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222 Cards in this Set
- Front
- Back
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Catecholamines
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Contain benzene ring with adjacent hydroxyls and amino groups. Includes dopamine, norepinephrine, and epinephrine. They are synthesized from the precursor tyrosine.
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Tyrosine is a precursor for what category of molecules?
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Catecholamines
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Phenylalanine hydroxylase
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Enzyme that produces tyrosine. If mutated (as in PKU) phenylketones accumulate and are neurotoxic.
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2-phenylethylamine
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Results from the decarboxylation of phenylalanine by AADC. It is elevated during paranoid schizophrenia crisis.
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Tyramine
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Results from the decarboxylation of tyrosine by AADC. It has an action similar to epinephrine and it found in cheese and fermented foods like wine.
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L-Dopa
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Produced by tyrosine hydroxylase, which is the rate limiting step of catecholamine synthesis.
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Tyrosine Hydroxylase
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Produces L-Dopa from Tyrosine. This is the rate limiting step in catecholamine synthesis. The enzyme is inhibited by lead and alpha-methyl-tyrosine (tyrosine analog) It is regulated short term by phosphorylation (activating) and long term by transcriptional regulation.
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Dopamine Synthesis
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Created from L-Dopa by Dopa Decarboxylase or AADC, LSD and Amphetamines can increase the activity of this enzyme.
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Norepinephrine Synthesis
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Created from Dopamine by Dopamine Beta Hydroxylase.
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Roles of Norepinephrine
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Sleep, arousal, attention, vigilance, learning, memory
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Epinephrine Synthesis
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Created from norepinephrine by Phenylethylamine N-methyl transferase.
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Roles of epinephrine
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Increases BP, HR, gluconeogenesis, ATP production. Dilates respiratory tract.
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Catecholamine Catabolism
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Monoamine Oxidase (MAO) converts amino group to aldehyde. This is followed by wither aldehyde reductase or aldehyde dehydrogenase. Catecholamine-O-Methyl Transferases (COMT) methylate an OH group.
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MAO
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Monoamine oxidase. Responsible for Catecholamine Catabolism. It converts an amino group to an aldehyde. An ingredient in smoke inhibits MAO-B, which may be relevant to smoking addiction.
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COMT
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Catecholamine-O-Methyl Transferases. Responsible for Catecholamine Catabolism. Inhibition of this enzyme increases L-Dopa and Dopamine levels, making it a potential Parkinson's treatment.
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Homovanillic acid (HVA)
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Principle metabolite of dopamine. Indicator or dopamine activity in CNS.
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3-methyl-4-hydroxyphenolglycol (MHPG)
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Principle metabolite of NE
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Dopamine Systems of the Brain
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1. Substantia nigra pars compacta to the striatum
2. Ventral tegmental area to nucleus accumbens to cerebral cortex and hypothalamus. The Nucleus Accumbens is associated with drug addiction. |
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Cocaine
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Inhibits dopamine transporter (DAT), increasing dopamine's half life in the synpase.
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Dopamine receptors
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All G-protein coupled
D1 and D5 increase cAMP (Gs) D2-4 decrease cAMP (Gi) Some are presynaptic receptors that regulate transmitter release. |
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Reserpine
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Inhibits vesicular monoamine transporter protein (VMAT) and is used as an anti-hypertensive agent.
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Amphetamine
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Stimulates dopamine release and blocks its uptake
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Pargyline
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MAO inhibitor
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Dopamine Hypothesis of Schizophrenia
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D2 and D4 agonists are anti-schizophrenic. A mutation in D4 creates a susceptibility to delusional disorder.
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MPTP
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Drug that is preferentially taken up by dopaminergic neurons (chemical sympathectomy). It is converted to toxic products inside the neuron and kills it, resulting in Parkinson-like syndrome.
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Direct Sympathomimetics
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Direct agonists on adrenergic receptors that mimic the action of the sympathetic nervous system. They do not require innervation.
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Indirect Sympathomimetics
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Mimic the action of the sympathetic nervous system. They require innervation to have an effect.
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Alpha-1 Receptor
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Located on arterioles. Activation results in vasoconstriction (and reflex vagal bradycardia). Also involved in mydriasis and arousal in the CNS. Alpha-1-a is a subtype found in the bladder.
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Tamsulosin
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Alpha-1-a antagonist (bladder subtype) for use in benign prostate hyperplasia.
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Phenylephrine
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Strong Alpha-1 agonist activity. Vasoconstriction from phenylephrine results in increased BP, no change in pulse pressure, and a vagal reflex bradycardia. Used as a nasal decongestant, pressor agent, and mydriatic.
