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).
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.
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.
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
