Hypertension= causes physiology, pathology, pharmacology , treatment, reason
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Hypertension: Complete Overview
1. Definition & Classification
Blood pressure (BP) = Cardiac Output (CO) × Peripheral Vascular Resistance (PVR). Hypertension exists when BP is persistently elevated. Standard classification (AHA/ACC):
| Category | Systolic (mmHg) | Diastolic (mmHg) |
|---|---|---|
| Normal | <120 | <80 |
| Elevated | 120-129 | <80 |
| Stage 1 | 130-139 | 80-89 |
| Stage 2 | ≥140 | ≥90 |
| Hypertensive crisis | >180 | >120 |
2. Causes
A. Primary (Essential) Hypertension - 90-95% of all cases
The cause is multifactorial and often not fully identifiable. Key contributing factors:
- Obesity/overweight: The single largest contributor - accounts for 65-75% of the risk. Framingham data show ~78% of primary hypertension in men and 65% in women can be ascribed to excess weight gain. Visceral fat compresses kidneys, raises intra-abdominal pressure (up to 35-40 mmHg), activates RAAS, and drives sympathetic tone.
- High sodium intake: Impairs renal pressure natriuresis, increases fluid retention.
- Sedentary lifestyle
- Excess alcohol consumption
- Low potassium intake
- Genetic predisposition: Polygenic susceptibility; positive family history is a major risk factor.
- Age: Vascular stiffness increases with age, raising systolic BP.
- Race: African Americans have higher prevalence and severity.
Rare monogenic causes (<1% of hypertension):
Most involve increased renal tubular sodium reabsorption or excess mineralocorticoid activity:
- Liddle syndrome (gain-of-function ENaC mutation)
- Gordon syndrome (increased NaCl cotransporter activity)
- Familial hyperaldosteronism types I & II
- Apparent mineralocorticoid excess (AME)
- Congenital adrenal hyperplasia (DOC overproduction)
B. Secondary Hypertension - 5-10% of cases
Specific identifiable cause; must be considered especially in young patients or resistant hypertension:
| System | Cause |
|---|---|
| Renal | Renovascular disease (renal artery stenosis), CKD, polycystic kidney disease, glomerulonephritis |
| Endocrine | Primary hyperaldosteronism (Conn's syndrome), pheochromocytoma, Cushing's syndrome, hypothyroidism/hyperthyroidism, acromegaly |
| Vascular | Coarctation of the aorta |
| CNS | Raised intracranial pressure (Cushing's reflex) |
| Drugs/toxins | Oral contraceptives, NSAIDs, sympathomimetics, cocaine, amphetamines, cyclosporin, steroids, licorice |
| Sleep | Obstructive sleep apnea |
| Pregnancy | Pre-eclampsia |
3. Physiology of Blood Pressure Regulation
BP is controlled through two major effector systems:
A. Renin-Angiotensin-Aldosterone System (RAAS) - Acts over minutes to hours
- Low renal perfusion pressure / low tubular NaCl / sympathetic stimulation → renin released from juxtaglomerular cells
- Renin cleaves angiotensinogen → Angiotensin I
- ACE (lung) converts Ang I → Angiotensin II (Ang II)
- Ang II effects:
- Direct vasoconstriction (AT1 receptors on vascular smooth muscle) → increases PVR
- Stimulates aldosterone release from adrenal cortex → Na+ and water retention → increases blood volume → increases CO
- Promotes renal tubular Na+ reabsorption directly
- Stimulates sympathetic nervous system
- Promotes vascular and cardiac hypertrophy (structural remodeling)
B. Sympathetic Nervous System (SNS) - Acts over seconds to minutes
- Norepinephrine binds α1-adrenoceptors on vessels → vasoconstriction → increased PVR
- Epinephrine binds β1-receptors on heart → increased heart rate and stroke volume → increased CO
- SNS stimulates renin release (β1 in kidney)
- SNS increases renal tubular Na+ reabsorption via direct innervation of nephrons
- Chronic increased sympathetic tone is a driver of sustained hypertension
C. Counter-regulatory Systems (that normally oppose hypertension)
- Kallikrein-kinin system: produces vasodilator kinins, stimulates prostaglandin and NO production
- Nitric oxide (NO): endothelium-derived vasodilator; deficiency promotes hypertension
- Natriuretic peptides (ANP, BNP): vasodilation + natriuresis; inhibit RAAS and SNS
- Endothelins: vasoconstrictors from endothelium that can contribute to hypertension
- Prostaglandin E & prostacyclin: counter Ang II and norepinephrine-mediated vasoconstriction
D. Renal Pressure Natriuresis
The kidney is the ultimate long-term controller of BP. Any rise in BP should trigger natriuresis (salt excretion) that reduces blood volume and returns BP to normal. Impairment of this mechanism - by renal disease, excess RAAS activity, or SNS activation - is a central defect in sustained hypertension.