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Alpha-2 Receptor
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Presynaptic autoreceptor that inhibits NE release.
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Clonidine
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Alpha-2 agonist used to treat hypertension.
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Beta-1 Receptor
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Located in the heart. Has positive choronotropic effect (SA node) and inotropic effect (ventricles). The result is an increased HR, mean BP, and pulse pressure.
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Dobutamine
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Beta-1 agonist used to treat heart failure.
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Beta-2 Receptor
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Found in skeletal muscle arterioles and bronchioles. Results in vasodilation and bronchial dilation.
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Albuterol
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Beta-2 agonist used to treat asthma.
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D1 Receptor
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Dopamine receptor. Low dose agonists reults in vasodilation. High dose engage Alpha-1 and Beta-1 which increases BP. Low dose fenoldopam used for hypertension, while high dose used for hypotensive crisis.
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Norepinephrine: receptors and actions?
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Alpha-1 and Beta-1
Stimulates heart and vasoconstricts. Greater increase in systolic than diastolic results in increased pulse pressure and mean BP. The positive choronotropy by Beta-1 is opposed by the vagal reflex, resulting in bradycardia. Used as pressor agent. |
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Isoproterenol: receptors and actions?
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Beta-1 and Beta-2
Stimulates heart, dilates bronchioles and skeletal smooth muscle arterioles. Beta-2 action decreases diastolic and mean BP and increases pulse pressure. Beta-1 and the sympathetic reflex increase the heart rate. Used to stimulate AV conduction (Beta-1) and dilate bronchioles (Beta-2) |
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Epinephrine: receptors and actions?
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Alpha-1, Beta-1, Beta-2
Low dose engages Beta receptors > Alpha-1 resulting in isoproterenol-like effects. (Decrease in diastolic/mean BP, increase in pulse pressure, Beta-1 and symp reflex increase HR) High dose engages Alpha-1 resulting in vasoconstriction, increased diastolic pressure, and increased mean BP. The vagal reflex opposes the Beta-1 choronotropy and results in bradycardia. Used in anaphylaxis to treat bronchospasm, congestion, and hypotension. |
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Vasoconstriction results in?
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Increase in diastolic pressure (And passive increase in systolic)
(Opposite for vasodilation). In other words look at diastolic change to determine whether vasodilation or vasoconstriction occured. |
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Inotropic effect on pulse pressure.
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Postiive inotropic effect results in increased pulse pressure (greater systolic increase)
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Cocaine
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Indirect sympathomimetic
Blocks uptake of NE and DA, potentiating sympathetic stimulation. Used as vasoconstrictor in nasal surgery (alpha-1 action) Also has local anaesthetic (Na blocker) and euphoric/arousal in the CNS actions. Symptoms include mydriasis, tachycardia, and increased blood pressure. |
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Amphetamines
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Example: Dextroamphetamine
Indirect sympathomimetic Like Cocaine, blocks uptake of NE and DA. But also increases catecholamine release by reversing the transporter direction. Has effects similar to cocaine (euphoria, tachycardia, mydriasis, and increased BP). Also potent appetite supressant and causes insomnia, tremor, and anxiety. |
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Methyphenidate
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Amphetamine variant used to treat ADD
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Tyramine
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Indirect sympathomimetic that is transported by NET and DAT into adrenergic terminal. It causes NE and DA release.
Found in chees/wine and must be avoided in patients taking MAO inhibitors for depression because of risk of hypertensive crisis. Effects of Tyramine can be blocked by blocking the transporter (Cocaine) or depleting cellular NE (reserpine) |
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Alpha-1 Antagonism results in?
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Vasodilation, decrease in BP, reflex tachycardia
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Side Effects of Alpha-1 Antagonism
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Postural Hypotension (greatest sympathetic tone in upright position), miosis, nasal stuffiness, reduced bladder tone, increased peristalsis (diarrhea), inability to ejaculate.
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Postural hypotension
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Results in the use of Alpha-1 blockers from venous dilation, venous pooling, and reduction in cardiac output.
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Alpha-2 Antagonism results in?
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Greater NE release (alpha-2 is an autoreceptor)
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Phentolamine
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Competitive Alpha-1/Alpha-2 antagonist. Results in vasodilation, reduction in BP, and reflex tachycardia. Used in Pheochromocytoma and male ED.
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Phenoxybenzene
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Alpha-1/Alpha-2 Blocker Non-competitive antagonist. Mostly used for pheochromocytoma.
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Prazosin
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Selective Alpha-1 antagonist. Used to treat hypertension.
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Tamsulosin
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Alpha-1-a (bladder subtype) antagonist. Useful to help urination in benign prostatic hyperplasia.
