Pharmacology
Pharmacology
Drugs That Affect The:
Drugs That Affect The:
Nervous System
Nervous System
INDIAN DENTAL ACADEMY
Leader in continuing dental education
www.indiandentalacademy.com
Topics
Topics
••
••
••
••
••
••
••

Analgesics and antagonists
Analgesics and antagonists
Anesthetics
Anesthetics
Anti-anx...
But first...
But first...

A colorful review of
A colorful review of
neurophysiology!
neurophysiology!
Nervous System
Nervous System
CNS
CNS

PNS
PNS
Autonomic
Autonomic

Sympathetic
Sympathetic

Parasympathetic
Parasympathet...
Analgesics
Analgesics
••
••

Decrease in sensation of pain.
Decrease in sensation of pain.
Classes:
Classes:
– Opioid.
– O...
Opioids
Opioids
•• Generic reference to
Generic reference to
morphine-like
morphine-like
drugs/actions
drugs/actions

–– O...
Actions of Opioid Receptors
Actions of Opioid Receptors
Response

Mu

Kappa

Analgesia





Respiratory
Depression



S...
Actions at Opioid Receptors
Actions at Opioid Receptors
Drugs

Mu

Kappa

Pure Agonists

Agonist

Agonist

-morphine, code...
General Actions of Opioids
General Actions of Opioids
••
••
••
••
••
••
••

Analgesia
Analgesia
Respiratory depression
Res...
Non-opioid Analgesics
Non-opioid Analgesics
•• Salicylates
Salicylates
– Aspirin (Bayer®® )) * (prototype for class)
– Asp...
NSAID Properties
NSAID Properties
Drug

Fever

Inflammation Pain

Aspirin







Ibuprofen







Acetaminophen



...
Aspirin Mechanism of Action
Aspirin Mechanism of Action
•• Inhibit synthesis of cyclooxygenase (COX)
Inhibit synthesis of ...
Aspirin Effects
Aspirin Effects
Good
Good
•• Pain relief
Pain relief
∀ ⇓ Fever
∀ ⇓ Fever
∀ ⇓ Inflammation
∀ ⇓ Inflammation...
®
Acetaminophen (Tylenol®))
Acetaminophen (Tylenol

••
••

NSAID similar to aspirin
NSAID similar to aspirin
Only inhibits...
Acetaminophen Metabolism
Acetaminophen Metabolism
Major Pathway
Non-toxic
Non-toxic
metabolites
metabolites

Acetaminophen...
Anesthetics
Anesthetics
•• Loss of all sensation
Loss of all sensation

– Usually with loss of consciousness
– Usually wit...
Anesthetics
Anesthetics
•• Local
Local
– Affect on area around injection
– Affect on area around injection
– Usually accom...
Anti-anxiety & SedativeAnti-anxiety & Sedativehypnotic Drugs
hypnotic Drugs
••
••
••

Sedation: ⇓ anxiety & inhibitions
Se...
Mechanism of action
Mechanism of action
•• Both promote the effectiveness of GABA
Both promote the effectiveness of GABA
r...
Benzodiazepines vs.
Benzodiazepines vs.
Barbiturates
Barbiturates
Criteria

BZ

Barb.

Relative Safety

High Low

Maximal ...
Benzodiazepines
Benzodiazepines
Benzodiazepines
Benzodiazepines
•• diazepam (Valium®®)
diazepam (Valium )
•• midazolam (Ve...
Barbiturates
Barbiturates
Subgroup

Prototype

Typical
Indication

Ultra-short
acting

thiopental
(Pentothol®)

Anesthesia...
Barbiturates
Barbiturates
••
••
••
••
••

amobarbital (Amytal®®))
amobarbital (Amytal
pentobarbital (Nembutal®®))
pentobar...
Anti-seizure Medications
Anti-seizure Medications
••
••

Seizures caused by hyperactive brain areas
Seizures caused by hyp...
Anti-Seizure Medications
Anti-Seizure Medications
Benzodiazepines
Benzodiazepines
•• diazepam (Valium®)
diazepam (Valium®)...
Ion Diffusion
Ion Diffusion
••
••

Key to neurophysiology
Key to neurophysiology
Dependent upon:
Dependent upon:
– Concent...
Where Does Diffusion Take the
Where Does Diffusion Take the
Ion?
Ion?
Na++
Na
150 mM
150 mM

K++
K
5 mM
5 mM

Cl- Cl
High
...
Action Potential Components
Action Potential Components
Membrane Potential (mV)

Depolarization!
Depolarization!

Na++equi...
0

Na + Influx

+30

K+ Efflux

Membrane Potential (mV)

Membrane Permeability
Membrane Permeability

Threshold
Threshold
...
0

Na + Influx

+30

K+ Efflux

Membrane Potential (mV)

What Happens to the Membrane If Cl-What Happens to the Membrane I...
Membrane Potential (mV)

What Happens to the Frequency of Action
What Happens to the Frequency of Action
Potentials If the...
Clinical Correlation
Clinical Correlation
•• Remember that it is the rate of action potential propagation
Remember that it...
Cl - Cl

Gamma Amino Butyric Acid
Gamma Amino Butyric Acid
Receptors
Receptors
GABA
GABA
Receptor
Receptor

Exterior

Hype...
Cl - Cl

GABA+Bz Complex
GABA+Bz Complex

Bz
Bz
Receptor
Receptor

GABA
GABA
Receptor
Receptor

Profoundly
Profoundly
Hype...
Are You Ready for a Big
Are You Ready for a Big
Surprise?
Surprise?

