dyscrasias, heart failure, MS, lupus

First line therapy for OA

PARACETAMOL

• Given in REGULAR divided doses

• Very important that the patient is aware of the need to REMAIN on this therapy and not use it “when required”

• Much more effective when used regularly as “background therapy” than as relief

Second line therapy for OA

NSAIDS

• Always use lowest effective dose

• Lots of ADRs: GIT, kidney, cardiac – Can be topical or oral

• Rubs can be quite useful for many patients

• Only to be used INTERMITTENTLY – e.g. before/after exercise or during flare of inflammation

• Should be on paracetamol for regular relief

Third line therapy for OA

Opioids

• ONLY use if 1st/2nd line don’t work or contraindicated

• Should avoid NSAIDs if patient has GORD/PUD, serious cardiac complications

• Always start with a WEAK opioid

Alternative therapy for OA

– Intra-articular corticosteroid injection (usually if only one large joint affected, e.g. knee or lower back)

Basal insulin

• A long acting insulin (insulin glargine)

• Offers the mandatory background effects of insulin

• Injected once daily independent of carbohydrate intake

• Typically 40% of the total insulin requirement as a single dose

Bolus insulin

• A short acting insulin (insulin aspart)

• Offers the glycogenesis effects of insulin

• Injected before each meal to cover carbohydrate intake

• Typically 60% of the total insulin requirement in divided doses

Insulin MOA

Mimics the effects of endogenous insulin

Insulin adverse effects

Hypoglycaemia

Insulin Practice Points

• Hypoglycaemia vs. fasting/recreational substances

• Temperature-sensitive storage requirements

• Delivery options include s/c injection or an insulin pump

• Monitoring involves [blood glucose], HbA1c, and ketones

Primary Choices for T2DM

1. Biguanides

2. Sulfonylureas

3. DPP-4 inhibitors

4. SGLT2 inhibitors

5. GLP-1 analogues

Secondary Choices for T2DM

1. Acarbose

2. Pioglitazone

3. Insulin

Example of a Biguanide

Metformin

Biguanides MOA:

Reduce the intestinal absorption of carbohydrates, increase insulin sensitivity, increase the uptake of glucose into peripheral tissues, reduce hepatic glucose production (glycogenolysis)

Biguanides Adverse Effects:

N/V/D

Biguanides Practice Points

• The first line agent for the management of T2DM

• Can not cause hypoglycaemia on its own

• Can come in both immediate release and extended release

• Lactic acidosis

Sulfonylureas examples:

Gliclazide, glipizide, glibenclamide

All Sulfonylureas start with…

gli

Sulfonylureas MOA:

Increase pancreatic insulin secretion (independent of food)

Sulfonylureas adverse effects:

Hypoglycaemia, weight gain

Sulfonylureas Practice Points:

Will absolutely cause hypoglycaemia on their own

Dipeptidyl peptidase-4 (DPP-4) inhibitors examples:

Linagliptin, sitagliptin, saxagliptin

All DPP-4 Inhibitors end with…

gliptin

DPP-4 Inhibitors MOA:

Inhibit DPP-4 to increase the concentration of incretins (GLP-1 and GIP) which increases glucose-dependent insulin secretion

DPP-4 Inhibitors adverse effects:

Well tolerated (± musculoskeletal pain)

DPP-4 Inhibitors Practice Points

• Very unlikely to cause hypoglycaemia on their own

• Compared to metformin/sulfonylureas, relatively new

Sodium-glucose co-transporter 2 (SGLT2) inhibitors examples:

Empagliflozin, dapagliflozin, ertugliflozin

All SGLT2 Inhibitors end with…

gliflozin

SGLT2 Inhibitors MOA

Inhibit the renal SGLT2 (reduce glucose resorption which increases glucose excretion via the urine)

SGLT2 Inhibitors adverse effects:

Polyuria, genital infections, euglycaemic ketoacidosis

SGLT2 Inhibitors Practice Points

• Very unlikely to cause hypoglycaemia on their own

• With glucose, follows sodium. Mild blood pressure reductions

• With sodium, follows water. Need to be mindful of dehydration

• Renal impairment?