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Yohimbine
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Alpha-2 antagonist. Can reverse clonidine (alpha-2 agonist used for hypertension) overdose. May aid ejaculation by increasing sympathetic tonus.
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Clinical uses of Alpha blockers
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1. Pheochromocytoma (Adrenal medullary tumor secretes high NE/Epi resulting in hypertenson, sweating, and palpitations)
2. Chronic Hypertension 3. Urinary Obstruction 4. Erectile Dysfunction 5. Norepinephrine Necrosis |
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Beta Blockers
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Most are competitive antagonists. The Beta-1 blocking action is what is preferred (but most have Beta-2 blocking as well) : negative choronotrope/inotrope. This is useful for angina pectoris, cardiac arrhythmias, and essential hypertension.
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Angina Pectoris
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Chest pain exacerbated by exercise as the result of coronary artery narrowing and ischemia. Beta-1 blocker are useful for lowering HR during exercise, with little decrease in resting HR (little sympathetic tone).
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Alpha-1 Blocker + Beta-1 Blocker
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The vasodilation by alpha-1 normally results in a reflex tachycardia. Administering Beta-1 blocker concurrently prevents this reflex.
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Isoproterenol vs. Albuterol
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Both are Beta agonists useful for asthma attacks. Isoproterenol (Beta-1=Beta-2) results in bronchodilation (Beta-2) but also cardiac stimulation (Beta-1). This can precipitate an anginal attack. Albuterol is more selective for Beta-2 and can avoid this problem.
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Propranolol
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Beta blocker (Beta-1=Beta-2)
Contraindicated in asthmatics |
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Atenolol
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Cardioselective Beta Blocker (Beta-1 >Beta-2)
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Pindolol
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Partial Beta agonist
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Labetolol
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Adrenergic blocker (Beta-1,2, Alpha-1). Results in BP reduction without tachycardia. It can reverse the effects of alpha and beta agonists.
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Additional effects of Beta-2 blocking
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Inhibition of hepatic gylcogenolysis (and lowered blood sugar)
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Essential Hypertension
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Unknown etiology. Results in organ damage (eye, brain, heart, kidney). Sympatholytics are useful for treatment
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Sympatholytics
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Drugs that decrease sympathetic activity and lower BP.
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Side effects of sympatholytics
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Diarrhea, ejac failure, postural hypotension, etc....
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Methyldopa
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Sympatholytic dopa analog. Converted to methyl-dopamine and methyl-norepinephrine in the catecholamine synthesis pathway. Methyl-NE lowers BP. It is released from the synaptic terminal and binds alpha-2 receptors with the greatest affinity, reducing NE release. (similar mechanism to alpha-2 agonist clonidine). Used for mild/mod hypertension. Lowers BP without reflex tachycardia. Typical sympatholytic side effects plus lactation (dopamine CNS mechanism)
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Clonidine
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Sympatholytic/Alpha-2 agonist used for hypertension. Hypertensive crisis can occur with abrupt cessation (withdrawal). This is a result of downregulated alpha-2 receptors and upregulated alpha-1.
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Guanethidine
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Sympatholytic that is inert. It depletes adrenergic neurons of NE by displacing it from vesicles at nerve terminals. It is more potent that methyldopa or clonidine, with more severe side effects. It does not cross the BBB, so only peripheral effects.
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Metyrosine
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Tyrosine analog that inhibits tyrosine hyroxylase. The result is inhibition of all catecholamine synthesis. Used in inoperable pheochromocytoma.
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Reserpine
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Blocks vesicular monoamine transporter (VMAT) and depletes vessicles of DA, NE, Epi, and 5-HT.
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What drugs are used to produce miosis in optho?
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Alpha-1 blockers (phentolamine) and muscarinic agonist (pilocarpine).
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What drugs are used to produce mydriasis in optho?
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Alpha-1 agonist (phenylephrine) and or muscarinic blocker (atropine)
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Accommodation
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Only under PSP control. Tightening of ciliary muscles round the lens and allow for close vision.
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Cycloplegia
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Paralysis of the ciliary muscle, resulting in loss of accommodation
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Near and far vision with muscarinic blocker (atropine) or muscarinic agonist (pilocarpine)
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Atropine= blurred near vision (cycloplegia)
Pilocarpine= blurred far vision |
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Light reflex
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PSP reflex. Inhibited by muscarinic blockers (atropine)
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How can u tell the difference in mydriasis with an alpha-1 agonist (phenylephrine) and muscarinic blocker (atropine)?
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In addition, atropine produces cycloplegia and absent light reflex
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Horner's syndrome
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Lack of sympathetic activity to the eye = miosis. Accommodation and light reflex are intact (PSP). The same effect can be obtained with an alpha-1 blocker (phentolamine).
