Patient
The pathway, step by step
| Step | Numbers | Why it matters |
|---|---|---|
| Intake | Brewed coffee 8 oz ≈ 95 mg (range 80–200); espresso 1 oz ≈ 63 mg; black tea 8 oz ≈ 47 mg; cola 12 oz ≈ 30–40 mg; energy drinks 80–300 mg/can; OTC tablets 100–200 mg; Excedrin Migraine 65 mg/tab. Pure powder: 1 tsp ≈ 3 g. | FDA: up to 400 mg/day in healthy adults. ACOG: under 200 mg/day in pregnancy. Ask about energy drinks, pre-workout and analgesic combinations; they are missed in the history. |
| Absorption | Bioavailability ≈ 100%. Tmax 30–60 min (up to 2 h with food). Negligible first pass. | Rapid and complete, so oral and IV doses are interchangeable (caffeine citrate PO = IV). |
| Distribution | Vd 0.6–0.7 L/kg (total body water). Protein binding 10–35%. Crosses the BBB, placenta and into breast milk (milk:plasma ≈ 0.5–0.8). | Brain level tracks plasma. The fetus and neonate are exposed but can't clear it. Small Vd and low binding make it dialysable. |
| Metabolism | Liver, CYP1A2 > 95%. N3-demethylation → paraxanthine ≈ 84%; N1 → theobromine ≈ 12%; N7 → theophylline ≈ 4%. Minor C8 oxidation to 1,3,7-trimethyluric acid. Downstream: CYP1A2, NAT2, xanthine oxidase, CYP2A6 → methylxanthines, methyluric acids, AFMU. | Everything that induces or inhibits CYP1A2 moves caffeine levels. Paraxanthine is itself an adenosine antagonist, so the effect outlasts the parent drug a little. |
| Excretion | Renal, as metabolites. Under 3% unchanged. | Renal failure barely changes caffeine clearance. |
| Half-life | Healthy adult 3–7 h (mean ≈ 5 h). Clearance ≈ 1–2 mL/kg/min. | Steady state with daily intake in about a day; 5 half-lives to wash out ≈ 1 day in adults, weeks in neonates. |
Mechanism: adenosine receptor antagonism
Adenosine accumulates in the extracellular space as ATP is used through waking hours and acts as a homeostatic sleep signal. Caffeine is a non-selective, competitive antagonist at adenosine receptors. At ordinary intake (plasma 1–10 mg/L, ≈ 5–50 µM) it occupies a meaningful share of A1 and A2A receptors (Ki in the ~10–50 µM range). It produces wakefulness by removing an inhibitory tone, not by direct stimulation.
| Receptor | Signalling | Where | What adenosine does | Block by caffeine |
|---|---|---|---|---|
| A1 | Gi/o: ↓ cAMP, ↑ K⁺ conductance, ↓ presynaptic Ca²⁺ | Cortex, hippocampus, basal forebrain cholinergic neurons; SA and AV node; afferent arteriole and proximal tubule; adipocytes | Inhibits release of glutamate, ACh, NE, DA; slows SA rate and AV conduction; mediates tubuloglomerular feedback and proximal Na⁺ reabsorption; anti-lipolytic | ↑ cortical arousal and transmitter release; natriuresis and mild diuresis; ↑ lipolysis |
| A2A | Gs: ↑ cAMP; forms A2A–D2 heteromers | Striatum and nucleus accumbens (indirect-pathway, D2-expressing neurons); cerebral and coronary arterioles; platelets, immune cells | Opposes D2 signalling; vasodilates; anti-inflammatory | Disinhibits D2 signalling: the main arousal and psychostimulant effect (A2A in the accumbens shell); cerebral vasoconstriction; blunts adenosine and regadenoson hyperaemia |
| A2B | Gs/Gq, low affinity | Mast cells, bronchial smooth muscle, vasculature | Active when adenosine is high (hypoxia, inflammation) | Minor at normal levels |
| A3 | Gi | Mast cells, immune cells | Mast-cell modulation | Low caffeine affinity in humans; little effect |
Targets that need toxic concentrations: phosphodiesterase inhibition (IC₅₀ hundreds of µM), ryanodine-receptor Ca²⁺ release (mM), GABAA antagonism. They matter in overdose, not with coffee.