4. Pathology (Structural Changes from Hypertension)
Hypertension causes end-organ damage through two main mechanisms: increased mechanical stress on vessel walls and neurohormonal activation (RAAS, SNS).
A. Vascular Pathology
- Hypertensive arteriosclerosis: medial hypertrophy of small arteries and arterioles, intimal thickening, and luminal narrowing
- Hyaline arteriolosclerosis: homogeneous pink thickening of arteriolar walls (protein deposition); seen in kidneys and retina
- Fibrinoid necrosis: in malignant hypertension - acute inflammatory necrosis of arteriolar walls, leads to thrombosis and ischemia
- Accelerated atherosclerosis: chronic hypertension damages endothelium, promotes lipid deposition and plaque formation in medium/large arteries
B. Cardiac Pathology (Hypertensive Heart Disease)
- Left ventricular hypertrophy (LVH): compensatory response to increased afterload; initially concentric (wall thickening, normal/small cavity), later eccentric (dilation)
- Diastolic dysfunction: stiff, hypertrophied ventricle - leads to heart failure with preserved ejection fraction (HFpEF)
- Systolic dysfunction: with prolonged hypertension, leads to heart failure with reduced EF (HFrEF)
- Coronary artery disease: accelerated by hypertension-driven atherosclerosis
- Risk: 2x increase in MI, stroke, HF, and sudden death
C. Renal Pathology (Hypertensive Nephropathy)
- Nephrosclerosis: hyalinization of afferent arterioles, glomerulosclerosis, tubular atrophy, interstitial fibrosis
- Glomerulomegaly and focal segmental glomerulosclerosis (FSGS): especially in obesity-related hypertension
- Proteinuria (can reach nephrotic range) followed by progressive CKD
- End-stage renal disease: hypertension + diabetes account for 70-75% of ESRD cases
D. Cerebrovascular Pathology
- Lacunar infarcts: small penetrating arteries undergo lipohyalinosis and occlusion
- Intracerebral hemorrhage: fibrinoid necrosis or Charcot-Bouchard microaneurysm rupture
- Hypertensive encephalopathy: failure of cerebral autoregulation at very high BP → cerebral edema
- Ischemic stroke: from accelerated atherosclerosis + thromboembolism
E. Retinal Pathology (Keith-Wagener-Barker Classification)
- Grade I: Mild arteriolar narrowing
- Grade II: A-V nicking (arteriovenous crossing changes)
- Grade III: Flame hemorrhages, cotton-wool spots
- Grade IV: Papilledema (indicates malignant hypertension)
F. Malignant Hypertension
A hypertensive emergency - BP typically >180/120 with end-organ damage. Characterized by:
- Progressive arteriopathy with fibrinoid necrosis of arterioles
- Renal involvement → renin release → further Ang II and aldosterone surge → vicious cycle
- Hypertensive encephalopathy, renal failure, cardiac failure, retinal changes (Grade III/IV)
5. Pharmacology & Treatment
Step 1: Non-Pharmacological (Lifestyle Modifications - first-line for Stage 1)
- Weight reduction (most effective single intervention)
- DASH diet (high fruits, vegetables, low saturated fat, reduced sodium)
- Sodium restriction (<2.3 g/day)
- Regular aerobic exercise (150 min/week moderate intensity)
- Alcohol limitation
- Smoking cessation (reduces overall cardiovascular risk)
Step 2: Pharmacological Treatment
A. Diuretics
| Drug | Class | Mechanism | Dose range | Key uses |
|---|---|---|---|---|
| Hydrochlorothiazide | Thiazide | Inhibit NaCl cotransporter (DCT) → reduce Na+/water reabsorption | 12.5-50 mg/day | First-line; all stages |
| Chlorthalidone | Thiazide-like | Same as above, longer half-life | 12.5-25 mg/day | Preferred over HCTZ in trials |
| Furosemide | Loop | Inhibit NKCC2 cotransporter (Loop of Henle) | 20-80 mg/day | CKD with reduced GFR, heart failure |
| Spironolactone | Aldosterone antagonist | Blocks mineralocorticoid receptor → inhibits Na+/K+-ATPase | 25-100 mg/day | Resistant hypertension, primary hyperaldosteronism |
| Amiloride | K+-sparing | Blocks ENaC in collecting duct | 5-10 mg/day | Liddle syndrome, adjunct |
Why they work: Reduce plasma volume → initially decrease CO; long-term, reduce PVR through vascular remodeling.