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Optho uses for atropine
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Pupil dilation to look at inner eye, fix lens. However, atropine is rarely used because of its long half-life. Pilocarpine (musc agonist) can reverse the effects of atropine.
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Parasympathomimetics used in Optho
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Musc agonist (pilocarpine)
ChE inhibitors (reversible)- physostigmine and neostigmine ChE inhibitors (irreversible)- isofluophate |
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Which is applied to the eye: physostigmine or neostigmine?
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Physostigmine because it is a tertiary amine and easily crosses the membrane.
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What is the treatment for closed angle glaucoma?
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Miotics! This includes pilocarpine (musc agonist) and physostigmine (ChE inhibitor)
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What is the treatment of open angle glaucoma?
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Agents to decrease aqueous production and increase aqueous outflow.
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Parasympathomimetics in the treatment of open angle glaucoma
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Pilocarpine (musc agonist) and physostigmine (ChE inhibitor) lower ICP by increasing aqueous outflow. Contraction of the ciliary muscle increases the porosity of the trabecular network.
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Dorzolamide
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Carbonic Anhydrase inhibitor. It is used in treating open angle glaucoma and reduces the amount of aqueous humor made.
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Beta-blockers used to treat open angle glaucoma?
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Beta blockers decrease the amount of aqueous made through an unknown mechanism.
Timolol (Beta-1=Beta-2) is contraindicated in asthmatics, as it can precipitate an asthmatic attack. Betaxol (Beta-1>Beta-2) has a lower risk. |
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Latanoprost
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PG analog that increases aqueous outflow via uveoscleral path and decreases aqueous formation. Side effects include pigmentation of iris and longer eyelashes.
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Apraclonidine
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Alpha-2 agonist that increases uveoscleral outflow and decreases aqueous formation.
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Marijuana (in open angle glaucoma)
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Lowers ICP through unknown mechanism
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What is the mechanism of Antidepressants?
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Modulate NT function (5-HT, NE, DA) by inhibiting their breakdown or reuptake. This results in elevated cAMP through G proteins and intracellular neuronal repair via CREB and BDNF.
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Time course of antidepressant action
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1-2 weeks: sleep/appetite improve, more calm
3 weeks: energy improves 4-6 weeks: mood improves |
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Classes of antidepressants
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Tricyclic, SSRI's, and Monoamine oxidase inhibitors. Others include mirtazapine and buproprion.
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Amitriptyline
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Tricyclic Antidepressant
Side effects include: sedation (H1/alpha-1 blockade), postural hypotension (alpha-1 blockade), dry mouth/constipation (musc blockade), weight gain, and CARDIOTOXICITY (myocardial depressant--lethal in overdose!!) |
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Fluoxetine
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SSRI.
Side effects include: nausea/diarrhea (5HT3 agonism), Restlessness/insomnia, headache (5HT2 agonism), sexual side effects (anorgasmia and delayed ejaculation--5HT agonism). Safe in overdose. |
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Phenelzine
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MAO inhibitor.
Side effects: postural hypotension (alpha-1 antagonism), insomnia, potentiation with tyramine leading to hypertensive crisis! (can not eat aged cheese or wine) |
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Mirtazapine
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5 HT antagonism increases presynaptic 5HT neurotransmission. Alpha-2 antagonism increases NE outflow. Biggest side effects are sedation and weight gain (no sexual dysfunction, HA, or nausea)
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Buproprion
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Presynaptic NE and DA reuptake inhibitor. No 5-HT effects. Helpful in smoking and ADHD. No weight gain or sexual dysfunction. Side effects are insomnia and upset stomach. Contraindicated in pts with history of seizures!!!!
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Mood Stabilizers
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Treat acute episode of Bipolar Disorder and prevent relapse. Treatment is lifelong. Includes Lithium and Valproate.
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Lithium
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Stabilizes NT's: inhibits NE and DA (excitatory NT's) and enhances 5-HT to aid in depression. Toxic in overdoes and renal excretion. Slow onset (1-3 weeks). Side effects include intention tremor, weight gain, polyuria and polydypsia. Can not be taken with ibuprofen or caffeine.
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Valproate
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Mood stabilizer. Facilitates GABA (inhibitory NT). Quicker onset than Lithium (2-5 days). Lower toxicity risk and hepatic elimination. Weight gain and sedation side effects. Not to be taken with asprin or antacids.
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Serotonin is made from what amino acid?
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Tryptophan.
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5-hydroxytryptophan
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Made from tryptophan by tryptophan hydroxylase (rate limiting step in serotonin synthesis). This enzyme is inhibited by p-chlorophenylamine.