Many CNS drugs act on GABA
receptors to effect the fr...
SNS Stimulants
SNS Stimulants
•• Two general mechanisms:
Two general mechanisms:

– Increase excitatory neurotransmitter r...
Amphetamines
Amphetamines
amphetamine
amphetamine
methamphetamine
methamphetamine
dextroamphetamine
dextroamphetamine
(Dex...
®
Methylphenidate (Ritalin®))
Methylphenidate (Ritalin

•• Different structure than other stimulants
Different structure t...
Methylxanthines
Methylxanthines
••
••
••

Caffeine
Caffeine
Theophylline (Theo-Dur®)
Theophylline (Theo-Dur®)
Aminophyllin...
A patient is taking theophylline and
A patient is taking theophylline and
becomes tachycardic (SVT). You want to
becomes t...
News You Can Use…
News You Can Use…
Source

Amount of Caffeine

Coffee
•Brewed
•Instant

40 – 180 mg/cup
30 – 120 mg/cup

...
Psychotherapeutic
Psychotherapeutic
Medications
Medications
•• Dysfunction related to neurotransmitter
Dysfunction related...
Anti-Psychotic Drugs
Anti-Psychotic Drugs
(Neuroleptics)
(Neuroleptics)
•• Schizophrenia
Schizophrenia
– Loss of contact w...
Other Uses for Antipsychotics
Other Uses for Antipsychotics
••
••
••
••
••

Bipolar depression
Bipolar depression
Tourette...
Antipsychotic MOA
Antipsychotic MOA
••
••

Mechanism is similar
Mechanism is similar
Strength ([]) vs. Potency (‘oomph’)
S...
Antipsychotic Side Effects
Antipsychotic Side Effects
••
••
••

Generally short term
Generally short term
Extrapyramidal s...
Extrapyramidal Symptoms
Extrapyramidal Symptoms
Reaction

Onset

Features

Acute dystonia

Hours to 5 days

Spasm of tongu...
Treatment of EPS
Treatment of EPS
•• Likely caused by blocking central
Likely caused by blocking central
dopamine22 recept...
Antipsychotic Agents
Antipsychotic Agents
••
••
••
••

chlorpromazine (Thorazine®)
chlorpromazine (Thorazine®)
thioridazin...
Antidepressants
Antidepressants
••
••

Likely cause: inadequate monoamine levels
Likely cause: inadequate monoamine levels...
Tricyclic Antidepressants
Tricyclic Antidepressants
(TCAs)
(TCAs)
•• Block reuptake of both NE & serotonin
Block reuptake ...
TCA Side Effects
TCA Side Effects
••
••
••
••

Orthostatic hypotension
Orthostatic hypotension
Sedation
Sedation
Anticholi...
Selective Serotonin Reuptake
Selective Serotonin Reuptake
Inhibitors (SSRIs)
Inhibitors (SSRIs)
•• Block only serotonin (n...
Monoamine Oxidase Inhibitors
Monoamine Oxidase Inhibitors
(MAOIs)
(MAOIs)
•• Monoamine oxidase
Monoamine oxidase
– Present...
MAOI Side Effects
MAOI Side Effects
•• CNS Stimulation
CNS Stimulation
– Anxiety, agitation
– Anxiety, agitation

••
••

O...
MAOI & Dietary Tyramine
MAOI & Dietary Tyramine
Antidepressant Mechanism
Antidepressant Mechanism
TCAs &
SSRIs
Block Here
Antidepressants Agents
Antidepressants Agents
TCAs
TCAs
••
••
••

imiprimine (Tofranil®®)
imiprimine (Tofranil)
amitriptyl...
Parkinson’s Disease
Parkinson’s Disease
•• Fine motor control dependent upon balance
Fine motor control dependent upon bal...
Parkinson’s Disease
Parkinson’s Disease
Parkinson’s Symptoms:
Parkinson’s Symptoms:
••
••

Similar to EPS
Similar to EPS
Dyskinesias
Dyskinesias
– Tremors, unstea...
Parkinson’s Treatment
Parkinson’s Treatment
•• Dopaminergic approach
Dopaminergic approach
⇑ Release of dopamine
⇑ Release...
Levodopa
Levodopa
••
••
••

Sinemet ® = levodopa + carbidopa
Sinemet ® = levodopa + carbidopa
Increase central dopamine le...
Levodopa Mechanism
Levodopa Mechanism
Other Agents
Other Agents
•• amantadine (Symmetrel®®))
amantadine (Symmetrel

⇑ release of dopamine from unaffected neuron...
Drugs That Affect the
Drugs That Affect the
Autonomic Nervous System
Autonomic Nervous System
Word of Warning
Word of Warn...
PNS Drugs
PNS Drugs
•• Cholinergic
Cholinergic
– Agonists & Antagonistis (Anticholinergics)
– Agonists & Antagonistis (Ant...
Acetylcholine Receptors
Acetylcholine Receptors

Figure 9-8, page 313, Paramedic Care, V1
Cholinergic Agonists
Cholinergic Agonists
Cholinergic agents
cause SLUDGE!
HINT!
These effects are
predictable by knowing
...
Direct Acting Cholinergics
Direct Acting Cholinergics
•• bethanechol (Urecholine) prototype
bethanechol (Urecholine) proto...
Indirect Acting Cholinergics
Indirect Acting Cholinergics
•• Inhibit ChE (cholinesterase) to prolong the
Inhibit ChE (chol...
Reversible ChE Inhibitors
Reversible ChE Inhibitors
•• neostigmine (Prostigmine®®))
neostigmine (Prostigmine

– Myasthenia...
Irreversible ChE Inhibitors
Irreversible ChE Inhibitors
••
••

Very rarely used clinically
Very rarely used clinically
Ver...
Anticholinergics
Anticholinergics
•• Muscarinic
Muscarinic
antagonists
antagonists
– Atropine
– Atropine

