Your Cardiac Medications Explained

Doses & Timing

When to take: Once daily at any consistent time. Evening dosing can reduce first-dose dizziness. Take with or without food.

Common Side Effects

• Dry, persistent cough — affects approximately 1 in 5 patients. Caused by accumulation of bradykinin. Does not indicate harm — if troublesome, switch to an ARB.
• Dizziness or light-headedness, especially on standing (postural hypotension)
• Raised potassium (hyperkalaemia) — usually mild but monitored
• Fatigue, especially on starting

Unusual Side Effects

• Angioedema — sudden swelling of lips, tongue, or throat. Rare (0.1–0.5%) but a medical emergency. Stop immediately and call 999. More common in Afro-Caribbean patients.
• Acute kidney injury — most commonly triggered by dehydration, illness, or NSAIDs alongside ACEi ("triple whammy" with diuretic)
• Metallic taste or loss of taste (ageusia) — usually temporary
• Raised liver enzymes — rare

Doses & Timing

When to take: Once daily at any consistent time, with or without food. Same monitoring as ACEi — potassium and kidney function check 1–2 weeks after starting.

Common Side Effects

• Dizziness, light-headedness on standing
• Raised potassium (hyperkalaemia)
• Fatigue on initiation
• Headache

Unusual Side Effects

• Angioedema — rare (much less common than with ACEi, but can occur). Stop immediately and seek emergency care if lip/tongue swelling develops. Do NOT switch to an ARB if angioedema occurred on an ACEi.
• Acute kidney injury — same risk as ACEi with NSAID combination
• Olmesartan: sprue-like enteropathy — chronic diarrhoea, weight loss (rare but distinctive — resolves on stopping)

Doses & Timing

When to take: Twice daily, approximately 12 hours apart. Consistent timing is important. Take with or without food.

Switching from ACEi: A mandatory 36-hour washout after the last ACEi dose before starting Entresto. This prevents dangerously high bradykinin levels (angioedema risk).

Common Side Effects

• Low blood pressure (hypotension) — very common on starting; usually improves. Rise slowly from sitting/lying.
• Dizziness, light-headedness
• Raised potassium — monitor as for ACEi
• Mild cough (less than ACEi)
• Raised creatinine on initiation (small rise acceptable)

Unusual Side Effects

• Angioedema: Risk is significantly higher if you have ever had angioedema on an ACEi. This is an absolute contraindication to Entresto. If lip/tongue swelling occurs — stop immediately and call 999.
• Hyperkalaemia — particularly if also on spironolactone/eplerenone

Doses & Timing

When to take: Once daily at any consistent time. Amlodipine has a very long half-life (~35 hours) — if you miss a dose, take it as soon as you remember unless it is nearly time for the next one. Food does not affect absorption.

Common Side Effects

• Ankle/lower leg swelling (oedema) — affects up to 1 in 3 at 10mg. More common in women and in warmer weather. Usually worse by evening.
• Flushing and warmth — particularly in the first few weeks
• Headache — especially on starting; usually settles
• Palpitations / slight increase in heart rate
• Dizziness

Unusual Side Effects

• Gingival hyperplasia (gum overgrowth) — particularly nifedipine; good dental hygiene reduces risk
• Worsening of acid reflux (GORD)
• Photosensitivity
• Reflex tachycardia — more common with short-acting nifedipine (not the LA formulation)

Doses & Timing

When to take: With food to reduce GI side effects. Diltiazem comes in many different brand formulations (Tildiem, Adizem, Dilzem, Viazem) — these are NOT interchangeable. Always take the specific brand prescribed and do not switch without your pharmacist's or cardiologist's advice.

Common Side Effects

• Constipation (verapamil) — very common; affects the majority of patients. Increase fluid and fibre intake; consider a laxative if needed.
• Bradycardia (slow pulse) — both drugs slow the heart rate; contact your team if pulse is consistently below 50
• Dizziness, ankle swelling (less than amlodipine)
• Nausea, headache

Unusual Side Effects

• Heart block — slowing of the heart's electrical conduction system. Risk greatly increased when combined with beta-blockers.
• Worsening of heart failure with reduced ejection fraction — these drugs reduce cardiac contractility; avoid in HFrEF
• Gingival hyperplasia (gum overgrowth — less common than with nifedipine)
• Verapamil raises digoxin levels — if on both, digoxin level must be monitored

Doses & Timing

When to take: Once daily at any consistent time, with or without food. The fixed combination simplifies the regimen and improves adherence compared with taking two separate tablets.