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5-HTP decarboxylase
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Decarboxylates 5-hydroxytryptophan to produce 5-HT (serotonin). This enzyme is similar to AADC.
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Serotonin can be localized to where?
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Enterochromaffin cells, platelets, CNS, pineal gland
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5-hydroxy indole acetic acid (5-HIAA)
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Major metabolic product of serotonin. Results from MAO and aldehyde dehydrogenase action. Low levels of this breakdown product are associated with violent behavior.
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What is melatonin produced from?
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Serotonin via 5-HT N-acetylase and 5-Hydroxyindole-O-methyltransferase.
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What are the effects of Melatonin?
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Skin pigment lightening, ovulation suppression, sleep control (released in the evening). Possible use in insomnia, jet lag, and sleep disorders.
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5-HT receptors
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Most are G-protein coupled, except 5-HT3 which is a Na+ ionophore.
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Ecstasy (MDMA)
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Indirect 5-HT agonist, causes 5-HT release. It can deplete the cell of 5-HT and cause neuronal loss. Consequences of this can show up much later in life.
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Mescaline and Psilocybin
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5-HT agonists that cause hallucinations.
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Histamine: neural and non-neural roles?
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Non-neural: gastric acid secretion and immune response to allergens.
Neural: found in tuberomamillary nucleus of hypothalamus. |
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Histamine is made from....?
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The amino acid histidine by histidine decarboxylase.
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Major histamine receptors
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H1: Bronchoconstriction (anti-histamines produce bronchodilation)
H2: Gastric acid secretion (H2 blockers reduce) |
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Histamine results in what systemic effects?
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Hypotension and Bronchoconstriction.
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H1 antagonists have what CNS effect?
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Sedation
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GABA
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Major inhibitory NT. It is implicated in epilepsy, schizophrenia, tardive dyskinesia, Huntington's, etc....
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GABA metabolism
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GABA is linked to the Kreb's cycle. It is produced by glutamic acid decarboxylase (GAD--the rate-limiting step). Glial cells participate in GABA metabolism and recycling. GABA transaminase is responsible for breaking down GABA.
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GABA-A receptor
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Inhibitory Chloride channel. It opens and causes hyperpolarization of the membrane (inhibitory). Benzodiazepines and Barbiturates are GABA-A agonists.
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Picrotoxin
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Non-competitive GABA-A inhibitor. It is a convulsant but can be used as an antidote for barbiturate poisoning.
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GABA-B receptor
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GABA autoreceptor. Baclofen is an agonist and acts as a muscle relaxant.
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Diversity of GABA-A receptors
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Very large diversity. Alcohol can change the subunit structure, and stimulates some GABA receptors.
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Gammahydroxybuturate (GHB)
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Breakdown product of GABA. It is a street drug with toxicity of coma, seizures, vomiting, respiratory depression, and amnesia.
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Glycine
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The major inhibitory NT of the brain stem and spinal cord, especially short axon interneurons.
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Glycine is synthesized from?
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Serine
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Glycine receptor
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Chloride ion channel (inhibitory)
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Strychnine
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Glycine receptor antagonist and convulsant
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Human Startle Disease (Hereditary hyperekplexia)
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Glycine receptor mutation results in under inhibition and exaggerated reflexes.
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Benzodiazepines
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Most end in "azepam." They cross the BBB and bind the GABA-A receptor, potentiating GABA. Used as an anxiolytic, but long term use is discouraged because of tolerance and dependence.
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Clinical uses of Benzodiazepines
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Calming and anxiety reduction (sedation), muscle relaxation, sleep induction (hypnosis), anesthesia adjunct. Diazepam is an anti-convulsant.
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Benzodiazepine metabolism/excretion
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Liver and Kidney, respectively. Some metabolites are also sedative and hypnotic.
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Side effects of Benzodiazepines
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Psychomotor and cognitive depression, impaired judgement, retrograde amnesia, loss of self-control. Respiratory depression usually not life threatening unless combined with alcohol or barbiturates. Contraindicated in pregnancy.
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Flumazenil
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Benzodiazepine antagonist, used to treat overdose.
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SSRI and SSNI
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(e.g. paroxetine and sertroline)
Used for generalized anxiety disorder, PTSD, panic disorder, OCD, social phobia. |
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Buspirone
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Partial 5HT1A agonist. Down regulates the presynaptic autoreceptor.
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Strychinine
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Convulsant stimulant. Glycine receptor antagonist with strong spinal cord effects. It results in CNS excitation and hyperreflexia to stimulii, tonic extension of body and limbs, convulsions, respiratory impairment, postictal depression, hypoxia, and death. No clinical use. A central depressant (e.g diazepam) can be used to control convulsions. Important to give respiratory support.