•• Ganglionic an...
Neuromuscular Blockers
Neuromuscular Blockers
•• Nicotinic Cholinergic Antagonists
Nicotinic Cholinergic Antagonists
– Giv...
Warning!
Warning!
•• Paralysis without loss of consciousness!
Paralysis without loss of consciousness!
– MUST also give se...
SNS Drugs
SNS Drugs
•• Predictable response based on knowledge of
Predictable response based on knowledge of
affects of ad...
Alpha11 Agonists
Alpha Agonists
•• Profound vasoconstriction
Profound vasoconstriction
– Increases afterload & blood press...
Alpha11 Antagonism
Alpha Antagonism
•• Inhibits peripheral vasoconstriction
Inhibits peripheral vasoconstriction
– Used fo...
Beta11 Agonists
Beta Agonists
•• Increases heart rate, contractility, and
Increases heart rate, contractility, and
conduct...
Beta Antagonists ((β Blockers)
Beta Antagonists β Blockers)
••
••
••

Frequently used
Frequently used
Lower Blood Pressure...
Adrenergic Receptor Specificity
Adrenergic Receptor Specificity
Drug
Epinephrine
Ephedrine
Norepinephrine
Phenylephrine
Is...
Web Resources
Web Resources
•• Web based synaptic transmission project
Web based synaptic transmission project
– http://ww...
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Central nervous system drugs /certified fixed orthodontic courses by Indian dental academy