What it does, organ by organ
| System | Effect | Clinical relevance |
|---|---|---|
| CNS | ↑ alertness, ↓ reaction time, ↓ perceived fatigue; at higher doses anxiety, tremor, insomnia; seizures in overdose. ↑ sleep latency and ↓ slow-wave sleep: 400 mg even 6 h before bed cuts total sleep by about 1 h. | Screen for caffeine in insomnia, anxiety, palpitations and tremor. Stop it 6–8 h before bedtime; later in slow metabolisers. |
| Cerebral vessels | A2A block → vasoconstriction; cerebral blood flow falls ≈ 20–30% after 250 mg. | Analgesic adjunct (with acetaminophen, aspirin, ergotamine). Post-dural puncture headache (300–500 mg; modest, short-lived benefit, epidural blood patch is definitive). Withdrawal headache comes from rebound vasodilation. |
| Heart and BP | Acute SBP ↑ ≈ 3–8 mmHg in non-habitual users, with partial tolerance. Heart rate little changed at moderate doses. Tachyarrhythmias (SVT, AF, VT) in overdose. | Habitual moderate coffee isn't linked to more AF. Energy-drink binges are a source of palpitations and arrhythmia. |
| Coronary stress testing | Blocks adenosine-, regadenoson- and dipyridamole-induced hyperaemia. | Hold all caffeine 12–24 h before vasodilator stress testing, or the result can be falsely negative. Theophylline/aminophylline reverse regadenoson side effects for the same reason. |
| SVT treatment | Antagonises IV adenosine at the AV node. | Heavy caffeine or theophylline users may need a higher adenosine dose. Dipyridamole and carbamazepine potentiate it; heart transplant patients are hypersensitive. |
| Respiratory | ↑ central respiratory drive and CO₂ sensitivity, ↑ diaphragm contractility, mild bronchodilation. | Apnoea of prematurity: caffeine citrate 20 mg/kg load, 5–10 mg/kg/day (citrate 2 mg = base 1 mg). The CAP trial showed less BPD and better neurodevelopmental outcome at 18 months. |
| Kidney | A1 block in the proximal tubule → natriuresis; afferent A1 block → ↑ renal blood flow. | Mild diuresis at ≥ 250–300 mg in non-habitual users, with tolerance in habitual users. Moderate coffee still counts toward daily fluid intake. |
| GI | ↑ gastric acid and gastrin; ↓ LES pressure; ↑ colonic motor activity within minutes. | Aggravates GERD and dyspepsia. Coffee's laxative effect is partly caffeine-independent: decaf does it too. |
| Metabolic | ↑ plasma adrenaline, lipolysis and free fatty acids; energy expenditure ↑ ≈ 3–11%; acute ↓ insulin sensitivity. | In overdose: hypokalaemia, hyperglycaemia and lactic acidosis (β₂-driven). |
| Muscle and exercise | Ergogenic at 3–6 mg/kg about 60 min before exercise: ↓ perceived exertion, ↑ endurance. | Monitored by WADA but not banned. |
| Pregnancy and infants | Half-life rises through pregnancy. The fetus has almost no CYP1A2. Neonatal half-life is 40–230 h. | Limit to under 200 mg/day in pregnancy. Breastfed infants of heavy users can be jittery and sleep poorly. |
What changes the half-life (the CYP1A2 valve)
| Condition | Typical t½ | Mechanism and consequence |
|---|---|---|
| Healthy adult | ≈ 5 h (3–7) | Reference. |
| Smoker | ≈ 3 h (30–50% shorter) | Polycyclic aromatic hydrocarbons in smoke induce CYP1A2 through the aryl hydrocarbon receptor (not nicotine). After quitting, clearance returns to normal over about a week, so the same coffee intake gives 2–3× the level. That causes jitteriness and insomnia that gets mistaken for nicotine withdrawal. The same applies to clozapine and olanzapine levels. |
| Oral contraceptives | ≈ 8–10 h | Ethinyl oestradiol inhibits CYP1A2. |
| Pregnancy | 11–18 h by the third trimester | Oestrogen and progesterone suppress CYP1A2; back to normal within weeks postpartum. |
| Fluvoxamine | ≈ 30 h (clearance ↓ ≈ 80%) | Potent CYP1A2 inhibitor. Advise patients to cut caffeine sharply when starting it. |
| Quinolones, cimetidine, mexiletine, others | Moderately prolonged | Enoxacin marked; ciprofloxacin and cimetidine moderate. |
| Cirrhosis | Often > 50 h, can approach 100 h | Caffeine clearance has been used as a quantitative liver-function test. |
| Neonate (preterm) | ≈ 100 h (40–230) | CYP1A2 is immature; adult clearance by about 6–9 months. That's why once-daily caffeine citrate works. |
| Genetics | Varies | CYP1A2 −163C>A (rs762551, *1F) sets inducibility (fast vs slow metabolisers). ADORA2A variants change anxiety and sleep sensitivity to caffeine. |
Tolerance, dependence, withdrawal
- Tolerance develops within days to the BP, diuretic and partly to the arousal effects, through upregulation of A1 receptors. Habitual users' alertness gain is partly reversal of overnight withdrawal.
- Withdrawal (DSM-5) after regular use of ≥ 100 mg/day: headache, fatigue, low mood, poor concentration and flu-like symptoms. It starts 12–24 h after the last dose, peaks at 20–51 h and lasts 2–9 days.
- Peri-operative and inpatient: NPO patients get withdrawal headaches. Consider caffeine, or taper before planned admissions.
Toxicity
- Levels: symptoms usually above ≈ 15 mg/L (vomiting, tachycardia, agitation, tremor). Severe toxicity (seizures, arrhythmia) above ≈ 50–80 mg/L. Deaths are usually above ≈ 80–100 mg/L, typically after several grams (powder, tablets, concentrated liquids; ≈ 150–200 mg/kg is often quoted as lethal).
- Mechanism at toxic levels: catecholamine surge plus PDE inhibition. β₁ effects give tachyarrhythmia; β₂ effects give vasodilatory hypotension, hypokalaemia, hyperglycaemia and lactic acidosis. Also seizures and rhabdomyolysis.
- Management: ABCs and continuous ECG. Activated charcoal if presentation is early and the airway is protected. Benzodiazepines for agitation and seizures. Correct K⁺ cautiously (it is a shift, so expect rebound). For tachyarrhythmia and β₂-mediated hypotension, use a short-acting β-blocker such as esmolol, as in theophylline toxicity, plus a pure α-agonist or vasopressin for pressure. Haemodialysis for life-threatening toxicity or very high levels: low Vd and low protein binding make caffeine readily dialysable. Call poison control.
One-line summary
Caffeine is ~100% absorbed and peaks within an hour. It distributes into total body water and blocks adenosine A1 and A2A receptors, removing the brain's sleep-pressure brake and adenosine's vascular, cardiac, renal and respiratory effects. CYP1A2 clears it over about 5 h, so anything that induces or inhibits that enzyme (smoking, oestrogens, pregnancy, fluvoxamine, liver disease, prematurity) changes the dose the patient is really taking.
Teaching material for clinicians. Numbers are typical published ranges, rounded; individual patients vary. Check current references before applying a dose.