Drugs Affecting the Central Nervous System

1. Drugs Affecting the Central Nervous System

2. Disease states of Central Nervous System • Typically caused by too much, or too little neurotransmission • Too much • Hyperexcitable neurons fire in absence of stimuli (e.g. seizure disorders) • Too many neurotransmitter molecules binding to post-synapse receptors • psychoses

3. Too little • Too few neurotransmitters binding to post-synapse receptors

4. Major Parts of the Brain • Cerebrum • Brainstem • Cerebellum

5. Cerebrum • Largest and uppermost part of the brain • Divided into right and left hemispheres • Controls all the higher intellectual and motor functions of the body • Cerebrum composed of an outer cortex and an inner medulla

6. Cerebral Cortex • Contains neuronal cell bodies (gray matter) that control all voluntary activities of the body • Divided up into 4 lobes: frontal, parietal, temporal, and occipital, each controlling specific brain functions • Electroencephalogram (EEG) is a recording of the electrical activity of the cortex

7. Cerebral Medulla • Referred to as the “white matter” and is composed of myelinated nerve axons • Functions to conduct nerve impulses to and from different parts of the nervous system • Basal ganglia are neuronal cell bodies (gray matter) located within the cerebral medulla that function in the regulation of motor activity

8. Brainstem and Spinal Cord • Located below the cerebrum and is continuous with the spinal cord • Brainstem divided into the thalamus, hypothalamus, pons, and medulla oblongata • Spinal cord is a collection of all the sensory and motor nerves going to and from the brain

9. Reticular Formation • A network of nerves and brain areas involved in regulating alertness, wakefulness, and sleep • Composed of both inhibitory and excitatory nerves • Excitatory nerves collectively referred to as the reticular activating system (RAS) • Many stimulants (amphetamines) and depressants (alcohol, barbiturates) affect the RAS

10. Limbic System • Network of nerves and brain areas involved in emotional and behavioral responses • Associated with emotional responses to fear, anger, anxiety, sexual behavior, and reward and punishment • Affected by drugs of abuse and involved in the development of drug dependency

11. Neurotransmitters

12. Norepinephrine • Adrenergic hormone released at the effector organ by sympathetic neurons • Monamine • Depression thought be caused by impaired monoamine transmission • Drugs that stimulate monoamine release are indicated for ADD or narcolepsy

13. Dopamine • Another monoamine derived from the amino acid tyrosine • Binds dopamine receptors (D1 or D2) • Antipsychotics prevent signals activated by dopamine binding • Parkinson’s disease also caused by altered dopamine binding

14. Serotonin (5-HT) • Monoamine hormone derived from the amino acid tryptophan • Typically released by inhibitory neurons • Lysergic acid diethylamide binds to serotonin receptors • Depression, ADD and headaches associated with serotonin imbalance

15. Gamma-amino butyric acid (GABA) • Inhibitory neurotransmitter of the brain and central nervous system • Synthesized from the amino acid glutamate • Cause Ca2+ influx into the neuron resulting in hyperpolarization • More difficult to excite • Benzodiazepines and barbituates enhance GABA effects

16. Excitatory Amino Acids • Amino acid glutamate or structurally related chemicals • Important for learning and memory • Abnormal increased activity will result in toxicity • Alzheimers, ALS, stroke, Huntington’s

17. Antidepressants

18. Mental Depression • Exogenous or reactive depression usually occurs in response to some external factor or adverse life event • Endogenous depression usually originates from within the psyche of the individual and the causes are less well understood • Bipolar mood disorder involves alternating cycles of depression and mania

19. Causes of Mental Depression • Exact causes not well understood • Mental depression appears to involve the development of low levels of the brain monoamine neurotransmitters, serotonin (SER) and norepinephrine (NE) • This explanation is referred to as the “Monoamine Theory of Mental Depression”

20. Treatment of Depression • Treatment involves a combination of psychotherapy and antidepressant drugs • Antidepressant drugs act to increase NE and SER levels in the brain • Tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRI) are the two most important antidepressant drug classes • Monoamine oxidase inhibitors (MAOI) are less frequently used and require dietary restriction