B. Beta-Adrenoceptor Blockers (β-blockers)
| Drug | Selectivity | Notes |
|---|---|---|
| Propranolol | Non-selective (β1+β2) | First β-blocker used; twice daily; largely replaced |
| Metoprolol | β1-selective | Preferred; reduces heart failure mortality; CYP2D6 metabolism |
| Atenolol | β1-selective | Renally excreted; once daily; less effective than metoprolol |
| Carvedilol | Non-selective + α1 | Also vasodilates; preferred in heart failure |
| Nebivolol | β1-selective + NO release | Vasodilatory; favorable metabolic profile |
Mechanism: Reduce CO (negative chronotropy/inotropy); reduce renin secretion (β1 in kidney); reduce central sympathetic outflow. Not first-line for uncomplicated hypertension but preferred with co-existing CAD, post-MI, HFrEF, or tachyarrhythmias.
Contraindications: Asthma (β2 blockade causes bronchoconstriction), severe bradycardia, heart block, decompensated heart failure.
Caution: Never stop abruptly - withdrawal syndrome (rebound tachycardia, angina, MI reported).
C. ACE Inhibitors (ACEi)
| Drug | Dose |
|---|---|
| Lisinopril | 10-40 mg/day |
| Ramipril | 2.5-10 mg/day |
| Enalapril | 5-40 mg/day |
| Captopril | 25-150 mg/day (TID) |
Mechanism: Block conversion of Ang I → Ang II → reduce vasoconstriction, reduce aldosterone release → reduce Na+/water retention. Also prevent bradykinin breakdown → increases NO and prostaglandin production (vasodilatory; also responsible for dry cough side effect).
Why favored: Particularly beneficial in diabetic nephropathy (reduce intraglomerular pressure), CKD with proteinuria, post-MI LV dysfunction, HFrEF.
Side effects: Dry cough (10-15%, due to bradykinin accumulation), angioedema (rare but serious), hyperkalemia, acute kidney injury in bilateral renal artery stenosis.
D. Angiotensin Receptor Blockers (ARBs)
| Drug | Dose |
|---|---|
| Losartan | 25-100 mg/day |
| Valsartan | 80-320 mg/day |
| Candesartan | 8-32 mg/day |
| Telmisartan | 20-80 mg/day |
Mechanism: Directly block AT1 receptors - prevent all Ang II effects (vasoconstriction, aldosterone release, sympathetic activation). Do NOT inhibit bradykinin breakdown, so no cough.
Key difference from ACEi: No cough; used when ACEi is not tolerated. Similar renoprotective and cardioprotective profile.
E. Calcium Channel Blockers (CCBs)
| Subclass | Examples | Primary Effect |
|---|---|---|
| Dihydropyridines (DHP) | Amlodipine, nifedipine, felodipine | Peripheral vasodilation (more selective); minimal cardiac depression |
| Non-DHP | Verapamil, diltiazem | Vasodilation + cardiac depression (reduce HR, conduction) |
Mechanism: Block L-type voltage-gated Ca2+ channels in vascular smooth muscle → vasodilation → reduced PVR. DHPs cause reflex sympathetic tachycardia (slight); non-DHPs slow heart rate and AV conduction.
Key uses: Amlodipine is a first-line agent for all patients. Preferred in African Americans, elderly, isolated systolic hypertension, angina. Non-DHPs are also used for rate control in AF.
Avoid: Non-DHPs with β-blockers (both depress heart → risk of heart block/bradycardia).
