USMLE (Fach) / Pharmacology - Neurology (Lektion)

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• Glaucoma drugs α-agonists:Epinephrine (α1): ↓ aqueous humor synthesis via vasoconstrictionBrimonidine, apraclonidine (α2): ↓ aqueous humor synthesis- Mydriasis (α1); do not use in closed-angle glaucoma.- Blurry vision, ocular hyperemia, foreign body sensation, ocular allergic reactions, ocular pruritus β-blockers (timolol, betaxolol, carteolol):- ↓ aqueous humor synthesis.- No pupillary or vision changes. Diuretics (acetazolamide):- ↓ aqueous humor synthesis via inhibition of carbonic anhydrase.- No pupillary or vision changes. Cholinomimetics (M3)- Direct: pilocarpine, carbachol- Indirect: physostigmine, echothiophate- ↑ outflow of aqueous humor via contraction of ciliary muscle and opening of trabecular meshwork- Use pilocarpine in acute angle closure glaucoma – very effective at opening meshwork into canal of Schlemm- Miosis (contraction of pupillary sphincter muscles) and cyclospasm (contraction of ciliary muscle). Prostaglandins (bimatoprost, lantanoprost [PGF2α]):- ↑ outflow of aqueous humor via ↓ resistance of flow through uveoscleral pathway- Darkens color of iris (browning), eyelash growth
• Opioid analgesics Mechanism: Act as agonists at opioid receptors (μ = β-endorphin, δ = enkephalin, κ = dynorphin) to modulate synaptic transmission – close presynaptic Ca2+ channel, open postsynaptic K+ channels → ↓ synaptic transmission. Inhibit release of ACh, NE, 5-HT, glutamate, substance P. Efficacy:- Full agonist: morphine, heroine, meperidine, methadone, codeine- Partial agonist: buprenorphine- Mixed agonist/antagonist: nalbuphine, pentazocine- Antagonist: naloxone, naltrexone, methylnaltrexone Clinical use: Moderate to severe refractory pain, cough suppression (dextormethorphan), diarrhea (loperamide, diphenoxylate), acute pulmonary edema, maintenance programs for heroin addicts (methadone, buprenorphine + naloxone) Adverse effects: Nausea, vomiting, addiction, respiratory depression, constipation, sphincter of Oddi spasm, miosis (except meperidine → mydriasis), additive CNS depression with other drugs. Tolerance does not develop to miosis and constipation. Toxicity treated with naloxone and relapse prevention with naltrexone once detoxified.
• Pentazocine κ-(dynorphin) opioid receptor agonist and μ-(β-endorphin) opioid receptor antagonist or partial agonist. Clincal use: Analgesia for moderate to severe pain. Adverse effects: Can cause opioid withdrawal symptoms if patient is also taking full opioid agonist (due to competition for opioid receptors).
• Butorphanol κ-(dynorphin) opioid receptor agonist and μ-(β-endorphin) opioid receptor partial agonist. Clinical use: Severe pain (eg, migraine, labor). Causes less respiratory depression than full opioid agonists. Adverse effects: Use will full opioid agonist can precipitate withdrawal. Not easily reversed with naloxone.
• Tramadol Mechanism: very weak opioid agonist, also inhibits 5-HT receptors. Clincial use: Chronic pain. Adverse effects: Similar to opioids. Decreases seizure threshold. Serotonin syndrome.
• Barbiturates Phenobarbital, pentobarbital, thiopental, secobarbital Mechanism: Facilitate GABAA action by ↑ duration of Cl- channel opening. (barbidurates ↑ duration).  Clinical use: Sedative for anxiety, seizures, insomnia, induction of anesthesia (thiopental). Adverse effects: - Respiratory or cardiovascular depression (can be fatal)- CNS depression (exacerbated by alcohol use)- Dependence- Drug interactions (induces cytochrome P-450).- Contraindicated in porphyria.- Overdose treatment is supportive (assist respiration and maintain BP).