21. Monoamine Oxidase Inhibitors (MAOI) • Monoamine oxidase is the enzyme that metabolizes the monoamines NE and SER • Inhibition of MAO increases SER and NE levels and functional activity in the brain • Requires 2–4 weeks for maximum effects • Foods containing tyramine must be avoided • Tyramine stimulates the release of NE and may cause a hypertensive crisis • MAOIs are indicated for patients who cannot tolerate TCAs and SSRIs

22. Tricyclic Antidepressants (TCA) • Mechanism of action of TCAs is to block reuptake of NE and SER into nerve endings • Blockage of reuptake increases NE and SER levels and stimulation of NE and SER receptors • Requires 2–4 weeks for maximum effect • TCAs are divided into secondary amines which increase NE more than SER and are less sedating than tertiary amines which increase SER more than NE

23. Autonomic Effects of TCAs • TCAs possess anticholinergic activity which can cause dry mouth, visual disturbances, constipation, and urinary retention • TCAs also possess alpha blocking activity that can lower blood pressure • TCAs can also affect cardiac rhythm and may cause cardiac arrhythmias

24. Selective Serotonin Reuptake Inhibitors (SSRI) • Selectively block the reuptake of SER • Cause little if any anticholinergic and alpha blocking effects • Are generally not sedating, and in some cases cause CNS stimulation • Common adverse effects include nausea, agitation, restlessness, and less frequently seizures

25. Psychomotor Stimulants • Generally referred to as the amphetamines • Produce CNS stimulation more than an antidepressant effect, little used for depression • Act by increasing NE and DA activity • Clinical use for narcolepsy and treatment of hyperkinetic children • Amphetamines have a high abuse potential • Adverse effects due to excessive CNS and autonomic stimulation

26. Lithium • Lithium is an elemental ion similar to sodium • Acts to depress nerve excitability that helps prevent mood swings and manic behavior • Common adverse effects include nausea, diarrhea, tremors, increased thirst, ringing in the ears (tinnitis), and more seriously kidney and heart damage • Periodic blood levels to prevent overdosage

28. Sedatives and Hypnotics • Sedatives are drugs used to induce a mild state of CNS depression characterized by both mental and physical calmness • Hypnotics are drugs used to induce and maintain sleep • The same drugs are used to induce both sedation and hypnosis; however, the dosage for inducing sedation is lower

29. Classification of Sedative- Hypnotic Drugs • Barbiturates – a drug family of chemically similar drugs with similar actions and features • Benzodiazepines – a drug family of chemically similar drugs with similar actions and features • Miscellaneous nonbarbiturates – a group of drugs with dissimilar chemical structures and pharmacologic features

30. Pharmacology of Barbiturates • Drugs classified as short, intermediate, and long-acting sedative-hypnotics • At low doses they increase the inhibitory effects of GABA • At high doses they act like general anesthetics, and can cause profound CNS depression and death in overdosage • Barbiturates are also anticonvulsants

31. Effects of Barbiturates on the Sleep Cycle • Decrease stage 1, falling asleep • Increase stage 2, a lighter stage of sleep • Decrease stages 3 and 4 referred to as deep sleep or slow-wave sleep • Decrease REM sleep, and may cause REM rebound

32. Adverse Features of Barbiturates • Cause drug tolerance with chronic use and drug dependency with abuse • Can cause a severe type of physical drug addiction when chronically abused • The withdrawal reaction from barbiturates can be serious, resulting in convulsions and death • Drug interactions, induce microsomal enzymes to increase the rate of drug metabolism of all drugs metabolized by the microsomal enzymes

33. Pharmacology of Benzodiazepines • Drugs classified as short, intermediate, and long-acting sedative-hypnotics • Drugs also produce antianxiety, skeletal muscle relaxing, and anticonvulsant effects • Act by increasing the inhibitory effects of GABA • Drugs do not induce the drug metabolizing microsomal enzymes

34. Effect of Benzodiazepines on the Sleep Cycle • Decrease stage 1, falling asleep • Increase stage 2 • Decrease stages 3 and 4 • Do not significantly decrease REM sleep • Benzodiazepines are considered safer drugs than the barbiturates, especially in overdosage