  1. 1. Pharmacology Pharmacology Drugs That Affect The: Drugs That Affect The: Nervous System Nervous System
  2. 2. INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com
  3. 3. Topics Topics •• •• •• •• •• •• •• Analgesics and antagonists Analgesics and antagonists Anesthetics Anesthetics Anti-anxiety and sedative-hypnotics Anti-anxiety and sedative-hypnotics Anti-seizure // anti-convulsants Anti-seizure anti-convulsants CNS stimulators CNS stimulators Psychotherapeutics Psychotherapeutics ANS/PNS/SNS agents ANS/PNS/SNS agents
  4. 4. But first... But first... A colorful review of A colorful review of neurophysiology! neurophysiology!
  5. 5. Nervous System Nervous System CNS CNS PNS PNS Autonomic Autonomic Sympathetic Sympathetic Parasympathetic Parasympathetic Somatic Somatic
  6. 6. Analgesics Analgesics •• •• Decrease in sensation of pain. Decrease in sensation of pain. Classes: Classes: – Opioid. – Opioid. •• Agonist. Agonist. •• Antagonist. Antagonist. •• Agonist-antagonist. Agonist-antagonist. – Non-opioids. – Non-opioids. •• Salicylates. Salicylates. •• NSAIDs. NSAIDs. •• Adjuncts. Adjuncts.
  7. 7. Opioids Opioids •• Generic reference to Generic reference to morphine-like morphine-like drugs/actions drugs/actions –– Opiate: derivative of opium Opiate: derivative of opium •• Prototype: morphine Prototype: morphine –– Morpheus: god of dreams Morpheus: god of dreams •• Act on endorphin Act on endorphin receptors: receptors: –– –– Mu (most important) Mu (most important) Kappa Kappa
  8. 8. Actions of Opioid Receptors Actions of Opioid Receptors Response Mu Kappa Analgesia   Respiratory Depression  Sedation  Euphoria  Physical Dependence  ⇓ GI motility   
  9. 9. Actions at Opioid Receptors Actions at Opioid Receptors Drugs Mu Kappa Pure Agonists Agonist Agonist -morphine, codeine, meperidine (Demerol®), fentanyl (Sublimaze®), remifentanil (Ultiva®), propoxyphene (Darvon®), hydrocodone (Vicodin®), oxycodone (Percocet®) Agonist-Antagonist -nalbuphine (Nubaine®), butorphanol (Stadol®) Antagonist Agonist Pure Antagonist Antagonist Antagonist -naloxone (Narcan®)
  10. 10. General Actions of Opioids General Actions of Opioids •• •• •• •• •• •• •• Analgesia Analgesia Respiratory depression Respiratory depression Constipation Constipation Urinary retention Urinary retention Cough suppression Cough suppression Emesis Emesis Increased ICP Increased ICP – Indirect through CO2 2 – Indirect through CO retention retention •• •• •• Euphoria/Dysphoria Euphoria/Dysphoria Sedation Sedation Miosis Miosis – Pupil constriction – Pupil constriction ∀ ⇓ Preload & afterload ∀ ⇓ Preload & afterload – Watch for – Watch for hypotension! hypotension!
  11. 11. Non-opioid Analgesics Non-opioid Analgesics •• Salicylates Salicylates – Aspirin (Bayer®® )) * (prototype for class) – Aspirin (Bayer * (prototype for class) •• Non-Steroidal Anti-Inflammatory Drugs Non-Steroidal Anti-Inflammatory Drugs •• Ibuprofen (Motrin®, Advil®®) Ibuprofen (Motrin®, Advil) –– Propionic Acid derivative Propionic Acid derivative •• Naproxen (Naprosyn®®) Naproxen (Naprosyn) •• Naproxen sodium (Aleve®®) Naproxen sodium (Aleve) •• All compete with aspirin for protein binding sites All compete with aspirin for protein binding sites – Ketorolac (Toradol®®) – Ketorolac (Toradol )
  12. 12. NSAID Properties NSAID Properties Drug Fever Inflammation Pain Aspirin    Ibuprofen    Acetaminophen  
  13. 13. Aspirin Mechanism of Action Aspirin Mechanism of Action •• Inhibit synthesis of cyclooxygenase (COX) Inhibit synthesis of cyclooxygenase (COX) – Enzyme responsible for synthesis of: – Enzyme responsible for synthesis of: Prostaglandins Prostaglandins ––Painresponse Pain response ––Suppressionof gastric acid secretion Suppression of gastric acid secretion ––Promotesecretion of gastric mucus and bicarbonate Promote secretion of gastric mucus and bicarbonate ––Mediationof inflammatory response Mediation of inflammatory response ––Productionof fever Production of fever ––Promoterenal vasodilation (⇑ blood flow) Promote renal vasodilation (⇑ blood flow) ––Promoteuterine contraction Promote uterine contraction Thromboxane A22 Thromboxane A ––Involvedin platelet Involved in platelet ––aggregation aggregation
  14. 14. Aspirin Effects Aspirin Effects Good Good •• Pain relief Pain relief ∀ ⇓ Fever ∀ ⇓ Fever ∀ ⇓ Inflammation ∀ ⇓ Inflammation Bad Bad •• GI ulceration: GI ulceration: ⇑ Gastric acidity ⇑ Gastric acidity ⇓ GI protection ⇓ GI protection ∀ ⇑ Bleeding ∀ ⇑ Bleeding ∀ ⇓ Renal elimination ∀ ⇓ Renal elimination ∀ ⇓ Uterine contractions ∀ ⇓ Uterine contractions during labor during labor
  15. 15. ® Acetaminophen (Tylenol®)) Acetaminophen (Tylenol •• •• NSAID similar to aspirin NSAID similar to aspirin Only inhibits synthesis of CNS Only inhibits synthesis of CNS prostaglandins prostaglandins – Does not have peripheral side effects of ASA: – Does not have peripheral side effects of ASA: •• Gastric ulceration Gastric ulceration ∀ ⇓ Platelet aggregation ∀ ⇓ Platelet aggregation ∀ ⇓ Renal flow ∀ ⇓ Renal flow ∀ ⇓ Uterine contractions ∀ ⇓ Uterine contractions
  16. 16. Acetaminophen Metabolism Acetaminophen Metabolism Major Pathway Non-toxic Non-toxic metabolites metabolites Acetaminophen Acetaminophen Induced by Induced by ETOH ETOH P-450 Toxic Toxic metabolites metabolites Minor Pathway Depleted by ETOH & Depleted by ETOH & APAP overdose APAP overdose Glutathione Non-toxic Non-toxic metabolites metabolites
  17. 17. Anesthetics Anesthetics •• Loss of all sensation Loss of all sensation – Usually with loss of consciousness – Usually with loss of consciousness ⇓ propagation of neural impulses ⇓ propagation of neural impulses •• General anesthetics General anesthetics – Gases – Gases •• Nitrous oxide (Nitronox®®),halothane, ether Nitrous oxide (Nitronox), halothane, ether – IV – IV •• Thiopental (Pentothal®®),methohexital (Brevitol®®), Thiopental (Pentothal), methohexital (Brevitol), diazepam (valium®), remifentanil (Ultiva®®) diazepam (valium®), remifentanil (Ultiva)