• Benzodiazepines Diazepam, lorazepam, triazolam, temazepam, oxazepam, midazolam, chlordiazeproxide, alprazolam Mechanism: Facilitate GABAA action by ↑ frequency of Cl- channel opening. ↓ REM sleep. Most have long half-lives and active metabolites.(exceptions [ATOM]: Alprazolam, Triazolam, Oxazepam and Midazolam are short-acting → higher addictive potential). Clinical use: Anxiety, spasticity, status epilepticus (lorazepam, diazepam, midazolam), eclampsia, detoxification (especially alcohol withdrawal), night terrors, sleepwalking, general anesthetic, hypnotic (insomnia). Oxazepam, Temazepam, and Lorazepam are OK for Terrible Livers: they can be used to treat alcohol withdrawal in patients with liver disease due to minimal first-pass metabolism. Adverse effects: Dependence, additive CNS depression effects with alcohol. Less risk of respiratory depression and coma than with barbiturates.- Should be excluded from use in conjunction wiht alcohol, barbiturates, neuroleptics, or 1st generation antihistamines.- Treat overdose with flumazenil (competitive antagonist at GABA receptor). Can precipitate seizures by causing acute benzodiazepine withdrawal.
• Nonbenzodiazepine hypnotics Zolpidem, zaleplon, eszopiclone Mechanism: Act via the BZ1 subtype of the GABA receptor. Effects reversed by flumazenil. Sleep cycle less affected as compared with benzodiazepine hypnotics. Clinical use: Insomnia Adverse effects: Ataxia, headaches, confusion. Short duration because of rapid metabolism by liver enzymes. Unlike older sedative-hypnotics, cause only modest day-after psychomotor depression and few amnestic effects. ↓ dependence risk than benzodiazepines.
• Inhaled anesthetics Desflurane, halothane, enflurane, isoflurane, sevoflurane, methoxyflurane, N2O. Mechanism unknown Effects: myocardial depression, respiratory depression, nausea/emesis, ↑ cerebral blood flow (↓ cerebral metabolic demand). Adverse effects: Hepatoxicity (halothane), nephrotoxicity (methoxyflurane), proconvulsant (enflurane, epileptogenic), expansion of trapped gas in a body cavity (N2O).Malignant hyperthermia – rare, life-threatening condition in which inhaled anesthetics or succinylcholine induce fever and severe muscle contractions. Susceptibility is often inherited as autosomal dominant with variable penetrance. Mutations in voltage-sensitive ryanodine receptor (RYR1 gene) cause ↑ Ca2+ release from sarcoplasmic reticulum. Treatment: dantrolene (ryanodine receptor antagonist).
• Intravenous anesthetics Thiopental (Facilitate GABAA, barbiturate): Used for induction of anesthesia and short surgical procedures. ↓ Cerebral blood flow. High lipid solubility. Effect terminated by rapid redistribution into tissue and fat. Midazolam (Facilitate GABAA, benzodiazepine): Used for procedural sedation (eg, endoscopy), anesthesia induction. May cause severe postoperative respiratory depression, ↓ BP, anterograde amnesia. Ketamine (NMDA receptor antagonist): Phencyclidine analogs that act as dissociative anesthetics. Sympathomimetic. ↑ Cerebral blood flow. Emergence reaction possible with disorientation, hallucinations, vivid dreams. Propofol (Potentiates GABAA): Used for rapid anesthesia induction, short procedures, ICU sedation. Morphine, fentanyl (Opioids): Used with other CNS depressents during general anesthesia.
• Local anesthetics Esters – procaine, cocaine, tetracaine, benzocaine, chloroprocaine.Amides – lidocaine, mepivacaine, bupivacaine, ropivacaine (amides have 2 i's in name). Mechanism: Block Na+ channels by binding to inner portion of channel. Most effective in rapidly firing neurons. 3° amine local anesthetics penetrate membrane in uncharged form, then bind to ion channels as charged form.- Can be given with vasoconstrictors (usually epinephrine) to enhance local action – ↓ bleeding, ↑ anesthesia by ↓ systemic concentration. - In infected (acidic) tissue, alkaline anesthetics are charged and cannot penetrate membrane → need more anesthetic.- Order of nerve blockade: small-diameter fibers > large diameter. Myelinated fibers > unmyelinated fibers. Overall, size predominates over myelination that small myelinated fibers > small unmyelinated fibers > large myelinated fibers > large unmyelinated fibers.- Order of loss: (1) pain, (2) temperature, (3) touch, (4) pressure. Clinical use: minor surgical procedures, spinal anesthesia. If allergic to esters, give amides. Adverse effects: CNS excitation, severe cardiovascular toxicity (bupivacaine), hypertension, hypotension, arrhythmias (cocaine), methemoglobinemia (benzocaine).