• Brand new, not as much experience with use

Glucagon-like peptide 1 (GLP-1) analogues examples:

Dulaglutide, liraglutide, exenatide

All GLP-1 analogues end with…

tide

GLP-1 analogues MOA

Mimics the effects of GLP-1 to increase glucose-dependent insulin secretion

GLP-1 analogues adverse effects:

Gastrointestinal ADRs, injection site reaction

GLP-1 analogues practice points:

• Very unlikely to cause hypoglycaemia on their own

• These drugs are only available through s/c injection

Acarbose class:

α–glucosidase inhibitor

Acarbose MOA:

Reduce intestinal carbohydrate absorption

Acarbose Practice Points:

Very troublesome GI ADRs

Pioglitazone class:

Thiazolidinedione

Pioglitazone MOA:

Increase glucose uptake into peripheral tissues

Pioglitazone Practice Points:

↑ risk bladder CA & HF

Liothyronine (T3) indications

Hypothyroidism

Liothyronine (T3) Contraindications:

Elderly: require slower dosage adjustment, and higher risk of CV ADRs

Children: not preferred in children as developing brain prefers thyroxine (T4 )

Safe to use in pregnancy, but rarely needed thyroxine preferred

Caution in diabetes: may need to reduce diabetic medication when starting

Caution in cardiovascular disorders: may worsen arrhythmias or ischaemia

thyroxine (T4 ) indications:

Hypothyroidism

T4 contraindications

Elderly: require slower dosage adjustment, and higher risk of CV ADRs

Children: preferred over T3

Pregnancy: Safe to use, preferred. Dose usually increased 25-40%. Safe in BF

Caution in diabetes: may need to reduce diabetic medication when starting.

Caution in CVD: may worsen arrhythmias/ischaemia

Hyperthyroidism Treatment Options

1. Pharmacotherapy

   – Carbimazole

   – Propylthiouracil (PTU)

   – Beta blockers to control symptoms (tremor/palpitations)

2. Surgery

3. Radioactive Iodine

carbimazole and PTU MOA

inhibit biosynthesis of thyroid hormones

propylthiauracil (PTU) contraindications

Children: avoid due to higher risk of hepatotoxicity

Pregnancy: preferred in 1st trimester (carmibazole preferred in 2nd and 3rd) use LOWEST effective dose an monitor

Watch for a fever, mouth ulcers, sore throat, rash, abdominal pain, jaundice– agranulocytosis

Hepatic: caution, hepatoxicity higher risk with PTU, monitor liver function

Carmibazole contraindications

Children: not recommended, avoid due to increased risk hepatoxicity

Pregnancy: Carbimazole preferred in 2nd and 3 rd trimester (PTU in 1 st trimester) Monitor every 6 weeks

WATCH for fever, mouth ulcers, sore throat, abdominal pain, jaundice

Monitor hepatic function regularly

Nitrates examples:

Glyceryl trinitrate, isosorbide mononitrate

Nitrates MOA:

• Provide exogenous source of nitric oxide (which mediates vasodilator effects)

• Predominantly venodilators, ↓ venous return and preload to the heart, ↓ myocardial oxygen requirement

Nitrates indications:

Prevention and treatment of angina

carbimazole and PTU indications

Hyperthyroidism

Nitrates ADRs:

Vasodilatory effects i.e. headache, flushing, palpitations, orthostatic hypotension, fainting, peripheral oedema

Nitrates Practice Points:

• Can be short (s/l spray or tablet) or long-acting (patch or tablet)

• Nitrate tolerance develops if no nitrate-free period over 24 hours

• Very serious interaction with PDE-5 inhibitors i.e. sildenafil

Nitrates contraindications

Pregnancy and Lactation: Limited data available; safety not established

Contraindicated in hypovolaemia, raised intracranial pressure, anaemia, numerous cardiovascular conditions (see AMH)

Drug interactions: NOT with sildenafil/tadalafil/ vardenafil- contraindicated can cause profound hypotension and MI

Remove nitrate patches before diathermy, defibrillation or cardioversion.

Beta Blockers MOA

Competitively block βreceptors.

- Cardio-selective betablockers (block β1 receptors in the heart)

- Non-selective betablockers (block β1 and β2 receptors)

Beta Blocker examples

Cardio-selective: Atenolol, bisoprolol, metoprolol Non-selective: Propranolol, carvedilol

Beta Blocker adverse effects

Bradycardia, bronchospasm, mask hypoglycaemia, cold extremities, transient worsening of CHF symptoms (when treatment starts)

Beta Blockers practice points:

• This medicine may cause dizziness or tiredness especially at the start of treatment or when the dose is increased; if affected, do not drive or operate machinery.

• If you feel dizzy, get up gradually from sitting or lying to minimise this effect; sit or lie down if you become dizzy.

• Do not stop taking suddenly unless your doctor tells you to.