  18. 18. Anesthetics Anesthetics •• Local Local – Affect on area around injection – Affect on area around injection – Usually accompanied by epinephrine – Usually accompanied by epinephrine •• Lidocaine (Xylocaine ®®),topical cocaine Lidocaine (Xylocaine ), topical cocaine
  19. 19. Anti-anxiety & SedativeAnti-anxiety & Sedativehypnotic Drugs hypnotic Drugs •• •• •• Sedation: ⇓ anxiety & inhibitions Sedation: ⇓ anxiety & inhibitions Hypnosis: instigation of sleep Hypnosis: instigation of sleep Insomnia Insomnia ⇑ Latent period ⇑ Latent period ⇑ Wakenings ⇑ Wakenings •• Classes: Classes: – Barbiturates – Barbiturates – Benzodiazepines – Benzodiazepines – Alcohol – Alcohol Chemically different, Chemically different, Functionally similar Functionally similar
  20. 20. Mechanism of action Mechanism of action •• Both promote the effectiveness of GABA Both promote the effectiveness of GABA receptors in the CNS receptors in the CNS – Benzodiazepines promote only – Benzodiazepines promote only – Barbiturates promote and (at high doses) – Barbiturates promote and (at high doses) stimulate GABA receptors stimulate GABA receptors •• GABA = chief CNS inhibitory GABA = chief CNS inhibitory neurotransmitter neurotransmitter – Promotes hyperpolarization via ⇑ Cl- - influx – Promotes hyperpolarization via ⇑ Cl influx
  21. 21. Benzodiazepines vs. Benzodiazepines vs. Barbiturates Barbiturates Criteria BZ Barb. Relative Safety High Low Maximal CNS depression Low High Respiratory Depression Low High Suicide Potential Low High Abuse Potential Low High Antagonist Available? Yes No
  22. 22. Benzodiazepines Benzodiazepines Benzodiazepines Benzodiazepines •• diazepam (Valium®®) diazepam (Valium ) •• midazolam (Versed®®) midazolam (Versed ) •• alprazolam (Xanax®®) alprazolam (Xanax ) •• lorazepam (Atiavan®®) lorazepam (Atiavan ) •• triazolam (Halcion®®) triazolam (Halcion ) “Non-benzo benzo” “Non-benzo benzo” •• zolpidem (Ambien®®) zolpidem (Ambien ) •• buspirone (BusPar®®) buspirone (BusPar )
  23. 23. Barbiturates Barbiturates Subgroup Prototype Typical Indication Ultra-short acting thiopental (Pentothol®) Anesthesia Short acting secobarbital (Seconal®) Insomnia Long acting phenobarbital (Luminal®) Seizures
  24. 24. Barbiturates Barbiturates •• •• •• •• •• amobarbital (Amytal®®)) amobarbital (Amytal pentobarbital (Nembutal®®)) pentobarbital (Nembutal thiopental (Pentothal®®)) thiopental (Pentothal phenobarbital (Luminal ®®)) phenobarbital (Luminal secobarbital (Seconal ®®)) secobarbital (Seconal
  25. 25. Anti-seizure Medications Anti-seizure Medications •• •• Seizures caused by hyperactive brain areas Seizures caused by hyperactive brain areas Multiple chemical classes of drugs Multiple chemical classes of drugs – All have same approach – All have same approach – Decrease propagation of action potentials – Decrease propagation of action potentials ∀ ⇓ Na+,+,Ca++++influx (delay depolarization/prolong ∀ ⇓ Na Ca influx (delay depolarization/prolong repolarization) repolarization) ∀ ⇑ Cl- -influx (hyperpolarize membrane) ∀ ⇑ Cl influx (hyperpolarize membrane)
  26. 26. Anti-Seizure Medications Anti-Seizure Medications Benzodiazepines Benzodiazepines •• diazepam (Valium®) diazepam (Valium®) •• lorazepam (Ativan®®) lorazepam (Ativan ) Barbiturates Barbiturates •• phenobarbital phenobarbital (Luminal®®) (Luminal ) Ion Channel Inhibitors Ion Channel Inhibitors •• carbamazepine carbamazepine (Tegretol®®) (Tegretol ) •• phenytoin (Dilantin®) phenytoin (Dilantin®) Misc. Agents Misc. Agents •• valproic acid valproic acid (Depakote®) (Depakote®)
  27. 27. Ion Diffusion Ion Diffusion •• •• Key to neurophysiology Key to neurophysiology Dependent upon: Dependent upon: – Concentration gradient – Concentration gradient – Electrical gradient – Electrical gradient •• Modified by: Modified by: – ‘Gated ion channels’ – ‘Gated ion channels’
  28. 28. Where Does Diffusion Take the Where Does Diffusion Take the Ion? Ion? Na++ Na 150 mM 150 mM K++ K 5 mM 5 mM Cl- Cl High High Exterior II N N Na++ Na 15 mM 15 mM O O U U T T II N N K++ K 150 mM 150 mM Cl- Cl Low Low Interior
  29. 29. Action Potential Components Action Potential Components Membrane Potential (mV) Depolarization! Depolarization! Na++equilibrium Na equilibrium Action Action Potential Potential +30 0 Threshold Threshold Potential Potential -50 -70 Hyperpolarized Hyperpolarized Time (msec) Resting Membrane Resting Membrane Potential Potential
  30. 30. 0 Na + Influx +30 K+ Efflux Membrane Potential (mV) Membrane Permeability Membrane Permeability Threshold Threshold Potential Potential -50 -70 Resting Membrane Resting Membrane Potential Potential Time (msec)
  31. 31. 0 Na + Influx +30 K+ Efflux Membrane Potential (mV) What Happens to the Membrane If Cl-What Happens to the Membrane If Cl Rushes Into the Cell During Repolarization? Rushes Into the Cell During Repolarization? It gets It gets hyperpolarized! hyperpolarized! Threshold Threshold Potential Potential -50 -70 Resting Membrane Resting Membrane Potential Potential Time (msec)
  32. 32. Membrane Potential (mV) What Happens to the Frequency of Action What Happens to the Frequency of Action Potentials If the Membrane Gets Potentials If the Membrane Gets Hyperpolarized? Hyperpolarized? +30 0 It It decreases! decreases! -50 -70 Time (msec)
  33. 33. Clinical Correlation Clinical Correlation •• Remember that it is the rate of action potential propagation Remember that it is the rate of action potential propagation that determines neurologic function. that determines neurologic function. –– Determined by frequency of action potentials. Determined by frequency of action potentials. What is a seizure? What would be the What is a seizure? What would be the effect on the membrane effect on the membrane of ⇑ Cl-- influx of ⇑ Cl influx Hyperpolarization & … during a seizure? during a seizure? ⇓ seizure activity!