• Neuromuscular blocking drugs Muscle paralysis in surgery or mechanical ventilation. Selective for Nm nicotinic receptors at neuromuscular junction but not autonomic Nn receptors. Depolarizing: Succinylcholine – strong ACh receptor agonist; produces sustained depolarization and prevents muscle contraction.- Reversal of blockade Phase I (prolonged depolarization) – no antidote. Block potentiated by cholinesterase inhibitors.Phase II (repolarized but blocked; ACh receptors are available, but desensitized) – may be reversed with cholinesterase inhibitors.- Complications include hypercalcemia, hyperkalemia, malignant hyperthermia. Nondepolarizing: atracurium, cisatracurium, pancuronium, rocuronium, tubocurarine, vecuronium – competitive with ACh for receptors.- Reversal of blockade – neostigmine (must be given with atropine or glycopyrrolate to prevent muscarinic effects such as bradycardia), edrophronium, and other cholinesterase inhibitors.
• Dantrolene Prevents release of Ca2+ from the sarcoplasmatic reticulum of skeletal muscle by binding to the ryanodine receptor. Clinical use: Malignant hyperthermia (a toxicity of inhaled anesthetics and succinylcholine) and neuroleptic malignant syndrome (a toxicity of antipsychotic drugs).
• Baclofen Skeletal muscle relaxant. GABAB receptor agonist in spinal cord. Clinical use: Muscle spasticity, dystonia, multiple sclerosis.
• Cyclobenzaprine Skeletal muscle relaxant. Acts within CNS. Clincal use: Muscle spasms. Adverse effects: Anticholinergic side effects. Sedation.
• Parkinson disease drugs Parkinsonism is due to loss of dopaminergic neurons and excess cholinergic activity Dopamine agonists:- Ergot – Bromocriptine - Non-ergot (preferred) – pramipexole, ropinirole; toxicity includes impulse control disorder (eg, gambling), postural hypotension, hallucinations/confusion. ↑ Dopamine availability: Amantidine (↑ dopamine release and ↓ dopamine reuptake)- Toxicity: ataxia, livedo reticularis ↑ L-DOPA availability (pre-BBB):- Levodopa (L-DOPA/carbidopa) – carbidopa blocks peripheral conversion of L-DOPA to dopamine by inhibiting DOPA decarboxylase. - Entacapone – prevents peripheral L-DOPA degradation to 3-O-methyldopa by inhibiting COMT. Use in conjunction with levodopa. Prevent dopamine breakdown (post-BBB):- Selegiline, rasagiline – block conversion of dopamine into DOPAC by selectively inhibiting MAO-B.- Entacapone – blocks conversion of dopamine to 3-methoxytyramine (3-MT) by inhibiting central COMT. Curb excess cholinergic activity: - Benztropine, trihexyphenidyl: antimuscarinic, improves tremor and rigidity but has little effect on bradykinesia in Parkinson disease.
• Dopamine agonists Parkinson disease drug Ergot – BromocriptineNon-ergot (preferred) – Pramipexole, ropinirole - Toxicity includes impulse control disorder (eg, gambling), postural hypotension, hallucinations/confusion.
• Benztropine Antimuscarinic - curbs excess cholinergic activity in Parkinson disease - improves tremor and rigidity but has little effect on bradykinesia
• Levodopa/carbidopa Prevent peripheral (pre-BBB) L-DOPA degradation → ↑ L-DOPA entering CNS → ↑ central L-DOPA available for conversion to dopamine. Unlike dopamine, L-DOPA can cross blood-brain barrier and is converted by dopa decarboxylase in the CNS to dopamine. Carbidopa, a peripheral DOPA decarboxylase inhibitor, is given with L-DOPA to ↑ the bioavailability of L-DOPA in the brain and limit peripheral side effects. Adverse effects: Nausea, hallucinations, postural hypotension from ↑ peripheral formation of catecholamines. Long-term use can lead to dyskinesia following administration ("on-off" phenomenon), akinesia between doses.