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Picrotoxin
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Convulsant stimulant. GABA-A antagonist. Results in CNS excitation. Formerly used to treat CNS depressant overdose. Toxicity results in convulsions, coma, and death. Treat with central depressant (diazepam) and with respiratory support.
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Metrazole
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Convulsant stimulant. Blocks GABA-A receptor, especially in brain. Results in CNS excitation. Used to activate EEG during seizure DDx and for drug screening anticonvulsants. Treat toxicity with diazepam and respiratory support.
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Xanthines
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Includes caffeine, theophylline, and theobromine. Found in coffee, tea, soda, and chocolate. They block the inhibitory adenosine A1 and A2 receptors, raising intracellular calcium and cAMP. They are mood stimulants and produce alertness, reduction of fatigue, bronchial relaxation, increased gastic acid secretion, and diuresis. High dose results in increased HR/BP, nausea, nervousness, insomnia, tremors, and hyperesthesia.
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Clinical use of xanthines
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Bronchodilator (theophylline), apnea in premature infants, headache/migraine.
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Toxicity of Xanthines
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Rare. Results in delirium, emesis, convulsions, tachycardia, arrhythmia, Treat with anticonvulsant (diazepam).
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Amphetamines
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Stimulate DA and NE release and block reuptake. The effects is sympathomimetic, euphoria, insomnia, appetite reduction, increased BP and bradycardia, resp. stimulation. Psychosis with chronic use.
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Benzedrine
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Amphetamine: L + D isomers
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Dexedrine
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Amphetamine: Potent D isomer
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Metamphetamine (methedrine)
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Amphetamine with potent CNS effects.
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Clinical use of amphetamines
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Narcolepsy, ADHD, obesity
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Acute toxicity of amphetamines
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Hyperactivity, tremor, sweating, anorexia, convulsions, anginal pain, hypertension, arrhythmia, coma. Fatigue and depression follow.
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Chronic toxicity of amphetamines
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Psychosis, motor stereotypy, necrotizing arteritis (with resulting brain hemmorhage or renal failure).
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Treatment of amphetamine toxicity
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Dopmaine antagonists, Alpha- antagonists, acidification of urine.
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Methylphenidate
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Amphetamine-related compound. Used to treat ADHD.
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Ephedrines
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Amphetamine-related compounds. Phenylephrine and Pseudoephedrine are used to treat nasal congestion, combined with antihistamines to offset sedating effect.
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Nicotine
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Increases DA release at nucleus accumbens producing euphoria. Increased NE/Epi release is stimulatory. Can also have calming effect via desensitization of receptors. Effects include alertness, euphoria, muscle relaxation, appetite reduction, transient increase in HR, BP, and HR, increased GI motility. Toxicity includes tremor, convulsions, CNS depression, respiratory failure, and emesis.
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Nicotine use in Alzheimers and Schizhophrenia/Parkinson's
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Self-medication to compensate for cholinergic and dopaminergic loss, respectively???
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Glutamate
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Major excitatory NT in the brain. Gial cells collaborate in recycling.
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Glu receptors
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Either ionotropic or G-protein-coupled. Three families of ionotropic: AMPA, Kainate, and NMDA.
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AMPA receptor
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Glu ionotropic receptor. Allows for inward Na and outward K flow. Also permeable to Ca and can trigger apoptosis.
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Kainate receptor
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Glu ionotropic receptor. High levels of Kainic acid kills neurons by excessive excitation and induces status epilepticus. Some neuro-active endogenous steroids are protective against KA-induced seizures.
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NMDA receptor
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Glu ionotropic receptor. Voltage sensitive--membrane desensitization displaces Mg2+ ions in the channel making it permeable to inward Na and Ca flow and outward K flow. Glycine is an essential co-agonist.
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Phencyclidine (PCP)
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Competes with regulatory Mg2+ binding site of NMDA receptor. Results in delusions, hallucinations, and cognitive defects.
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Excitotoxicity
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Results when toxic levels of Ca2+ enters the cells triggering apoptosis. NMDA antagonists and Ca2+ blockers are protective.
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Red tide
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Dinoflagellates produce NMDA agonists that are neurotoxins (excitotoxicity).
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Important role of NMDA receptor.
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Synaptic plasticity and memory consolidation. NMDA receptors are sensitive to alcohol.
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Opiates
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Morphine derivatives with analgesic activity.
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Endogenous opiates
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Includes enkaphalins, endorphins, and dynorphins. These peptides results from cutting larger precursors.
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Opiod receptors
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Include mu, kappa, and delta. Mu has the most important role in supraspinal analgesia. Agonists are analgesic and respiratory depressants.