35. Miscellaneous Nonbarbiturates • Zolpidem and zaleplon are short-acting hypnotics that do not disrupt the sleep cycle • These drugs increase the inhibitory effects of GABA but differently than other drugs • Both drugs are considered to be safer than other hypnotics and are at low risk for abuse • Side effects include dizziness, headache, GI disturbances, and mental confusion

36. Alcohol • Classified as a CNS depressant drug • Unlike other drugs, alcohol provides nutritional calories • Like other drugs of abuse, alcohol causes development of drug tolerance, dependency, and withdrawal reactions • Most of the pharmacology of alcohol centers around its chronic use, abuse, and toxicology

37. Disulfiram • Used to treat alcoholism and deter drinking • Disulfiram inhibits metabolism of alcohol, allowing acetaldehyde to accumulate • Increased acetaldehyde produces severe nausea, vomiting, headache, and hypotension • Alcoholics take the drug on a daily basis, knowing that if they drink any alcohol they will become violently ill

39. Parkinson’s Disease • A neurological movement disorder of the brain involving the basal ganglia • Symptoms include tremor, muscular rigidity, and disturbances of movement • Major cause is a deficiency of the inhibitory neurotransmitter dopamine (DA) and the resulting excessive activity of the excitatory neurotransmitter acetylcholine (ACH)

40. Drug Therapy • Primary therapy is the administration of drugs that increase the levels of DA in the basal ganglia • Secondary therapy is the administration of anticholinergic drugs that decrease ACH activity in the basal ganglia • Goal is to restore the balance between DA and ACH activity

41. Drugs that Increase Dopamine • Levodopa • Dopamine agonists • Amantadine • Enzyme inhibiting drugs that slow the metabolic breakdown of dopamine

42. Levodopa • The precursor of DA that is taken orally and converted into DA in the basal ganglia • Administered in combination with carbidopa that increases the amount of DA that enters the brain • Levodopa and carbidopa drug combination known as Sinemet • Levodopa is considered the most effectivedrug for the treatment of Parkinson’s disease

43. Adverse Effects of Levodopa • Nausea, vomiting, and loss of appetite • Hypotension, and rapid/irregular heart rate • Dystonias, slow or weak movements that usually occur when levels of DA are low • Dyskinesias, uncontrolled or involuntary movements when DA levels are too high • “On-off” phenomenon when drug effects suddenly increase or decrease due to fluctuating levels of DA in the basal ganglia • Behavioral and mental disturbances

44. Dopamine Agonists • Drugs: bromocriptine, pergolide, pramipexole, and ropinirole • Stimulate DA receptors in the basal ganglia • Used alone or in combination with levodopa • Adverse effects similar to levodopa: nausea, hypotension, dyskinesias, and mental disturbances

45. Amantadine (Symmetrel) • An antiviral drug that additionally increases the release of DA in the brain • Used in early stages of treatment and in combination with other drugs • Effectiveness usually decreases in 6–12 months • Adverse effects include nausea, mental disturbances, and occasionally skin discoloration

46. Enzyme Inhibitors • Selegiline (Eldepryl) inhibits MAO-B enzyme that slows metabolism of DA in the brain, increases DA levels; used alone or with levodopa • Tolcapone (Tasmar) and entacapone (Comtan) inhibit another enzyme, COMT, that also slows metabolism of DA; usually used with levodopa

47. Anticholinergic Drugs • Used to decrease the activity of ACH and restore the normal balance between DA and ACH • Benztropine (Cogentin)and trihexyphenidyl (Artane) most widely used drugs • Antihistamine drugs, diphenhydramine (Benadryl), with high anticholinergic activity occasionally used • Used alone early in treatment or in combination with other drugs

48. Central Analgesics

50. Clinical Indication Produce a state of unconsciousness to prevent painful stimulation during surgical and dental procedures Types of anesthetics • Inhalation gases & volatile liquids: chloroform, halothane, nitrous oxide • Injectable: fentanyl, ketamine, midazolam, propofol