Common Side Effects

• Ankle swelling — from the amlodipine component (see Amlodipine card)
• Dizziness on standing (postural hypotension) — particularly in warm weather or after exercise
• Headache, flushing
• Raised potassium — from the valsartan component (monitor as for ARBs)

Unusual Side Effects

• Angioedema — from the valsartan (ARB) component. Rare but stop immediately if swelling of lips/tongue/throat occurs.
• Acute kidney injury — same NSAID interaction risk as all ARBs
• Fatigue

Doses & Timing

When to take: Morning, once daily (bisoprolol, atenolol, nebivolol). Carvedilol twice daily with food — food slows absorption and reduces dizziness. Do not stop abruptly — reduce gradually over 2–4 weeks.

Common Side Effects

• Fatigue and reduced exercise tolerance — very common on starting; often improves over 4–8 weeks as the body adjusts
• Cold hands and feet — beta-blockade reduces peripheral circulation
• Dizziness, light-headedness
• Sexual dysfunction (erectile dysfunction) — consider switching to nebivolol (vasodilatory properties, better profile)
• Vivid dreams and nightmares — more common with lipophilic agents (bisoprolol, metoprolol)

Unusual Side Effects

• Worsening of Raynaud's phenomenon
• Bronchospasm — beta-blockers can worsen asthma. Use with caution in COPD (bisoprolol is cardioselective and safer). Avoid in active asthma.
• Masking hypoglycaemia in Type 1 diabetes — tremor and tachycardia (warning signs of low blood sugar) are blunted; sweating still occurs
• Depression — association reported; switch if new depressive symptoms develop

Doses & Timing

When to take: Morning — avoids increased urination during the night. Take with or without food. Indapamide (particularly the SR/modified-release formulation) is preferred over older thiazides for its better cardiovascular outcome data.

Common Side Effects

• Increased urination, especially in the first few weeks
• Low sodium (hyponatraemia) — dizziness, confusion, nausea — more common in elderly
• Low potassium (hypokalaemia) — muscle cramps, weakness
• Dizziness, postural hypotension
• Thirst, dry mouth

Unusual Side Effects

• Gout — thiazides reduce uric acid excretion. If you have a history of gout, discuss this with your doctor before starting.
• Worsening of blood sugar control (hyperglycaemia) in diabetes or pre-diabetes
• Impotence / sexual dysfunction
• Photosensitivity — avoid prolonged sun exposure or use high SPF
• Raised calcium (hypercalcaemia) — usually mild; useful in osteoporosis

Doses & Timing

When to take: Morning — or morning and early afternoon if twice daily. Never take in the evening or you will be awake urinating through the night. If you miss a morning dose, take it by lunchtime — skip it if later than that.

Common Side Effects

• Frequent urination — particularly in the 2–4 hours after taking. This is the intended effect.
• Dehydration and thirst — if severe (dry mouth, dark urine, dizziness on standing) contact your team
• Low potassium (hypokalaemia) — muscle cramps, weakness, palpitations. May need potassium supplements or combination with spironolactone
• Low sodium (hyponatraemia) — more common at higher doses or in elderly

Unusual Side Effects

• Hearing loss / tinnitus — at very high doses, especially with rapid IV injection. Not usually a concern with standard oral doses.
• Gout — as with thiazides
• Photosensitivity
• Blood glucose elevation — mild

Doses & Timing

When to take: Once daily in the morning or evening — consistently with food. Eplerenone is more selective (fewer hormonal side effects) and is preferred in men who develop gynaecomastia on spironolactone.

Monitoring: Potassium and kidney function 1 week after starting and after each dose change. Potassium above 5.5 mmol/L — reduce dose. Above 6.0 mmol/L — stop and contact your team urgently.