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Substance-P
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A tachykinin involved in pain pathways. Modulation of this neuropeptide is involved in inhibiting pain pathways.
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Anandamide
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Endogenous cannabinoid. THC in marijuana binds its receptor. It is synthesized from arachidonic acid.
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PGE
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Acts at NE neurons and is synthesized in response to neural overstimulation. It can interfere with calcium availability for NE release.
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Nitric Oxide (NO)
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Free radical diffusable gas. Made from arginine. Induces guanyl-cyclase, increasing cGMP.
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Precursors of beta-endorphin, dynorphins, and enkephalins.
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POMC results in Beta-endorphin. Preprodynorphin results in dynorphins. The above two plus preproenkephalin produces met/leu-enkephalins
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Oral absorption of opiods
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Varies by drug: methadone, codeine, and oxycodone are the best. Morphine has poor oral availability.
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Pro-drugs of morphine
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Heroin and Codeine. They pass the BBB better.
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Mu receptor
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Opiod receptor most responsible for analgesia, euphoria, and respiratory depression.
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Kappa and Delta receptors
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Opiod receptors that are best for spinal analgesia.
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Mechanism of opiods
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Are G-protein coupled and lower cAMP. Inhibit voltage gated Ca2+ channels in presynaptic pain neurons, open K+ channels post-synaptically (hyperpolarize) in dorsal horn neurons. Mu receptors in the CNS actually increase dopaminergic firing, producing euphoria.
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Opiods effects on Cardio
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Orthostatic hypotension from histamine release and vasomotor center depression.
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Opiods effects on Renal
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Depressed renal function, elevated ADH release (water retention)
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Opiods effects on GI
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Constipation and anti-diarrheal (no tolerance)
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Opiods effects on Respiratory
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Bronchoconstriction from histamine release. Also depression of respiratory drive. Note: direct application of opiods to lungs actually causes bronchodilation.
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Opiods and histamine
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Cause histamine release from mast cells by interrupting the interaction between histamine and heparin.
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Opiods effects on skin
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Vasodilation, flushing, itching/urticaria (histamine release)
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Opiods effects on CNS
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Analgesia (better for dull pain), sedation, euphoria, nausea, vomiting, anti-tussive, convulsions, miosis (no tolerance), dizziness, respiratory depression!! (most common cause of death in toxicity)
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Morphine
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Opiod. Mostly given IV (poor oral availability). Used for severe pain. Long duration of action partly due to active metabolite morphine 6 glucuronide.
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Codeine
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Opiod. Good oral availability. Less potent than morphine, not for severe pain. Often combined with NSAID's. Has strong anti-tussive properties. High abuse potential
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Heroin
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Opiod. More potent than morphine. Has strong CNS effects because it is lipid soluble and easily penetrates BBB.
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Methadone
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Opiod. Partial mu agonist. Less efficacy than morphine. Good oral availability and useful for treating opiate dependence.
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Meperidine
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Opiod. Orally effective, but short duration. Useful for acute severe pain (like labor). It is also anticholinergic so contraindicated in tachycardic patients and patients on SSRI's or MAOI. It is not useful for cough, does not cause constipation, and does not result in miosis (because anticholinergic).
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Fentanyl
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Opiod. Very potent and short duration. Lipid soluble and large volume of distribution. Useful for anesthesia because of fast induction and emergence. Intrathecal, epidural, and transdermal applications are used for severe chronic pain.
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Propoxyphene
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Similar to codeine-- orally active but less effective. Not helpful for cough. High abuse potential.
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Mixed opiod drugs
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They are full agonists at kappa receptor but antagonists or partial agonists at mu receptor. This means less abuse potential and less side effects.
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Butorphanol
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Mixed opiod. Very lose abuse potential. More use = more antagonism of mu. More potent but less effective than morphine. Sometimes associated with hallucinations (kappa mediated)
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Pentazocine
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Mixed opiod. Low abuse potential. High does can cause increase in BP. Less respiratory depression than morphine in overdose. Sometimes associated with hallucinations
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Buprenorphine
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Mixed opiod. Potent and long acting--slow to dissociate from mu receptor. Some abuse potential. Less respiratory depression in overdose than morphine.
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Loperamide
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Special use opiod. Used for anti-diarrheal property. Very little crosses BBB so minimal analgesia, CNS effects, or abuse potential.
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Dextromethorphan
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Special use opiod. Low affinity for mu receptor. Primarily a Glu receptor antagonist. Used for antitussive property. No analgesia or respiratory depression. Low abuse potential.