F. Other Drug Classes
| Drug | Class | Mechanism | Use |
|---|---|---|---|
| Clonidine | Central α2 agonist | Reduces central sympathetic outflow | Resistant hypertension; withdrawal |
| Hydralazine | Direct vasodilator | Increases cGMP → vascular smooth muscle relaxation | Heart failure (with nitrates); pregnancy |
| Minoxidil | Direct vasodilator | Opens K+ channels → hyperpolarization → vasodilation | Severe/resistant hypertension |
| Prazosin/doxazosin | α1 blocker | Blocks peripheral vasoconstriction | BPH + hypertension |
| Methyldopa | Central α2 agonist | First-line in pregnancy | Pregnancy hypertension |
| Nitroprusside | Direct vasodilator (NO) | Rapidly reduces both PVR and venous capacitance | Hypertensive emergency (IV) |
| Labetalol | α + β blocker | Combined effect | Hypertensive emergency; pregnancy |
| Nicardipine IV | CCB | Rapid vasodilation | Hypertensive emergency |
| Fenoldopam | DA1 agonist | Peripheral vasodilation + natriuresis | Hypertensive emergency |
6. Treatment Algorithm & Drug Selection Rationale
General Approach (Why we choose specific agents)
| Clinical Scenario | Preferred Drug(s) | Reason |
|---|---|---|
| Uncomplicated hypertension (first-line) | Thiazide, CCB, ACEi, or ARB | All proven to reduce CV events; choose based on comorbidities |
| Diabetes / CKD with proteinuria | ACEi or ARB | Reduce intraglomerular pressure; slow nephropathy progression |
| Post-MI / CAD / angina | β-blocker + ACEi/ARB | Reduce myocardial oxygen demand; prevent remodeling |
| Heart failure (HFrEF) | ACEi/ARB + β-blocker + aldosterone antagonist | RAAS blockade + sympatholysis + anti-fibrosis |
| Isolated systolic HTN in elderly | CCB (amlodipine) or thiazide | Well tolerated; efficacious in this group |
| African American patients | Thiazide or CCB (avoid β-blockers, ACEi as monotherapy) | β-blockers and ACEi less effective due to low-renin HTN |
| Asthma + HTN | Avoid β-blockers | β2 blockade → bronchoconstriction |
| Benign prostatic hyperplasia | α1 blocker (doxazosin) | Dual benefit: lower BP + relax prostate/bladder neck |
| Pregnancy | Methyldopa, labetalol, nifedipine | ACEi/ARBs are teratogenic (contraindicated) |
| Hyperaldosteronism / Resistant HTN | Spironolactone / eplerenone | Block excess mineralocorticoid effect |
Combination Therapy Rationale
When one drug is not sufficient (BP target ≥130/80 mmHg):
- Two-drug: ACEi/ARB + CCB or ACEi/ARB + thiazide
- Three-drug: ACEi/ARB + CCB + thiazide (most effective triple combo)
- Four-drug: Add spironolactone or β-blocker or clonidine for resistant hypertension
Fixed-dose triple combinations (e.g., telmisartan 20 mg + amlodipine 2.5 mg + chlorthalidone 12.5 mg) show high efficacy in moderate hypertension with minimal side effects and improve compliance.
BP Targets
- General population: <130/80 mmHg
- High CV risk / SPRINT trial supports: SBP target ~120 mmHg
- Elderly with isolated systolic HTN: treat if SBP >150 mmHg
- CKD with proteinuria: <130/80 mmHg
Causes of Treatment Failure (Resistant Hypertension)
- Medication non-compliance
- Excessive sodium intake
- Inadequate diuretic / volume overload
- Drug interactions: NSAIDs, TCAs, sympathomimetics, cocaine, caffeine, oral contraceptives
- Unidentified secondary cause (always re-assess)
7. Why Treat Hypertension? (The "Reason")
Untreated hypertension is the leading modifiable risk factor for:
- Stroke (both ischemic and hemorrhagic - 35-40% attributable to HTN)
- Myocardial infarction and coronary artery disease
- Heart failure (both HFrEF and HFpEF)
- Chronic kidney disease and ESRD (second leading cause after diabetes)
- Aortic aneurysm and dissection
- Peripheral artery disease (2.5-4x increased risk)
- Retinopathy and vision loss
- Vascular dementia
Treatment reduces:
- Stroke risk by ~35-40%
- Coronary events by ~20-25%
- Heart failure by ~50%
- Cardiovascular mortality significantly
Sources: Fuster & Hurst's The Heart 15th ed. | Katzung's Basic & Clinical Pharmacology 16th ed. | Comprehensive Clinical Nephrology 7th ed. | Brenner & Rector's The Kidney | Goldman-Cecil Medicine
Recent evidence note: A 2025 systematic review [PMID 40885884] highlights aldosterone synthase inhibitors as emerging agents for resistant hypertension, adding to the existing drug classes above.
Psoriasis physiology, pathology pharmacology causes
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Psoriasis: Complete Overview
1. Definition & Epidemiology
Psoriasis is a common, chronic, immune-mediated inflammatory skin disease affecting 1-2% of the world's population. It is characterized by discrete, well-demarcated erythematous plaques covered by silvery-white micaceous scale. It is now recognized as a systemic disease - not merely a skin condition - with significant cardiovascular, metabolic, and articular comorbidities that increase morbidity and reduce life expectancy.
2. Causes & Risk Factors
Psoriasis results from an interplay of genetic susceptibility and environmental triggers.
A. Genetic Factors
- HLA association: HLA-Cw6 (also written HLA-C*06:02) is the strongest genetic risk factor - present in ~60-65% of early-onset psoriasis patients
- GWAS findings: Susceptibility loci involve genes for:
- Adaptive immunity (T-cell activation pathways)
- TNF signaling (TNFA gene polymorphisms)
- Skin barrier function
- IL-23/IL-17 axis regulation
- Genetic susceptibility loci for psoriasis are largely non-overlapping with those for atopic dermatitis, confirming distinct pathogenic mechanisms
- First-degree relatives have ~10-fold increased risk
B. Environmental Triggers
| Trigger | Mechanism |
|---|---|
| Streptococcal pharyngitis | Most strongly linked to guttate psoriasis; streptococcal superantigens activate T cells |
| Stress | HPA axis activation, neuropeptide release, immune dysregulation |
| Physical trauma | Koebner (isomorphic) phenomenon - plaques form at sites of skin injury |
| Drugs | Lithium, beta-blockers, antimalarial drugs (chloroquine), NSAIDs, systemic steroid withdrawal |
| Infections | HIV (can trigger severe/atypical psoriasis), fungal infections |
| Obesity | Metabolic inflammation drives cytokine production; visceral fat is proinflammatory |
| Alcohol & smoking | Both associated with increased severity and treatment resistance |
| Pregnancy | Can exacerbate or improve psoriasis (unpredictable); pustular psoriasis risk |
| Sunburn | Paradoxically can trigger new lesions via Koebner phenomenon |
3. Physiology / Pathophysiology
Psoriasis involves a self-perpetuating cycle of immune activation and keratinocyte hyperproliferation, centered on the IL-23/IL-17 axis.
Step-by-step Immunological Cascade:
Step 1 - Innate triggering (initiating event)
An unknown trigger (possibly microbial antigens, self-peptides, or stress signals) activates plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) in the dermis. These DCs produce:
- TNF-α - primary proinflammatory cytokine
- IL-23 - the critical "master regulator" - a heterodimer (p19 + p40 subunits)
- IL-12 - promotes Th1 differentiation (shares p40 subunit with IL-23)
Step 2 - Adaptive immune activation (T-cell polarization)
- IL-23 drives differentiation and survival of Th17 cells
- Th17 cells produce IL-17A, IL-17F, IL-22, IL-21
- IL-12 drives Th1 cells → produce IFN-γ
- Both Th1 and Th17 memory T cells home to skin via chemokine gradients (CTACK, RANTES, LARC, MCP-1) and chemokine receptors (CCR2, CCR6, CXCR3, CCR10, CCR4)
Step 3 - Keratinocyte hyperproliferation
- IL-17 acts on keratinocytes to:
- Massively upregulate antimicrobial peptides (defensins, LL-37)
- Increase chemokine production (IL-8/CXCL8, GRO-α) → recruit neutrophils
- Drive keratinocyte proliferation
- IL-22 acts on keratinocytes to cause acanthosis (epidermal thickening)
- TNF-α augments all IL-17 effects on keratinocytes - creating a feed-forward inflammatory amplification loop
- Normal keratinocyte transit time from basal layer to surface = ~28 days; in psoriasis this is reduced to 3-5 days - cells don't mature properly
Step 4 - Vascular remodeling ("squirting papillae")
Capillary loops in dermal papillae:
- Elongate, dilate, and remodel their basement membrane to resemble postcapillary venules
- Express adhesion molecules (E-selectin, ICAM-1) supporting leukocyte extravasation
- Leukocytes (lymphocytes + neutrophils) can now exit directly within papillary tips into the epidermis - the "squirting papillae" sign unique to psoriasis
Step 5 - Neutrophil recruitment
- IL-8 and GRO-α produced by keratinocytes recruit neutrophils into the epidermis
- Neutrophils aggregate in the stratum corneum → Munro microabscesses
- Neutrophils aggregate in the spinous layer → spongiform pustules of Kogoj (especially in pustular psoriasis)
The IL-17/TNF feed-forward loop (key concept):
TNF-α + IL-17 → keratinocytes produce more IL-8 → more neutrophils → more inflammation → more cytokine release → sustained chronic inflammation
4. Pathology (Histopathology)
Gross Appearance
- Well-demarcated pink/salmon-red plaques with loosely adherent silver-white (micaceous) scale
- In darker skin types: hyperpigmented plaques with gray scale
- Auspitz sign: punctate bleeding points when scale is removed (exposed dilated capillary tips)
Microscopic Features (H&E)
| Feature | Description |
|---|---|
| Acanthosis | Marked epidermal thickening with regular elongation of rete ridges ("test tubes in a rack") |
| Parakeratosis | Retention of nuclei in stratum corneum (cells don't mature = keratinocytes shed nuclei too late) |
| Loss of stratum granulosum | Due to rapid cell turnover and abnormal differentiation |
| Hypogranulosis | Reduced/absent granular layer |
| Dilated and tortuous capillaries | Within dermal papillae - elongated, reaching up to the epidermis |
| Thinning of suprapapillary epidermis | Epidermis over tips of papillae is paradoxically thin despite overall thickening |
| Munro microabscesses | Collections of neutrophils in the parakeratotic stratum corneum |
| Spongiform pustule of Kogoj | Neutrophil aggregates within the spinous layer (especially pustular psoriasis) |
| Mixed dermal infiltrate | Predominantly CD4+ Th1/Th17 T cells, macrophages, dendritic cells; neutrophils |
Clinical Variants and Their Pathology
| Variant | Key Features |
|---|---|
| Plaque psoriasis (psoriasis vulgaris) | Most common (80-90%); chronic stable plaques; elbows, knees, scalp, lumbosacral |
| Guttate psoriasis | Small "raindrop" papules; acute onset; often post-streptococcal; younger patients |
| Pustular psoriasis | Sterile pustules on erythematous skin; generalized form has fever; triggered by steroid withdrawal |
| Erythrodermic psoriasis | >90% BSA involvement; life-threatening; thermoregulation failure, high-output cardiac failure risk |
| Inverse psoriasis | Intertriginous areas (axilla, groin, submammary); moist, minimal scale |
| Nail psoriasis | Pitting, onycholysis, subungual hyperkeratosis, "oil drop" sign; seen in 30% |
| Psoriatic arthritis (PsA) | Up to 30% of patients; seronegative; five subtypes (see below) |
Psoriatic Arthritis Subtypes
- Symmetric PsA (~50%): resembles RA
- Asymmetric PsA (~35%): "sausage digits" (dactylitis)
- Distal PsA (~5%): classic, DIP joints with nail disease
- Spondylitis (~5%): axial involvement
- Arthritis mutilans (<5%): severe destructive, "pencil-in-cup" deformity
5. Pharmacology & Treatment
Treatment is stratified by severity using the PASI score (Psoriasis Area and Severity Index) and BSA (Body Surface Area).
STEP 1: Topical Therapy (Mild-Moderate Disease)
| Drug | Class | Mechanism | Notes |
|---|---|---|---|
| Corticosteroids (e.g., betamethasone, clobetasol) | Anti-inflammatory | Inhibit phospholipase A2, reduce cytokine production, vasoconstriction | First-line for most patients; high-potency for body; low-potency for face/flexures |
| Calcipotriol (calcipotriene) | Vitamin D3 analogue | Binds VDR → inhibits keratinocyte proliferation, promotes differentiation, immunomodulatory | Effective; combined with betamethasone in "Dovobet" (synergistic) |
| Tazarotene | Topical retinoid | Binds RAR → normalizes keratinocyte differentiation, anti-proliferative | Effective; can be irritating; teratogenic (pregnancy Category X) |
| Coal tar | Keratolytic/antipruritic | Reduces epidermal proliferation; mechanism not fully understood | Old but effective; smelly; photosensitizing |
| Salicylic acid | Keratolytic | Reduces scale by disrupting corneocyte attachments | Used as adjunct to enhance penetration of other drugs |
| Anthralin (dithranol) | Antiproliferative | Inhibits mitochondrial function in keratinocytes | Effective; stains skin and clothing |
| Tacrolimus / pimecrolimus | Calcineurin inhibitor (topical) | Inhibit T-cell activation; no skin atrophy | Useful for face, flexures; not first-line |
STEP 2: Phototherapy (Moderate-Severe Disease)
| Type | Mechanism | Notes |
|---|---|---|
| Narrowband UVB (NB-UVB) | Immunosuppressive; induces T-cell apoptosis, reduces cytokines | Preferred phototherapy; 3x/week; safer than PUVA |
| PUVA (psoralen + UVA) | Psoralens intercalate DNA → UVA induces cross-links → anti-proliferative | Effective but increased melanoma/non-melanoma skin cancer risk; contraindicated with cyclosporine |
| Broadband UVB | Less selective than NB-UVB | Less commonly used now |
STEP 3: Systemic Non-biologic Agents
| Drug | Class | Mechanism | Dose | Key Side Effects |
|---|---|---|---|---|
| Methotrexate | Antimetabolite (DMARD) | Inhibits dihydrofolate reductase → blocks DNA synthesis in rapidly dividing cells (keratinocytes + lymphocytes); anti-inflammatory via adenosine release | 7.5-25 mg/week (oral or SC) | Hepatotoxicity, bone marrow suppression, teratogenicity, pneumonitis; supplement folic acid |
| Cyclosporine | Calcineurin inhibitor | Binds cyclophilin → inhibits calcineurin → blocks NFAT → reduces IL-2, T-cell activation | 3-5 mg/kg/day | Nephrotoxicity, hypertension, infections, malignancy risk; use short-term |
| Acitretin | Oral retinoid (systemic) | Binds nuclear retinoic acid receptors (RARs) → normalizes keratinocyte differentiation | 25-50 mg/day | Teratogenic (3-year contraception after stopping); dyslipidemia; mucocutaneous dryness; preferred when immunosuppression must be avoided |
| Apremilast | PDE-4 inhibitor (small molecule) | Inhibits phosphodiesterase 4 → raises intracellular cAMP → reduces TNF-α, IL-17, IL-23 production | 30 mg twice daily (after titration) | Diarrhea, nausea, depression; dose reduce in renal failure; no immunosuppression risk |
| Deucravacitinib | TYK2 inhibitor | Inhibits tyrosine kinase 2 → blocks IL-23, IL-12, type-I interferon signaling | 6 mg daily | Oral; approved for moderate-severe plaque psoriasis; favorable safety vs JAK inhibitors |
CAUTION: Oral glucocorticoids are contraindicated in psoriasis - withdrawal can precipitate life-threatening generalized pustular psoriasis (von Zumbusch variant).
STEP 4: Biologic Agents (Moderate-Severe Disease)
The development of biologics transformed psoriasis management. Each class targets a specific cytokine proven essential in psoriasis pathogenesis:
a) Anti-TNF-α Agents
Rationale: TNF-α is a primary driver of inflammation; elevated in psoriatic skin and synergizes with IL-17.
| Drug | Route | Notes |
|---|---|---|
| Adalimumab (Humira) | SC | Human anti-TNF-α mAb; also approved for PsA |
| Etanercept (Enbrel) | SC | TNF-receptor fusion protein; milder effect than mAbs |
| Infliximab (Remicade) | IV | Chimeric mAb; rapid onset; effective in severe disease |
| Certolizumab (Cimzia) | SC | PEGylated Fab fragment; preferred in pregnancy (minimal placental transfer) |
| Golimumab (Simponi) | SC | Approved for PsA only |
Warnings: Serious infections (TB reactivation - screen before starting), hepatotoxicity, worsening CHF, hematologic events, risk of demyelinating disease, potential increased malignancy.