Common Side Effects

• Raised potassium (hyperkalaemia) — the most important side effect to monitor. Potassium rises occur especially when combined with ACEi/ARB/Entresto.
• Dizziness, low blood pressure — especially on standing
• Increased urination (mild diuretic effect)
• Nausea, stomach upset

Unusual Side Effects

• Gynaecomastia (breast tissue growth in men) — common with spironolactone (up to 1 in 10). Can be painful. Switch to eplerenone if this occurs — it does not have this side effect.
• Menstrual irregularities in women — spironolactone has anti-androgen effects
• Reduced libido, erectile dysfunction
• Leg cramps

Doses & Timing

When to take: Morning, with or without food. The morning is preferred because of mild diuretic effects — taking in the evening may cause overnight urination.

Sick day rules: Stop temporarily if you are acutely unwell, vomiting, fasting (e.g. before surgery), or severely dehydrated. Restart when eating and drinking normally. This reduces the risk of ketoacidosis.

Common Side Effects

• Genital thrush / mycotic infections — very common (the drug causes glucose to spill into urine, encouraging yeast growth). Keep the genital area clean and dry. Treat with standard antifungal cream or oral fluconazole.
• Urinary tract infections
• Increased urination, mild dehydration
• Mild dizziness / low blood pressure
• Urinary urgency

Unusual Side Effects

• Euglycaemic diabetic ketoacidosis — DKA without elevated blood glucose. Rare but serious. Presents with nausea, vomiting, abdominal pain, difficulty breathing. Seek emergency care immediately. Risk highest during fasting, illness, or surgery.
• Fournier's gangrene — necrotising fasciitis of the genitalia. Extremely rare but severe. Seek urgent care if there is any genital pain, swelling, redness, or fever.
• Lower limb infections (in patients with diabetic foot disease)

Doses & Timing

Timing: Atorvastatin and rosuvastatin have long half-lives — take at any consistent time. Simvastatin and pravastatin are shorter-acting and are more effective taken in the evening (the liver makes most cholesterol overnight). Post-heart attack: atorvastatin 80mg is started immediately regardless of baseline cholesterol.

Common Side Effects

• Muscle aches (myalgia) — the most commonly reported side effect (5–10% in clinical practice). However, large placebo-controlled trials suggest much of this is a nocebo effect — participants on placebo reported similar rates of muscle aches when they knew they were taking a statin. A CK blood test distinguishes true muscle damage from aching.
• Headache, nausea, GI upset — usually mild and transient
• Elevated liver enzymes — mild rise common; significant hepatotoxicity very rare

Unusual Side Effects

• Myositis / rhabdomyolysis — true muscle inflammation with significantly elevated CK. Rhabdomyolysis (severe muscle breakdown causing kidney failure) is very rare (<1 in 10,000). If muscles are very painful, dark brown urine, or extreme weakness — stop and seek urgent care.
• Modest increase in Type 2 diabetes risk (~10% relative increase in those already predisposed) — benefits of statin vastly outweigh this risk in any patient with CV disease
• Memory and cognitive complaints — reported by patients, but multiple large trials including HOPE-3 found no cognitive harm from statins
• Interstitial lung disease — rare, more reported with rosuvastatin

Doses & Timing

Ezetimibe 10mg — once daily at any consistent time, with or without food. There is only one dose. It can be taken at the same time as a statin for convenience.

Ezetimibe works in the gut, blocking NPC1L1 — the transporter that absorbs dietary and biliary cholesterol. It reduces LDL by a further 20–25% on top of statin therapy.

Common Side Effects

• Generally very well tolerated — one of the best-tolerated cardiac drugs
• Occasional headache, GI upset, diarrhoea
• Fatigue
• Joint pain (arthralgia) — mild

Unusual Side Effects

• Myopathy — rare; risk increases when combined with high-dose statin
• Hepatitis — rare; liver function occasionally checked at baseline
• Allergic skin reactions — rare
• Pancreatitis — very rare

Doses & Timing

Self-injection: Evolocumab and alirocumab come as auto-injectors for home use (similar to insulin pens). Inclisiran is administered by a healthcare professional in clinic — making it the preferred option for patients who struggle with adherence.

Common Side Effects

• Injection site reactions — redness, bruising, mild pain at injection site
• Nasopharyngitis (cold-like symptoms)
• Flu-like symptoms
• Back pain, joint pain
• Urinary tract infection

Unusual Side Effects

• Neurocognitive effects — memory complaints and confusion have been reported in some patients. Large trials (FOURIER, ODYSSEY) found no statistically significant difference from placebo overall, but the FDA added a warning. Report any new memory problems to your cardiologist.
• Allergic/hypersensitivity reactions — rare; discontinue if rash, hives, or difficulty breathing

Doses & Timing

75mg once daily — the standard UK secondary prevention dose. (300mg loading dose is given in hospital at time of heart attack or stroke.)