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Acute opiod toxicity treatment
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IV naloxone and respiratory support
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Contraindications of opiods
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Do not mix opiods
Avoid use with head injury-can raise ICP. Pregnancy Impaired lung function Don't combine with other depressants-can potentiate respiratory depression. |
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Narcotic antagonists
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Block mu receptor. Have little effect in absence of opiod (little endogenous tonus). Reverses morphine effects in 1-3 minutes, withdrawal seen immediately. Penetrate BBB. No tolerance or withdrawal.
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Naloxone
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Opiod antagonist. Low oral availability. Short action (1-2 hours) via IV. Used in acute opiod overdose--may have to repeat dosing.
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Nalmafene
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Similar to naloxone (must be given IV), but long duration. Avoids possible need to repeat dose.
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Naltrexone
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Opiod antagonist. Oral availability and long duration. Maintenance drug for recovering addicts.
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Dopamine Hypothesis of Schizophrenia
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Schizophrenia is a hyperdopaminergic pathology. Amphetamine, which stimulates release and blocks reuptake of DA, can cause schizophrenic symptoms. DA receptor antagonists are therapeutic. However, no evidence of elevated DA in schizophrenic brains.
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Antipsychotic characteristics
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Low bio availability. Lipophillic and cross BBB easily. High volume of distribution and much longer therapeutic half life than plasma half life.
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Important DA projections
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Nigro-striatal
Mesolimbic Mesocortical-output to prefrontal and anterior cingulate cortex (target in schizo?) DA system in hypothalamus inhibits prolactin release. |
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Typical Antipsychotics
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Are for acute use only, not maintenence
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Chlorpromazine and Thioridazine
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Low potency (high dose) typical antipsychotics. Low extrapyramidal side effects, but high anticholinergic, cardiovasuclar, and sedative effects.
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Fluphenazine and Haloperidol
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High potency (low dose) typical antipsychotics. High risk of extrapyramidal effects but low anticholinergic, cardiovascular, and sedative effects.
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Side effects of typical antipsychotics:
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Anticholinergic: blurred near vision, dry mouth, urinary retention, confusion, constipation, tachycardia, sexual arousal difficulty
Anti-alpha-adrenergic: postural hypotension, ejaculatory dysfunction Anti-dopamine: extrapyramidal symptoms, lactation, amenorrhea. |
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Atypical antipsychotics
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These are newer drugs and are the maintenance drug of choice. They also block serotonin receptors. Less side effects than typicals. Clozapine has risk of agranulocytosis and infection.
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Clozapine, risperidone, olanzapine
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Atypical antipsychotics. Clozapine is selective for D4 and has risk of agranulocytosis.
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Extrapyramidal symptoms of antipsychotics
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Dystonic reaction and Parkinson's (treat by discontinuing drug and administering anticholinergic), akathisia(motor restlessness), tardive dyskinesia (increase antipsychotic dose--this symptom due to upregulation of dopamine receptors)
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Sedative-hypnotics
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Produce dose-dependent CNS depression. Either increase inhibitory neurotransmission (GABA) or block stimulant NT's.
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Ethanol
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Potentiates GABA-A receptor. Acute effects include pardoxical excitation, sedation, ataxia, diuresis, gastric acid secretion. High doses can produce cardio and resp depression, coma, and death. Chronic effects include Karsakoff syndrome (amnesia from thiamine def), psychological and physical dependence ,etc. Withdrawal can produce seizures, psychosis, and delirium tremens.
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Ethanol metabolism
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Converted to acetylaldehyde by alcohol dehydrogenase by zero order kinetics. Acetylaldehyde dehydrogenase converts to acetate.
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Clinical uses of ethanol
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Solvent, disinfectant, inject into trigeminal ganglia in neuralgia, methanol poisoning (outcompetes for alcohol dehydrogenase).
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Disulfiram
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Inhibits acetylaldehyde dehydrogenase. Used to treat chronic alcoholism.
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Barbiturates
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End in "barbital." They prolong the GABA-induced chloride channel opening, reduce glutamate depolarization at AMPA receptors, and depress voltage-gated sodium and calcium channels. Effects range from mild sedation to general anesthsia. Phenobarbital is an anticonvulsant.
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Other effects of barbiturates
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Anxiolytic and euphoric (some), increase in sleep but daytime drowsiness, tolerance to other sedative-hypnotics, resp depression, potentiation by alcohol, MAOI, and antihistamines.
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Clinical use of barbiturates:
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Emergency convulsion treatment (phenobarbital), short IV anesthetic (thiopental), amobarbital infusion to determine dominant hemisphere, neonatal hyperbilirubinemia.
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Barbiturate toxicity
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Resp depression, hypoxia, coma, hypotension, renal failure.
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