Pharmacology 1

Pharmacology to CNS Drugs

Cellular organization of the Brain
 Hierarchical systems
Drugs acting in CNS  Non-specific or diffuse neuronal systems
- Used to treat neurologic and psychiatric conditions, relieve pain, suppress nausea
and reduce fever.
- Used without prescription to increase sense of well-being Hierarchical System
- Include the pathway directly involved in sensory perception and motor control
2 Types of Channels based on mechanism of gating: - Information is phasic and occurs in burst of action potential.
Voltage-Gated Channel Ligand-Gated Channel - 2 types of cells
o Relay or Projection Neuron
Voltage-gated Channels o Local Circuit Neurons
- Modulate the rate at which the neuron discharge and respond to changes in the
membrane potential of the cell. Relay or Projection Neurons
- Types o Very-short lived and excitatory and the excitatory transmitter is glutamate
o Calcium and Potassium Channels.
- MUCH SLOWER Long Circuit Neurons
o Smaller than projection neurons and inhibitory.
Ligand-Gated Channel o Releases GABA or Glycine
- Consists of multiple subunits and binding of the neurotransmitter ligand directly
opens channels 2 Common type of pathways for these neurons:
- Insensitive or weakly sensitive to membrane potential and fast synaptic transmission. 1. Recurrent feedback pathways
- First Class 2. Feed-forward Pathways

Metabotropic Receptors
- A seven-transmembrane G-CHONS coupled receptor and modulate the voltage-gated Site of Drug Actions:
channels by generation of diffusible second messenger. 1. Action potential that goes to pre-synaptic terminal
- It does not result in direct acting of a channel 2. Synthesis of neurotransmitter in the pre-synaptic terminal
- Production of second messenger 3. Storage
4. Metabolism
Synapse and Synaptic Potential 5. Release
EPSP IPSP 6. Reuptake
- Small depolarization - Postsynaptic membrane is 7. Degradation
- Excitatory postsynaptic potential hyperpolarized resulting in selective 8. Receptor for transmission
opening of chloride channel. 9. Receptor induced increase or decrease in ionic conductance
- The pathway is inhibitory 10. Retrograde signaling.
stimulated.

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 Pharmacology 1
Non-specific or Diffuse Neuronal Systems Inhibitory Postsynaptic Potential
- Contains neurotransmitter- monoamine and Acetylcholine - A long lasting
- Produced by limited number of neurons whose cell bodies are located in small Acetylcholine
discrete nuclei - First compound to be identified as neurotransmitter in the CNS and mediated by G-
CHONS coupled muscarinic receptors
Criteria for Transmitter Identification: Monoamine Neurotransmitter
1. Location - Catecholamines are Dopamine, NE and 5-HT.
o Suspected transmitter must reside in the presynaptic terminal of the pathway - Present in very small amount in CNS
of interests
2. Release Dopamine
o Suspected transmitter must be released from a neuron in response to - Anti-Parkinsonism, Anti-Psychotic
neuronal activity and in a calcium-dependent manner. - Exerts slow inhibitory action on CNS neurons
3. Synaptic mimicry Norepinephrine
o Application of the candidate substance should produce a response that - Located in caeruleus
mimics the actions of transmitters released by the nerve stimulation and - Metabotropic
application of selective antagonists must block the response. - Alpha-2 receptors
5-HT
2 Categories of Amino Acid Neurotransmitter - Originate from neurons in the midline raphe nuclei of the Pons and upper brainstem.
1. Acidic Amino Acid - Has a strong inhibitory action and excitatory
2. Neutral Amino Acid Neuropeptides
- Contains substance P- spinal cord and Brainstem, both excitatory and Inhibitory
Glutamate Endocanabinoids
- An acidic amino acid neurotransmitter - Psychoactive ingredients in cannabis
- Excitatory Synaptic Transmission - Δa-tetrahydrocannabinol
Nitric Oxide
3 subtypes of ionotropic receptors based on the action of selective agonists: - Activated by calcium-calmodulin and activation of NMDA
1. Alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid
2. Kainic Acid
3. N-methyl-D-aspartate

GABA and Glycine

- Inhibitory neurotransmitters
- Neutral amino acids neurotransmitters

2 main types of GABA:

1. GABAA- Fast component
2. GABAB- Slow Component

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 Pharmacology 1
SEDATIVE-HYPNOTIC DRUGS - Binds to molecular components of GABAa receptor and will open chloride channels
and produce inhibitory transmission of impulses.
- They are also known as GABAERGIC, they mimic the effect of GABA in the CNS
Sedative-hypnotics drugs causes sedation and encourage sleep, they are the same and the
only difference is the DOSE. Benzodiazepines has high margin of safety while the barbiturates have low margin of safety.

Sedative EFFECTS:
- An anxiolytic agent that reduces anxiety and exert calming effect without putting 1. Sedation
sleep. 2. Hypnosis
Hypnotic 3. Anesthesia
- Produce drowsiness and encourage the onset and maintenance of a state of sleep. 4. Anticonvulsant effect
5. Muscle Relaxation
All sedative-hypnotics follow a great dose dependent depression of CNS. 6. Effects on respiration and cardiovascular

Older sedative-hypnotics (alcohols and barbiturates) Clinical uses of Sedative-Hypnotics

 Dose- General Anesthesia 1. Relief of anxiety
 Dose- depress respiratory and Vasomotor centers- Coma and Death 2. Insomnia
3. Sedation and amnesia before and during medical and surgical procedure
Benzodiazepines 4. Treatment of epilepsy and seizures states
- A newer hypnotic and widely used as sedative-hypnotics 5. Control of ethanol or other sedative-hypnotic withdrawal
- Most undergo microsomal oxidation (phase 1) 6. Component of balanced anesthesia
- Can easily penetrate blood brain barrier, very lipophilic and easily absorbed through 7. Muscle relaxation in specific neuromuscular disorder
oral. 8. Treatment in psychiatry
o Even if the half-life of benzodiazepines is very short, but if the metabolite 9. For sleep disorder
that is produce by the metabolism is still active you have a residual effect of
benzodiazepines General effects of benzodiazepines and older-sedative hypnotics:
Barbiturates 1. Latency of sleep onset is decreased
- Phenobarbital 2. Duration of stage 2 NREM is increased
o An enzyme inducer and can destroy other drugs in its present. 3. Duration of REM is decreased.
- It has the capacity to accumulate in the body, half-life 5 days. o Zolpidem-decrease REM sleep
o Zalepion-decrease latency of sleep onset, REM and NREM
Sodium bicarbonate o Eszopidone-increase stage 2 NREM
- Alkalinize the urine particularly the benzodiazepines and barbiturates drugs for its
excretions. Anesthesia
- Increase dose depress CNS- Stage 3 general anesthesia
MOA of Barbiturates and Benzodiazepines o Benzodiazepines(e.g. Diazepam, Lorazepam, Midazolam)
 Used in IV anesthetics

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 Pharmacology 1
Anticonvulsant effects 5. Skeletal muscle relaxation.
- Sedative-hypnotic inhibit development and spread of epileptiform electrical activity in
the CNS. None of the currently available anesthetic agents when used alone can achieve all five
Muscle Relaxation desired effects.
- