Pharmacology Chapter 4 PDF

Pharmacology Chapter 4 Lecture Preview § Principles of Psychopharmacology § Sites of Drug Action § Neurotransmitters and Neuromodulators Are all drugs equally addictive? • Nope • Features that make a drugs and drug use more or less addictive 1. Level of reward system stimulation • 2. 3. 4. A...

Pharmacology Chapter 4 Lecture Preview § Principles of Psychopharmacology § Sites of Drug Action § Neurotransmitters and Neuromodulators Are all drugs equally addictive? • Nope • Features that make a drugs and drug use more or less addictive 1. Level of reward system stimulation • 2. 3. 4. All drugs of abuse stimulate the reward system as a final common pathway. Rate of entry into the blood Peak blood concentration of drug Rate of clearance from body Opiates and Opioids • Opiates are derived from the poppy plant – – – – Opium Morphine Heroin 2-5 x potency of Morphine Codeine 1/10th the potency of Morphine • Opioids are synthetic drugs that are similar to, and often far more powerful than Opiates – – – – – Hydrocodone 2/3rd potency of Morphine Oxycodone 1.5-2 x potency of Morphine Hydromorphone 5 x potency of Morphine Methadone 5-10 x potency of Morphine Fentanyl 100-150 x potency of Morphine The Opioid Epidemic • • • • • • Not the 1st but different Pain was under treated Purdue Pharma to the rescue Purdue Parma to the rescue again Heroin returns Fentanyl Have we learned our lesson? Does this make sense to you? Principles of Psychopharmacology § Pharmacokinetics – The process by which drugs are absorbed, distributed within the body, metabolized, and excreted. – Routes of Administration • Intravenous (IV) Injection – injection of a substance directly into a vein. • Intraperitoneal (IP) Injection – injection of a substance into the peritoneal cavity, the space that surrounds the stomach, intestines, liver, and other abdominal organs. Principles of Psychopharmacology (Continued) • Intramuscular (IM) Injection – injection of a substance into a muscle. • Subcutaneous (SC) Injection – injection of a substance into the space beneath the skin. • Oral Administration – administration of a substance into the mouth so that it is swallowed. • Sublingual Administration – administration of a substance by placing it beneath the tongue. • Intra-rectal Administration – administration of a substance into the rectum. • Inhalation – administration of a vaporous substance into the lungs. Principles of Psychopharmacology (Continued) • Topical Administration – administration of a substance directly onto the skin • Intranasal – “snorting” substance or spraying substance into nasal cavities Methods used in Animal Research • Intracerebral Administration – administration of a substance directly into the brain. • Intracerebroventricular (ICV) Administration – administration of a substance into one of the cerebral ventricles. Same substance administered in 4 different ways Principles of Psychopharmacology (Continued) § Drug Effectiveness – Dose-Response Curve – a graph of the magnitude of an effect of a drug as a function of the amount of drug administered. – Many drugs have more than one effect, which should be taken into consideration when determining the effect dose for treatment. Figure 4.3 A Dose-Response Curve Figure 4.4 Dose-Response Curves for Morphine Principles of Psychopharmacology (Continued) – Therapeutic Index – the ratio between the dose that produces the harmful effect in 50% of the animals and the dose that produces desirable effects in 50% of the animals. Principles of Psychopharmacology (Continued) § Effects of Repeated Administration – Tolerance – a decrease in the effectiveness of a drug that is administered repeatedly. Principles of Psychopharmacology (Continued) – Sensitization – an increase in the effectiveness of a drug that is administered repeatedly. – Withdrawal Symptom – the appearance of symptoms opposite to those produced by a drug when the drug is administered repeatedly and then suddenly no longer taken. § Placebo Effects – An inert substance that is given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug. Sites of Drug Action § Antagonist – A drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell. § Agonist – A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell. Sites of Drug Action (Continued) § Effects on Production of Neurotransmitters – Drugs may exert their agonistic or antagonistic effects by influencing the production of neurotransmitters. § Effects on Storage and Release of Neurotransmitters – Drugs may exert their agonistic or antagonistic effects by influencing the storage and release of neurotransmitters. Figure 4.5 Drug Affects on Synaptic Transmission Sites of Drug Action (Continued) § Effects on Receptors – Drugs may exert their agonistic or antagonistic effects by influencing receptors. – Activate Receptor – Block Receptor – Direct (competitive) vs Indirect (non-competitive) action – Partial vs. Full – Affinity Figure 4.6 Drug Actions at Binding Sites Sites of Drug Action (Continued) Neurotransmitters and Neuromodulators (Continued) § Acetylcholine – Primary neurotransmitter secreted by efferent axons of the PNS. – Major concentrations of ACh in the CNS include: • Dorsolateral Pons (role in REM sleep) • Basal Forebrain (role in learning) • Medial Septum (role in memory) Neurotransmitters and Neuromodulators (Continued) – Botulinum Toxin – an ACh antagonist; prevents release by terminal buttons. – Black Widow Spider Venom – a poison produced by the black widow spider that triggers the release of acetylcholine. – Hemicholinium – a drug that inhibits the uptake of choline. – Neostigmine – a drug that inhibits the activity of acetylcholinesterase. Neurotransmitters and Neuromodulators (Continued) – Nicotinic ACh Receptor – an ionotripic ACh receptor that is stimulated by nicotine and blocked by curare. – Muscarinic ACh Receptor – a metabotropic ACh receptor that is stimulated by muscarine and blocked by atropine. Neurotransmitters and Neuromodulators (Continued) § The Monoamines – A class of amines that includes indolamine, such as serotonin; and catecholamines, such as dopamine, norepinephrine, and epinephrine. • Catecholamines 1. Dopamine 2. Norepinepherine 3. Epinepherine (Adrenaline) Neurotransmitters and Neuromodulators (Continued) – Dopamine • A catecholamine synthesized from L-DOPA. • Major CNS dopaminergic systems include: – Nigrostriatal System (role in movement) » Dopamine produced in substantia niagra and sent to the basal ganglia (aka striatum) – Mesolimbic System (role in reinforcement/reward) » Dopamine produced in Ventral Tegmental Area and sent to the nucleus accumbens. – Mesocortical System (role in short-term memory, planning, and problem solving) » Dopamine produced in the VTA and sent to the frontal cortex. • Dopaminergic Drugs – Amphetamine, Methamphetamine, cocaine. (but all drugs of abuse eventually agonize dopamine neurons) – Methylphenidate – a drug that inhibits the reuptake of dopamine. – Monoamine Oxidase (MAO) – a class of enzymes that destroy the monoamines. – Deprenyl – a drug that blocks the activity of MAO-B; acts as a dopamine agonist. – Chlorpromazine – a drug that reduces the symptoms of schizophrenia by blocking dopamine D2 receptors. Figure 4.15 Role of Monoamine Oxidase Neurotransmitters and Neuromodulators (Continued) – Norepinephrine (and Epinephrine) • Norepinephrine – one of the catecholamines; a neurotransmitter found in the brain and in the sympathetic division of the ANS. • Epinephrine – one of the catecholamines; a hormone secreted by the adrenal medulla; serves also as a neurotransmitter in the brain. – Adrenergic Drugs • Moclobemide (Depranil) – a drug that blocks the activity of MAO-A; acts as a noradrenergic agonist. • Beta Blockers – block a Beta 1 and 2 receptors, reducing the effects of norepinephrine and epinephrine in the periphery. Neurotransmitters and Neuromodulators (Continued) • Norepinepherine produced in the Locus Coeruleus – a darkcolored group of noradrenergic cell bodies located in the pons near the rostral end of the floor of the fourth ventricle. Neurotransmitters and Neuromodulators (Continued) – Indolamines: Serotonin and Melatonin – Serotonin • An indolamine neurotransmitter; also called 5hydroxytryptamine. • Regulates –Mood –Appetite –Sleep Neurotransmitters and Neuromodulators • PCPA – a drug that inhibits the activity of tryptophan hydroxylase and thus interferes with the synthesis of 5-HT. • Fluoxetine (Prozac) – a drug that inhibits the reuptake of 5-HT. • Fenfluramine – a drug that stimulates the release of 5-HT. • MDMA – a drug that serves as a dopaminergic and serotonergic agonist, also known as “ecstasy”; has excitatory and hallucinogenic effects. • Produced in the Raphe Nuclei • Psychedelic drugs universally agonize the serotonin system • “Different” than other drugs Antidepressants Through the Generations • Tricyclic antidepressants (1950s) – – – – Blocks reuptake of serotonin and norepinephrine Blocks muscarinic Ach receptors Blocks histamine receptors EKG changes • Monoamine oxidase inhibitor (MAO-I) (1970’s) – Non-selectively increases levels of the monoamine neurotransmitters. • Selective Serotonin Reuptake Inhibitor (SSRI) (1990’s) – Greatest action is in slowing reuptake of serotonin • Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) (1990’s-2000’s) – Inhibits reuptake of serotonin and norepinephrine • Norepinephrine Reuptake Inhibitor (NRI) (2000’s) – Inhibits reuptake of norepinephrine Histamine • Highly arousing neurotransmitter • Major component of the allergic response Non-Drowsy antihistamines? Neurotransmitters and Neuromodulators (Continued) § Excitation and Inhibition In Balance § Glutamate primary excitatory neurotransmitter § Gamma-Aminobutyric Acid (GABA) primary inhibitory neurotransmitter § Balance is key § Too much glutamate can lead to seizures, excitotoxicity and brain death § Too much GABA can lead to unresponsiveness, coma and death – Glutamate • An amino acid; the most important excitatory neurotransmitter in the brain. • NMDA Receptor – a specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; has several other binding sites. • AMPA Receptor – an ionotropic glutamate receptor that controls a sodium channel; stimulated by AMPA. Learning at the Cellular Level • Long Term Potentiation (LTP) • Long Term Depression (LTD) Figure 4.19 NMDA Receptor Neurotransmitters and Neuromodulators (Continued) • AP5 – a drug that blocks the glutamate binding site on NMDA receptors. • PCP – phencyclidine; a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist. Neurotransmitters and Neuromodulators (Continued) • Gamma-Aminobutyric Acid (GABA) – An amino acid; the most important inhibitory neurotransmitter in the brain. Produced from glutamic acid by the action of an enzyme called GAD. • Benzodiazepine – a category of anxiolytic drugs; an indirect agonist for the GABAA receptor. – Anxiolytic – an anxietyreducing effect. – Xanax, Ativan, Valium, Klonopin, Neurotransmitters and Neuromodulators (Continued) • Adenosine – a nucleoside; a combination of ribose and adenine; serves as a neuromodulator in the brain. – Caffeine – a drug that blocks adenosine receptors. – – – – – – Coffee 85mg per 5 oz (decaf still has 3 mg per 5 oz) Tea (3 min steep) 28 mg/5 oz Hot Chocolate 30 mg/5 oz Cola 30-45/12 oz Baking chocolate 36 mg/oz Milk Chocolate 6mg/oz