b) Anti-IL-12/IL-23 (p40 Subunit)
| Drug | Route | Notes |
|---|---|---|
| Ustekinumab (Stelara) | SC | Human mAb targeting p40 (shared subunit of IL-12 and IL-23); every 12 weeks after loading; effective in psoriasis and PsA |
c) Anti-IL-23 (p19 Subunit) - Most Selective
Rationale: IL-23 is the upstream "master regulator" of Th17 differentiation; more selective than p40 inhibition.
| Drug | Route | Notes |
|---|---|---|
| Guselkumab (Tremfya) | SC | IL-23 p19 specific; high efficacy |
| Risankizumab (Skyrizi) | SC | IL-23 p19 specific; every 12 weeks |
| Tildrakizumab (Ilumya) | SC | IL-23 p19 specific |
d) Anti-IL-17 Agents - Fastest/Highest Efficacy
Rationale: IL-17A is the direct effector cytokine causing keratinocyte hyperproliferation; blocking it gives dramatic responses (often complete clearance).
| Drug | Target | Route | Notes |
|---|---|---|---|
| Secukinumab (Cosentyx) | IL-17A | SC | First anti-IL-17A; remarkable efficacy; rapid onset |
| Ixekizumab (Taltz) | IL-17A | SC | Similar to secukinumab; very high PASI 90/100 response rates |
| Brodalumab (Siliq) | IL-17 receptor A | SC | Blocks all IL-17 isoforms; black box warning for suicidal ideation |
Side effect note for IL-17 blockers: Increased risk of Candida infections (IL-17 is important for mucosal antifungal immunity); avoid in inflammatory bowel disease (can worsen it).
Drug Selection Summary
| Scenario | Preferred Treatment |
|---|---|
| Mild (BSA <3%, PASI <5) | Topical corticosteroid ± calcipotriol |
| Scalp psoriasis | High-potency topical steroid (foam/solution) + calcipotriol |
| Nail psoriasis | Topical steroids, calcipotriol; biologics if severe |
| Moderate (BSA 3-10%) | NB-UVB phototherapy or topical + one systemic |
| Severe (BSA >10%, PASI >10) | Methotrexate, cyclosporine, or biologic |
| Psoriatic arthritis | Methotrexate + anti-TNF or anti-IL-17 (anti-IL-17 preferred for skin + joints) |
| Pregnancy | Topical steroids (low-to-mid potency), NB-UVB; certolizumab if biologic needed |
| Rapid response needed | Cyclosporine (fastest systemic) or infliximab IV |
| Avoid immunosuppression | Acitretin or NB-UVB |
| When anti-TNF inadequate | Switch to anti-IL-17 or anti-IL-23 (higher efficacy) |
| Avoid injections (mild-mod) | Apremilast or deucravacitinib (oral small molecules) |
6. Comorbidities (The Systemic Disease Concept)
Psoriasis is a systemic inflammatory disease - chronic immune activation affects multiple organ systems:
| Comorbidity | Risk/Notes |
|---|---|
| Psoriatic arthritis | ~30% of patients; often undertreated |
| Cardiovascular disease | Accelerated atherosclerosis; increased MI, stroke risk |
| Metabolic syndrome | Obesity, insulin resistance, dyslipidemia, hypertension |
| Depression/anxiety | Due to disease burden + shared neuroinflammatory mechanisms |
| Non-alcoholic fatty liver disease | Especially with methotrexate use (hepatotoxic) |
| Inflammatory bowel disease | ~7% prevalence; anti-IL-17 drugs are contraindicated |
| Malignancy | Lymphoma risk (especially with PUVA); squamous cell carcinoma |
Sources: Fitzpatrick's Dermatology (Volumes 1 & 2) | Robbins & Kumar Basic Pathology | Harrison's Principles of Internal Medicine 22nd ed. | Katzung's Basic and Clinical Pharmacology 16th ed.
Recent evidence note: A 2025 systematic review [PMID 39960751] highlights emerging pathophysiological links between psoriasis and type 2 diabetes, suggesting shared inflammatory mediators (TNF-α, IL-17, IL-6) may explain the concurrent metabolic dysregulation seen in psoriatic patients - supporting early metabolic screening in all psoriasis patients.
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