  34. 34. Cl - Cl Gamma Amino Butyric Acid Gamma Amino Butyric Acid Receptors Receptors GABA GABA Receptor Receptor Exterior Hyperpolarized! Hyperpolarized! Interior
  35. 35. Cl - Cl GABA+Bz Complex GABA+Bz Complex Bz Bz Receptor Receptor GABA GABA Receptor Receptor Profoundly Profoundly Hyperpolarized! Hyperpolarized! Exterior Interior
  36. 36. Are You Ready for a Big Are You Ready for a Big Surprise? Surprise? Many CNS drugs act on GABA receptors to effect the frequency and duration of action potentials!
  37. 37. SNS Stimulants SNS Stimulants •• Two general mechanisms: Two general mechanisms: – Increase excitatory neurotransmitter release – Increase excitatory neurotransmitter release – Decrease inhibitory neurotransmitter release – Decrease inhibitory neurotransmitter release •• Three classes: Three classes: •• Amphetamines Amphetamines •• Methylphendidate Methylphendidate •• Methylxanthines Methylxanthines
  38. 38. Amphetamines Amphetamines amphetamine amphetamine methamphetamine methamphetamine dextroamphetamine dextroamphetamine (Dexedrine®®)) (Dexedrine MOA: MOA: promote release of promote release of norepinephrine, norepinephrine, dopamine dopamine Indications Indications ••Diet suppression Diet suppression ∀⇓ Fatigue ∀⇓ Fatigue ∀⇑ Concentration ∀⇑ Concentration Side Effects Side Effects ••Tachycardia Tachycardia ••Hypertension Hypertension ••Convulsion Convulsion ••Insomnia Insomnia ••Psychosis Psychosis
  39. 39. ® Methylphenidate (Ritalin®)) Methylphenidate (Ritalin •• Different structure than other stimulants Different structure than other stimulants – Similar mechanism – Similar mechanism – Similar side effects – Similar side effects •• Indication: ADHD Indication: ADHD – Increase ability to focus & concentrate – Increase ability to focus & concentrate
  40. 40. Methylxanthines Methylxanthines •• •• •• Caffeine Caffeine Theophylline (Theo-Dur®) Theophylline (Theo-Dur®) Aminophylline Aminophylline Mechanism of action Mechanism of action •• Reversible blockade of adenosine receptors Reversible blockade of adenosine receptors
  41. 41. A patient is taking theophylline and A patient is taking theophylline and becomes tachycardic (SVT). You want to becomes tachycardic (SVT). You want to give her adenosine. Is there an interaction give her adenosine. Is there an interaction you should be aware of? How should you you should be aware of? How should you alter your therapy? alter your therapy? Methylxanthines blocks Methylxanthines blocks adenosine receptors. A adenosine receptors. A typical dose of adenosine typical dose of adenosine may not be sufficient to may not be sufficient to achieve the desired achieve the desired result. result. Double the Double the dose! dose!
  42. 42. News You Can Use… News You Can Use… Source Amount of Caffeine Coffee •Brewed •Instant 40 – 180 mg/cup 30 – 120 mg/cup Decaffeinated Coffee 2 - 5 mg/cup Tea 20 – 110 mg/cup Coke 40 – 60 mg/12 oz
  43. 43. Psychotherapeutic Psychotherapeutic Medications Medications •• Dysfunction related to neurotransmitter Dysfunction related to neurotransmitter imbalance. imbalance. – Norepinephrine. – Norepinephrine. – Dopamine. – Dopamine. – Seratonin. – Seratonin. Monoamines •• Goal is to regulate excitory/inhibitory Goal is to regulate excitory/inhibitory neurotransmitters. neurotransmitters.
  44. 44. Anti-Psychotic Drugs Anti-Psychotic Drugs (Neuroleptics) (Neuroleptics) •• Schizophrenia Schizophrenia – Loss of contact with reality & disorganized – Loss of contact with reality & disorganized thoughts thoughts – Probable cause: increased dopamine release – Probable cause: increased dopamine release – Tx. Aimed at decreasing dopamine activity – Tx. Aimed at decreasing dopamine activity Two Chemical Two Chemical Classes: Classes: •• Phenothiazines Phenothiazines •• chlorpromazine (Thorazine ®®) chlorpromazine (Thorazine ) •• haloperidol (Haldol ®) haloperidol (Haldol ) •• Butyrophenones Butyrophenones ®
  45. 45. Other Uses for Antipsychotics Other Uses for Antipsychotics •• •• •• •• •• Bipolar depression Bipolar depression Tourette’s Syndrome Tourette’s Syndrome Prevention of emesis Prevention of emesis Dementia (OBS) Dementia (OBS) Temporary psychoses from other illness Temporary psychoses from other illness
  46. 46. Antipsychotic MOA Antipsychotic MOA •• •• Mechanism is similar Mechanism is similar Strength ([]) vs. Potency (‘oomph’) Strength ([]) vs. Potency (‘oomph’) – Phenothiazines – low potency – Phenothiazines – low potency – Butyrophenones – high potency – Butyrophenones – high potency •• Receptor Antagonism Receptor Antagonism – Dopamine2 2in brain – Dopamine in brain – Muscarinic cholinergic – Muscarinic cholinergic – Histamine – Histamine – Norepi at alpha1 1 – Norepi at alpha Therapeutic effects Uninteded effects
  47. 47. Antipsychotic Side Effects Antipsychotic Side Effects •• •• •• Generally short term Generally short term Extrapyramidal symptoms (EPS) Extrapyramidal symptoms (EPS) Anticholinergic effects (atropine-like) Anticholinergic effects (atropine-like) •• •• •• •• Orthostatic hypotension Orthostatic hypotension Sedation Sedation Decreased seizure threshold Decreased seizure threshold Sexual dysfunction Sexual dysfunction – Dry mouth, blurred vision, photophobia, tachycardia, – Dry mouth, blurred vision, photophobia, tachycardia, constipation) constipation)
  48. 48. Extrapyramidal Symptoms Extrapyramidal Symptoms Reaction Onset Features Acute dystonia Hours to 5 days Spasm of tongue, neck, face & back Parkinsonism 5 – 30 days Tremor, shuffling gait, drooling, stooped posture, instability Akathesia 5 – 60 days Compulsive, repetitive motions; agitation Tarditive dyskinesia Months to years Lip-smacking, worm-like tongue movement, ‘fly-catching’
  49. 49. Treatment of EPS Treatment of EPS •• Likely caused by blocking central Likely caused by blocking central dopamine22 receptors responsible for dopamine receptors responsible for movement movement •• Anticholinergic therapy rapidly effective Anticholinergic therapy rapidly effective – diphenhydramine (Benadryl®®) – diphenhydramine (Benadryl )