When to take: With or after food — significantly reduces gastric irritation. Take at any consistent time. Enteric-coated (EC) aspirin may reduce GI side effects further, though evidence is mixed.

Common Side Effects

• GI upset, heartburn, nausea — take with food
• Easy bruising, prolonged bleeding from minor cuts
• Nosebleeds

Unusual Side Effects

• GI haemorrhage — aspirin increases the risk of stomach and intestinal bleeding approximately 3-fold. Seek urgent medical attention for any black or tarry stools, vomiting blood, or severe abdominal pain.
• Aspirin-exacerbated respiratory disease (AERD) — triggers bronchospasm in approximately 10% of asthmatics (and up to 30% with nasal polyps). If you have asthma, confirm with your cardiologist before taking aspirin.
• Tinnitus — at high doses (not a concern at 75mg)
• Allergy — urticaria, angioedema

Doses & Timing

When to take: Clopidogrel and prasugrel — once daily with or without food. Ticagrelor must be taken twice daily, 12 hours apart — missing doses significantly impairs antiplatelet effect.

Duration after stenting: 12 months for heart attack (ACS); 1–6 months for elective stenting depending on bleeding vs thrombosis risk. Your cardiologist will specify your duration.

Common Side Effects

• Easy bruising, prolonged bleeding from cuts
• Nosebleeds, bleeding gums
• Heavier menstrual periods
• Headache (ticagrelor)

Unusual Side Effects

• Clopidogrel — TTP (Thrombotic Thrombocytopenic Purpura): Very rare but potentially fatal. Presents within 2 weeks of starting with blood in urine, confusion, fever, and bruising. Stop immediately and seek emergency care.
• Ticagrelor — dyspnoea (breathlessness): Affects approximately 1 in 7 patients. Not bronchospasm — exact mechanism unclear. Usually mild, often improves over weeks. Contact your team if severe — may need to switch to clopidogrel.
• Ticagrelor — ventricular pauses (brief heart rhythm pauses) detected on Holter monitoring; rarely symptomatic
• Prasugrel — avoid in patients over 75 or under 60kg (increased bleeding risk)
• Gout — clopidogrel occasionally

Doses & Timing

*Apixaban dose reduction criteria: age ≥80, weight ≤60kg, or creatinine ≥133 — reduce if ≥2 of these apply.

Rivaroxaban: Must be taken with the main evening meal — food increases absorption by 40%. This is critically important; taking it fasted greatly reduces blood levels.

Dabigatran: Keep in the original blister pack — the capsule is moisture-sensitive and degrades rapidly if stored in a dosette box.

Common Side Effects

• Easy bruising and prolonged bleeding from cuts
• Nosebleeds, bleeding gums
• Heavier menstrual periods
• GI upset — dabigatran most commonly causes nausea; take with food
• Anaemia from minor GI ooze

Unusual Side Effects

• GI haemorrhage: Rivaroxaban and dabigatran have higher GI bleed rates than warfarin. Apixaban has the lowest GI bleed risk among NOACs. Seek emergency care for black/tarry stools, vomiting blood, or severe abdominal pain.
• Intracranial haemorrhage: All anticoagulants carry this risk; NOACs have lower rates than warfarin. Seek emergency care immediately for sudden severe headache, facial drooping, arm weakness, or speech difficulty.
• Dabigatran — oesophageal ulceration; sit upright for 30 minutes after each dose

Doses & Timing

Dose is highly individual — ranges from 0.5mg to 15mg daily, adjusted based on INR (International Normalised Ratio) blood test results. There is no standard dose.

INR targets: 2.0–3.0 for AF, DVT, PE, and most indications. 2.5–3.5 for mechanical mitral valve or recurrent clot on standard warfarin.

When to take: Evening — this allows a morning INR blood test result to inform your dose adjustment the same day without a gap in anticoagulation.

Vitamin K and diet: Warfarin works by blocking vitamin K. Consistency matters more than avoidance — do not suddenly increase or decrease leafy greens (kale, spinach, broccoli, sprouts). Eat them regularly and consistently.