Beta Blocker contraindications

Pregnancy: Labetalol and oxprenolol used for HT in pregnancy, avoid atenolol in early stages causes fetal growth retardation

Hepatic Impairment: Titrate dose according to response and adverse effects (except atenololrenal elimination)

Elderly: Start at a lower dose

Drug interactions: AVOID combination with verapamil-heart block /care with bradycardic drugs

Comorbidities:

Diabetes-can mask hypoglycaemia

Respiratory- bronchospasm

Vascular disease - can impair peripheral circulation

Cardiac disease - contraindicated in bradycardia

Calcium Channel Blockers (CCBs) MOA

Block inward current of calcium in vascular smooth muscle, myocardium and cardiac conduction system

Examples of non-dihydropyridine CCBs

• Verapamil

• Diltiazem

Examples of dihydropyridine CCBs

• Amlodipine

• Felodipine

• Nifedipine

• Lercanidipine

• Nimodipine

CCBs contraindications

Pregnancy: Contact drug info centres for advice

Lactation: Limited data

Hepatic Impairment: May need to reduce dose

Elderly: Start with lower dose

Drug Interactions: Metabolised by CYP3A4 and avoid Verapamil and Beta blockers

Systolic heart failure- depression of myocardial function

Anticoagulants indications:

• Treat/prevent venous thromboembolism (VTE) and pulmonary embolism (PE)

• Treat/prevent stroke/ TIA

• ACS

Anticoagulant examples:

• Warfarin

• Heparins (incl LMWH)

• Novel Oral Anticoagulants (NOACs)

• Anti-Factor Xa Inhibitors

• Direct Thrombin Inhibitors

Anticoagulants – Practice Points

• Patient MUST understand how to take & how to check for signs of bleeding- gums, bruises, faeces/urine

• Avoid other drugs which cause bleeding (unless under specialist advice)

Monitor for:

• Signs of bleeding

• Renal function

• INR (Warfarin)

• Factor Xa levels (where appropriate) for LMWHs

Surgery - must be ceased prior

Timing depends on specific drug

Warfarin – Practice Points

Narrow therapeutic index

♥ INR monitoring – aim for 2-3 in non valvular AF (target likely higher in valve replacement)

♥ Antidote-Vitamin K

♥ Drug interactions

♥ Pregnancy – Category D

♥ Food interactions: Consistent consumption of vitamin K containing food (i.e. green leafy vegetables)

♥ Keep to same brand and strength

♥ Marevan/Coumadin - colour coded & not bioequivalent

♥ Alcohol - keep to 1-2 standard drinks per day. ♥ Patient counselling books are available

Warfarin MOA:

Vitamin K antagonist; inhibits synthesis of vitamin K-dependent clotting factors (II, VII, IX, X) and the antithrombotic factors protein C and protein S.

Heparins/LMWH MOA:

Inactivate clotting factors IIa (thrombin) and Xa by binding to antithrombin III; LMWHs and danaparoid have a much greater effect on factor Xa than on thrombin. Danaparoid is a more selective inhibitor of factor Xa than LMWHs.

Heparins/LMWH Practice Points:

When compared to warfarin:

– Shorter half-life = more rapid onset of effect/clearance

– Preferred anticoagulation for bridging to surgery

• Use LMWH with caution in ↓ renal function (heparin preferred in severe impairment)

• Contraindicated in severe hepatic impairment or disease

• Can cause thrombocytopenia – Be aware of Heparin Induced Thrombocytopenia (HIT)

• Used to treat/prevent thromboembolism* in pregnancy and safe for breastfeeding.

*LMWH are not recommended for prosthetic heart valve in pregnancy as they provide inadequate anticoagulation.

Factor Xa inhibitors - MOA

Selectively inhibit factor Xa, blocking thrombin production, conversion of fibrinogen to fibrin, and thrombus development.

Factor XA inhibitors examples:

• Apixaban

• Rivaroxaban

Factor Xa inhibitors – Practice Points

No monitoring of INR

• Not suitable in severe renal impairment

• No antidote – Not suitable in individuals with ↑ bleeding risk

• When compared to warfarin: – Shorter half-life = more rapid clearance

• Caution with drug-interactions – Metabolised by CYP3A4

Direct Thrombin Inhibitors - MOA

Reversibly inhibit both free and fibrin-bound thrombin, preventing conversion of fibrinogen to fibrin, preventing thrombus formation. Thrombin-induced platelet aggregation is also inhibited.