• Selegiline, rasagiline Act centrally (post-BBB).Selectively inhibit MAO-B (metabolize dopamine) → ↑ dopamine availability. Clinical use: Adjunctive agent to L-DOPA to reduce motor fluctuations in Parkinson disease Adverse effects: May enhance adverse effects of L-DOPA.
• Alzheimer disease drugs Memantine:- NMDA receptor antagonist; helps prevent excitotoxicity (mediated by Ca2+).- Adverse defects: Dizziness, confusion, hallucinations. Donepezil, galantamine, rivastigmine:- AChE inhibitors.- Adverse effects: Nausea, dizziness, insomnia.
• Huntington disease drugs Tetrabenazine and reserpine - inhibit vesicular monoamine transporter (VMAT) --> ↓ dopamine vesicle packaging and release Haloperidol - D2 receptor antagonist
• Riluzole ↓ neuron glutamate excitotoxicity  Clinical use: ALS, ↑ survival
• Triptans Sumatriptan Mechanism: 5-HT1A/1D agonists. Inhibit trigeminal nerve activation; prevent vasoactive peptide release; induce vasoconstriction. Clinical use: Acute migrane, cluster headache attacks Adverse effects: coronary vasospasm (contraindicated in patients with CAD or Prinzmetal angina), mild paresthesia, serotonin syndrome (in combination with other 5-HT agonists).
• Acetazolamide Diuretic ↓ aqueous humor synthesis via inhibition of carbonic anhydrase
• Pilocarpine Direct cholinomimetic ↑ outflow of aqueous humor via contraction of ciliary muscle and opening of trabecular meshwork - use in emergencies - very effective at opening meshwork into canal of Schlemm Side effects: Miosis and cyclospasm (contraction of ciliary muscle)
• Carbachol Direct cholinomimetic ↑ outflow of aqueous humor via contraction of ciliary muscle and opening of trabecular meshwork Side effects: Miosis and cyclospasm (contraction of ciliary muscle)
• Physostigmine Indirect cholinomimetic ↑ outflow of aqueous humor via contraction of ciliary muscle and opening of trabecular meshwork Side effects: Miosis and cyclospasm (contraction of ciliary muscle)
• Lantanoprost (PGF2α) ↑ outflow of aqueous humor Side effects: darkens color of iris (browning)
• Phenytoin, fosphenytoin Na+ channel inactivation; zero-order kinetics. Clinical use: - 1st line for recurrent seizure prophylaxis- Tonic-clonic seizures- Partial (focal) seizures- Also a class IB antiarrhythmic. Side effects:- Horizontal nystagmus- Gingival hyperplasia- Hirsutism- Megaloblastic anemia, inhibited folate uptake- Teratogenesis- Yellow-brown skin- Osteopenia- Neuropathy- Induction of cytochrome P-450- Rare adverse reactions including Stevens-Johnson syndrome, DRESS syndrome, SLE-like syndrome.- Toxicity leads to diplopia, ataxia, slurred speech, hyperreflexia, altered mental status, coma
• Carbamazepine Epilepsy drug Blocks Na+ channels Indication:- 1st line for trigeminal neuralgia- Partial (focal) and tonic-clonic seizures Side effects: Diplopia, ataxia, blood dyscrasias (agranulocytosis, aplastic anemia), liver toxicity, teratogenesis (cleft lip/palate, spina bifida), induction of cytochrome P-450, SIADH, Stevens-Johnson syndrome 
• Lamotrigine Blocks voltage-gated Na+ channels, inhibits the release of glutamate.  Indication:- Partial (focal) seizures- Tonic-clonic seizures- Absence Side effects: Stevens-Johnson syndrome (must be titrated slowly)
• Gabapentin Primarily inhibits high-voltage-activated Ca2+ channels; designed as GABA analog. Indication:- Partial (focal) seizures- Also used for peripheral neuropathy, postherpetic neuralgia Side effects: Sedation, ataxia
• Topiramate Blocks Na+ channels, ↑ GABA action Indications:- Partial (focal) seizures- Tonic-clonic seizures- Also used for migraine prevention Side effects: Sedation, mental dulling, word-finding difficulty, kidney stones, weight loss, glaucoma.