  50. 50. Antipsychotic Agents Antipsychotic Agents •• •• •• •• chlorpromazine (Thorazine®) chlorpromazine (Thorazine®) thioridazine (Mellaril®) thioridazine (Mellaril®) trifluoperazine (Stelazine®) trifluoperazine (Stelazine®) haloperidol (Haldol®) haloperidol (Haldol®)
  51. 51. Antidepressants Antidepressants •• •• Likely cause: inadequate monoamine levels Likely cause: inadequate monoamine levels Treatment options: Treatment options: – Increasing NT synthesis in presynaptic end – Increasing NT synthesis in presynaptic end bulb bulb – Increasing NT release from end bulb – Increasing NT release from end bulb – Blocking NT ‘reuptake’ by presynaptic end – Blocking NT ‘reuptake’ by presynaptic end bulb bulb
  52. 52. Tricyclic Antidepressants Tricyclic Antidepressants (TCAs) (TCAs) •• Block reuptake of both NE & serotonin Block reuptake of both NE & serotonin – Enhance effects – Enhance effects •• Similar side effects to phenothiazines Similar side effects to phenothiazines
  53. 53. TCA Side Effects TCA Side Effects •• •• •• •• Orthostatic hypotension Orthostatic hypotension Sedation Sedation Anticholinergic effects Anticholinergic effects Cardiac toxicity Cardiac toxicity – Ventricular dysrythmias – Ventricular dysrythmias
  54. 54. Selective Serotonin Reuptake Selective Serotonin Reuptake Inhibitors (SSRIs) Inhibitors (SSRIs) •• Block only serotonin (not NE) reuptake Block only serotonin (not NE) reuptake – Elevate serotonin levels – Elevate serotonin levels •• Fewer side effects than TCS Fewer side effects than TCS – No hypotension – No hypotension – No anticholinergic effects – No anticholinergic effects – No cardiotoxicity – No cardiotoxicity •• Most common side effect Most common side effect – Nausea, insomnia, sexual dysfunction – Nausea, insomnia, sexual dysfunction
  55. 55. Monoamine Oxidase Inhibitors Monoamine Oxidase Inhibitors (MAOIs) (MAOIs) •• Monoamine oxidase Monoamine oxidase – Present in liver, intestines & MA releasing – Present in liver, intestines & MA releasing neurons neurons – Inactivates monoamines – Inactivates monoamines – Inactivates dietary tyramine in liver – Inactivates dietary tyramine in liver •• Foods rich in tyramine: cheese & red wine Foods rich in tyramine: cheese & red wine
  56. 56. MAOI Side Effects MAOI Side Effects •• CNS Stimulation CNS Stimulation – Anxiety, agitation – Anxiety, agitation •• •• Orthostatic hypotension Orthostatic hypotension Hypertensive Crisis Hypertensive Crisis – From increased tyramine consumption – From increased tyramine consumption •• Excessive arteriole constriction, stimulation of heart Excessive arteriole constriction, stimulation of heart
  57. 57. MAOI & Dietary Tyramine MAOI & Dietary Tyramine
  58. 58. Antidepressant Mechanism Antidepressant Mechanism TCAs & SSRIs Block Here
  59. 59. Antidepressants Agents Antidepressants Agents TCAs TCAs •• •• •• imiprimine (Tofranil®®) imiprimine (Tofranil) amitriptyline (Elavil®®) amitriptyline (Elavil) nortriptyline (Pamelor ®®) nortriptyline (Pamelor ) SSRIs SSRIs •• •• •• fluoxetine (Prozac®®) fluoxetine (Prozac) paroxetine (Paxil®®) paroxetine (Paxil) sertraline (Zoloft®®) sertraline (Zoloft) MAOIs MAOIs •• phenelzine (Nardil®®) phenelzine (Nardil) Atypical Antidepressants Atypical Antidepressants •• bupropion (Wellbutrin®®) bupropion (Wellbutrin)
  60. 60. Parkinson’s Disease Parkinson’s Disease •• Fine motor control dependent upon balance Fine motor control dependent upon balance between excitatory and inhibitory NT between excitatory and inhibitory NT – Acetylcholine = excitatory – Acetylcholine = excitatory – Dopamine =inhibitory – Dopamine =inhibitory GABA= inhibitory GABA= inhibitory Control GABA release
  61. 61. Parkinson’s Disease Parkinson’s Disease
  62. 62. Parkinson’s Symptoms: Parkinson’s Symptoms: •• •• Similar to EPS Similar to EPS Dyskinesias Dyskinesias – Tremors, unsteady gait, instability – Tremors, unsteady gait, instability •• •• Bradykinesia Bradykinesia Akinesia in severe cases Akinesia in severe cases
  63. 63. Parkinson’s Treatment Parkinson’s Treatment •• Dopaminergic approach Dopaminergic approach ⇑ Release of dopamine ⇑ Release of dopamine ⇑ [Dopamine] ⇑ [Dopamine] ⇓ Dopamine breakdown ⇓ Dopamine breakdown •• Cholinergic approach Cholinergic approach ⇓ Amount of ACh released ⇓ Amount of ACh released – Directly block ACh receptors – Directly block ACh receptors •• All treatment is symptomatic and temporary All treatment is symptomatic and temporary
  64. 64. Levodopa Levodopa •• •• •• Sinemet ® = levodopa + carbidopa Sinemet ® = levodopa + carbidopa Increase central dopamine levels Increase central dopamine levels Side effects: Side effects: – Nausea and vomiting – Nausea and vomiting – Dyskinesia (~80% of population) – Dyskinesia (~80% of population) – Cardiovascular (dysrythmias) – Cardiovascular (dysrythmias)
  65. 65. Levodopa Mechanism Levodopa Mechanism
  66. 66. Other Agents Other Agents •• amantadine (Symmetrel®®)) amantadine (Symmetrel ⇑ release of dopamine from unaffected neurons ⇑ release of dopamine from unaffected neurons •• bromocriptine (Parlodel®®)) bromocriptine (Parlodel – Directly stimulated dopamine receptors – Directly stimulated dopamine receptors •• selegiline (Carbex®®,, Eldepryl®®)) selegiline (Carbex Eldepryl – MAOI selective for dopamine (MAO-B) – MAOI selective for dopamine (MAO-B) •• benztropine (Cogentin®®)) benztropine (Cogentin – Centrally acting anticholinergic – Centrally acting anticholinergic
  67. 67. Drugs That Affect the Drugs That Affect the Autonomic Nervous System Autonomic Nervous System Word of Warning Word of Warning Carefully review the A&P material & Carefully review the A&P material & tables on pages 309 – 314 and 317 – 321! tables on pages 309 – 314 and 317 – 321!