Common Side Effects

• Bruising, prolonged bleeding, heavy periods
• Nosebleeds, bleeding gums
• Sensitive to many drug and food interactions — INR fluctuates widely

Unusual Side Effects

• Warfarin skin necrosis: Rare (first few days of therapy in patients with protein C or S deficiency). Painful, dark, spreading skin patches — usually on limbs or breasts. Requires immediate medical attention.
• "Purple toe syndrome" — cholesterol crystal embolism; rare, presents as blue-purple discolouration of toes
• Osteoporosis — long-term warfarin inhibits vitamin K-dependent bone proteins
• Hair thinning with long-term use

Doses & Timing

When to take: Once daily maintenance dose — with food to reduce nausea. Very long half-life (40–55 days) — amiodarone takes weeks to reach full effect and its effects persist for months after stopping.

Annual monitoring: Thyroid function (TFT), liver function (LFT), chest X-ray, and ophthalmology eye check — every 12 months minimum.

Common Side Effects

• Photosensitivity — sun exposure causes severe burning and persistent skin discolouration. Apply SPF50+ sunscreen daily, wear protective clothing year-round, even on cloudy UK days.
• Thyroid dysfunction — affects 15–20% of patients over time. Both hypothyroidism (underactive — fatigue, weight gain) and hyperthyroidism (overactive — weight loss, palpitations, tremor). TFTs checked annually.
• Grey-blue skin discolouration — long-term; on sun-exposed areas; partially reversible on stopping
• GI upset, nausea — most common in first weeks; take with food

Unusual Side Effects

• Pulmonary toxicity: Interstitial lung disease — 1–2% per year. Presents as new breathlessness, dry cough, or reduced exercise tolerance. Chest X-ray and CT required to diagnose. Stop amiodarone if suspected.
• Hepatotoxicity — liver enzyme elevation; rarely significant liver failure
• Corneal microdeposits — almost universal on slit-lamp examination; rarely affect vision significantly
• Peripheral neuropathy — tingling, numbness in feet
• Raises warfarin INR substantially — warfarin dose typically halved when amiodarone started; INR must be monitored closely

Doses & Timing

Timing: Twice daily doses, 12 hours apart, with or without food. The "pill-in-pocket" approach — taking a single dose at the onset of AF to restore normal rhythm — is only suitable for selected patients with structurally normal hearts and must be initiated under cardiology supervision.

Common Side Effects

• Visual disturbances — blurred vision, double vision, seeing halos, or visual distortion especially at higher doses or in bright light. Usually not dangerous but can be disabling.
• Dizziness, light-headedness
• Nausea, vomiting
• Headache
• Tremor, coordination difficulties at higher doses

Unusual Side Effects

• CRITICAL — Pro-arrhythmic effect in structural or ischaemic heart disease: The CAST trial (1989) showed that flecainide increased mortality in patients with coronary artery disease or previous heart attack. It is absolutely contraindicated in these patients. Always disclose any history of coronary disease, previous MI, or heart failure with reduced EF.
• AF → atrial flutter with rapid 1:1 conduction — flecainide can slow the atrial flutter rate, paradoxically allowing faster ventricular rates. A rate-limiting drug (bisoprolol or diltiazem) is usually prescribed alongside for this reason.
• QRS widening on ECG — a pharmacological effect; your cardiologist will check the ECG after starting

Doses & Timing

62.5–250 micrograms once daily — lower doses in the elderly and in kidney impairment (digoxin is renally cleared). The target serum level is now recommended at the lower end of the therapeutic range: 0.5–0.9 ng/mL.

When to take: Once daily — consistent timing. Blood level is checked at least 6 hours after the last dose (not immediately before the next dose). Your team will specify when to take the blood test.

Common Side Effects

• Nausea, loss of appetite — often an early sign of rising levels
• Bradycardia — pulse below 60. Do not take that day's dose and contact your team if pulse is below 50.
• Fatigue, weakness

Signs of Digoxin Toxicity (Unusual)

• Xanthopsia — seeing yellow or green halos around lights and objects. A classic, specific sign of digoxin toxicity. Contact your team urgently if this occurs.
• Dangerous arrhythmias — digoxin toxicity causes heart rhythm abnormalities that can be fatal. Seek emergency care for palpitations, collapse, or near-blackout.
• Confusion, delirium — particularly in the elderly
• Gynaecomastia (breast growth in men) — long-term use
• Verapamil, amiodarone, clarithromycin, and erythromycin all significantly increase digoxin levels — dose adjustment required when these are added

Doses & Timing

Important: Ivabradine only slows heart rate in sinus rhythm. It has no rate-slowing effect during atrial fibrillation. If you notice your heart rate is not falling on the drug, contact your cardiologist — it may mean you are in AF.