• Phenobarbital ↑ GABAA action Indication:- 1st line in neonates- Partial (focal) seizures- Tonic-clonic seizures- Status epilepticus Side effects: - Sedation, tolerance, dependence, induction of cytochrome P-450, cardiorespiratory depression.
• Valproic acid ↑ Na+ channel inactivation, ↑ GABA concentration by inhibiting GABA transaminase. Indication:- Broad-spectrum- Tonic-clonic seizures- Partial (focal) seizures- Absences- Also used for myoclonic seizures, bipolar disorder, migraine prophylaxis  Side effects:- GI distress, rare but fatal hepatotoxicity (measure LFTs), pancreatitis, neural tube defects, tremor, weight gain, contraindicated in pregnancy.
• Ethosuximide Blocks thalamic T-type Ca2+ channels Indication:- 1st line for absences (less hepatotoxicity than valproic acid) Side effects:- GI distress, fatigue, headache, itching and urticaria, Stevens-Johnson syndrome 
• Tiagabine ↑ GABA by inhibiting reuptake Indication:- Partial (focal) seizures
• Vigabatrin Irreversible GABA transaminase inhibitor → ↑ GABA.Vigabatrin Indication:- Partial (focal) seizures Side effects: Permanent visual loss (black box warning)
• Levetiracetam Binds to synaptic vesicle protein (SV2A) to modulate release of GABA and glutamate neurotransmitters. Indication:- Partial (focal) seizures- Tonic-clonic seizures Side effects: Neuropsychiatric symptoms (eg, personality change), fatigue, drowsiness, headache.
• Sumatriptan 5-HT agonist - inhibits trigeminal nerve activation; prevents vasoactive peptide release; induces vasoconstriction Clinical use: acute migraine, cluster headache attacks Toxicity: coronary vasospasm
• Suvorexant Orexin (hypocretin) receptor antagonist Clinical use: Insomnia Adverse effects: CNS depression, headache, dizziness, abnormal dreams, upper respiratory tract infection. - Contraindicated in patients with narcolepsy. - Not recommended in patients with liver disease. - No or low physical dependence. - Contraindicated with strong CYP3A4 inhibitors.
• Ramelteon Melatonin receptor agonist, binds MT1 and MT2 in suprachiasmatic nucleus. Clincal use: Insomnia Adverse effects: Dizziness, nausea, fatigue, headache. No dependence.
• Amantadine Parkinson disease drug. ↑ dopamine release and ↓ dopamine reuptake. Side effects:- Ataxia- Livedo reticularis - Edema
• Tetrabenazine, reserpine Inhibit vesicular monoamine transporter (VMAT) dopamine → decreased vesicle packaging and release. Clinical use: Huntington disease, tardive dyskinesia.
• Ketamine NMDA receptor antagonist Use: Dissociative anesthesia. Sympathomimetic.  Increases cerebral blood flow. Emergence reaction possible with disorientation, hallucination, vivid dreams
• Propofol Potentiates GABAA Use: Rapid anesthesia induction, short procedures, ICU sedation
• Midazolam Facilitates GABAA (benzodiazepine) Use: Procedural sedation (eg, endoscopy), anesthesia induction  May cause postoperative respiratory depression, hypotension, anterograde amnesia 
• Anesthetics – general principles CNS drugs must be lipid soluble (cross the BBB) or be actively transported. Drugs with ↓ solubility in blood = rapid induction and recovery times.Drugs with ↑ solubility in lipids = ↑ potency = 1/MAC MAC = Minimal Alveolar Concentration (of inhaled anesthetic) required to prevent 50% of subjects from moving in response to noxious stimulus (eg, skin incision).Examples: nitrous oxide (N2O) has ↓ blood and lipid solubility, and thus fast induction and low potency. Halothane, propofol, and thiopental, in contrast, have ↑ lipid and blood solubility, and thus high potency and slow induction.
• Tizanidine α2 agonist - Effective as monotherapy for the treatment of spasticity, eg in multiple sclerosis

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