  68. 68. PNS Drugs PNS Drugs •• Cholinergic Cholinergic – Agonists & Antagonistis (Anticholinergics) – Agonists & Antagonistis (Anticholinergics) – Based on response at nicotinic(N&M) & muscarinic – Based on response at nicotinic(N&M) & muscarinic receptors receptors
  69. 69. Acetylcholine Receptors Acetylcholine Receptors Figure 9-8, page 313, Paramedic Care, V1
  70. 70. Cholinergic Agonists Cholinergic Agonists Cholinergic agents cause SLUDGE! HINT! These effects are predictable by knowing PNS physiology (table 9-4) Salivation Salivation Lacrimation Lacrimation Urination Urination Defecation Defecation Gastric motility Gastric motility Emesis Emesis
  71. 71. Direct Acting Cholinergics Direct Acting Cholinergics •• bethanechol (Urecholine) prototype bethanechol (Urecholine) prototype – Direct stimulation of ACh receptors – Direct stimulation of ACh receptors – Used for urinary hesitancy and constipation – Used for urinary hesitancy and constipation
  72. 72. Indirect Acting Cholinergics Indirect Acting Cholinergics •• Inhibit ChE (cholinesterase) to prolong the Inhibit ChE (cholinesterase) to prolong the duration of ACh stimulation in synapse duration of ACh stimulation in synapse •• Reversible Reversible •• Irreversible Irreversible
  73. 73. Reversible ChE Inhibitors Reversible ChE Inhibitors •• neostigmine (Prostigmine®®)) neostigmine (Prostigmine – Myasthenia Gravis at nicotinicMMreceptors – Myasthenia Gravis at nicotinic receptors – Can reverse nondepolarizing neuromuscular – Can reverse nondepolarizing neuromuscular blockade blockade •• physostigmine (Antilirium®) physostigmine (Antilirium®) – Shorter onset of action – Shorter onset of action – Used for iatrogenic atropine overdoses @ – Used for iatrogenic atropine overdoses @ muscarinic receptors muscarinic receptors
  74. 74. Irreversible ChE Inhibitors Irreversible ChE Inhibitors •• •• Very rarely used clinically Very rarely used clinically Very common in insecticides & chemical Very common in insecticides & chemical weapons weapons – VX and Sarin gas – VX and Sarin gas – Cause SLUDGE dammit and paralysis – Cause SLUDGE dammit and paralysis •• Tx: atropine and pralidoxime (2-PAM®®)) Tx: atropine and pralidoxime (2-PAM – Anticholinergics – Anticholinergics
  75. 75. Anticholinergics Anticholinergics •• Muscarinic Muscarinic antagonists antagonists – Atropine – Atropine •• Ganglionic antagonists Ganglionic antagonists – block nicotinicNN – block nicotinic receptors receptors – Turns off the ANS! – Turns off the ANS! – trimethaphan – trimethaphan (Arfonad®®) (Arfonad) •• Hypertensive crisis Hypertensive crisis •• Atropine Overdose Atropine Overdose – Dry mouth, blurred – Dry mouth, blurred vision, anhidrosis vision, anhidrosis Hot as Hell Hot as Hell Blind as aaBat Blind as Bat Dry as aaBone Dry as Bone Red as aaBeet Red as Beet Mad as aaHatter Mad as Hatter
  76. 76. Neuromuscular Blockers Neuromuscular Blockers •• Nicotinic Cholinergic Antagonists Nicotinic Cholinergic Antagonists – Given to induce paralysis – Given to induce paralysis •• Depolarizing Depolarizing – succinylcholine (Anectin®®) – succinylcholine (Anectin ) •• Nondepolarizing Nondepolarizing – tubocurarine from curare – tubocurarine from curare – rocuronium (Zemuron®®) – rocuronium (Zemuron ) – vecuronium (Norcuron®®) – vecuronium (Norcuron )
  77. 77. Warning! Warning! •• Paralysis without loss of consciousness! Paralysis without loss of consciousness! – MUST also give sedative-hypnotic – MUST also give sedative-hypnotic – Common agents: – Common agents: •• fentanyl (Sublimaze®®) fentanyl (Sublimaze) •• midazolam (Versed®®) midazolam (Versed)
  78. 78. SNS Drugs SNS Drugs •• Predictable response based on knowledge of Predictable response based on knowledge of affects of adrenergic receptor stimulation affects of adrenergic receptor stimulation •• HINT: Know table 9-5, page 321 HINT: Know table 9-5, page 321 •• Each receptor may be: Each receptor may be: – Stimulated (sympathomimetic) – Stimulated (sympathomimetic) – Inhibitied (sympatholytic) – Inhibitied (sympatholytic)
  79. 79. Alpha11 Agonists Alpha Agonists •• Profound vasoconstriction Profound vasoconstriction – Increases afterload & blood pressure when – Increases afterload & blood pressure when given systemically given systemically – Decreases drug absorption & bleeding when – Decreases drug absorption & bleeding when given topically given topically
  80. 80. Alpha11 Antagonism Alpha Antagonism •• Inhibits peripheral vasoconstriction Inhibits peripheral vasoconstriction – Used for hypertension – Used for hypertension – prazosin (Minipress®®) – prazosin (Minipress ) – doxazosin (Cardura®®) – doxazosin (Cardura ) – phentolamine (Regitine®®) – phentolamine (Regitine ) •• Blocks alpha1&2 receptors Blocks alpha1&2 receptors
  81. 81. Beta11 Agonists Beta Agonists •• Increases heart rate, contractility, and Increases heart rate, contractility, and conductivity conductivity
  82. 82. Beta Antagonists ((β Blockers) Beta Antagonists β Blockers) •• •• •• Frequently used Frequently used Lower Blood Pressure Lower Blood Pressure Negative chronotropes & inotropes Negative chronotropes & inotropes Beta11Selective Blockade Beta Selective Blockade •• atenolol (Tenormin®®) atenolol (Tenormin ) •• esmolol (Brevibloc®®) esmolol (Brevibloc ) •• metoprolol (Lopressor®®) metoprolol (Lopressor ) Nonselective Nonselective •• propranolol (Inderal®®) propranolol (Inderal ) •• labetalol (Normodyne®®, labetalol (Normodyne , Trandate®®) Trandate ) •• sotalol (Betapace®®) sotalol (Betapace )
  83. 83. Adrenergic Receptor Specificity Adrenergic Receptor Specificity Drug Epinephrine Ephedrine Norepinephrine Phenylephrine Isoproterenol Dopamine Dobutamine terbutaline α1 α2 β1 β2 Dopaminergic
  84. 84. Web Resources Web Resources •• Web based synaptic transmission project Web based synaptic transmission project – http://www.williams.edu/imput/index.html – http://www.williams.edu/imput/index.html
  85. 85. www.indiandentalacademy.com Leader in continuing dental education

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