Common Side Effects

• Phosphenes (visual bright flashes) — transient luminous phenomena; bright spots or flickering in the visual field, especially when moving from a dark room to a brightly lit one. Affects approximately 15% of patients. Usually mild, often resolves within weeks, and is not dangerous.
• Bradycardia — resting pulse below 50; reduce dose or contact cardiologist
• Headache, dizziness

Unusual Side Effects

• Atrial fibrillation — BEAUTIFUL trial found a modestly increased incidence of new AF; stop if AF develops (drug no longer effective)
• Blurred vision, visual disturbances (beyond phosphenes)
• QTc prolongation — caution with other QT-prolonging drugs
• Bradycardia-related syncope

How to Use

1 spray (400 micrograms) under the tongue — sit or lie down first. Do not inhale or swallow. Allow the spray to absorb under the tongue.

If pain not relieved after 5 minutes — take a second spray. If pain persists 5 minutes after the second spray (10 minutes total) — call 999 immediately. Do not take a third spray and wait. This may be a heart attack.

GTN may also be taken before exertion — spray 1–2 minutes before an activity known to trigger angina (e.g. walking uphill, stairs). The effect lasts 20–30 minutes.

Common Side Effects

• Headache — very common; caused by vasodilation. Usually brief (10–15 minutes). Paracetamol can be taken alongside.
• Flushing, warmth, redness of the face and neck
• Dizziness and light-headedness — sit or lie down when using
• Palpitations — transient
• Low blood pressure — transient; standing up quickly after using GTN can cause fainting

Unusual Side Effects

• Severe hypotension with PDE5 inhibitors: NEVER use GTN spray within 24 hours of sildenafil (Viagra, Revatio) or within 48 hours of tadalafil (Cialis, Adcirca). The combination causes a severe, potentially fatal drop in blood pressure. This interaction has caused deaths. Inform your cardiologist if you take these medications.
• Fainting — if standing when spray takes effect
• Methaemoglobinaemia — extremely rare at spray doses; a concern only with high-dose IV nitrates

Doses & Timing

Why timing is critical: Nitrate tolerance — the loss of drug effect — develops when nitrate levels in the blood are continuously high. An 8–12 hour nitrate-free period overnight is essential to prevent tolerance. Standard-release ISMN must be taken morning and lunchtime (not evening or night). Modified-release taken once in the morning achieves the same nitrate-free overnight gap.

Common Side Effects

• Headache — very common when first starting (affects the majority); usually improves substantially over the first 1–2 weeks as tolerance to the headache develops. Paracetamol helps. If you stop the drug and restart, headaches often return.
• Flushing, dizziness, low blood pressure
• Palpitations
• Nausea

Unusual Side Effects

• Nitrate tolerance — if the nitrate-free period is not maintained, the drug gradually loses effectiveness. If your GTN spray also stops working as well, this may be a sign of tolerance — discuss with your cardiologist.
• Paradoxical angina (rare) — in some patients with coronary artery spasm
• Reflex tachycardia — the heart speeds up to compensate for vasodilation

Doses & Timing

When to take: Twice daily, 12 hours apart. Swallow whole — do not crush or chew (modified-release tablet). Take with or without food.

Advantage: Ranolazine does not lower heart rate or blood pressure — it can be added to maximally tolerated doses of beta-blockers, nitrates, and amlodipine without worsening low BP or bradycardia. This makes it particularly useful as an add-on.

Common Side Effects

• Dizziness, light-headedness
• Headache
• Constipation — fairly common
• Nausea
• Peripheral oedema

Unusual Side Effects

• QTc prolongation — ranolazine prolongs the QT interval on ECG. Avoid combining with other QT-prolonging drugs (amiodarone, some antibiotics, antifungals). ECG check before and after starting.
• Bradycardia (mild)
• Confusion, hallucinations — particularly in the elderly at higher doses
• Raised creatinine — mild, usually not clinically significant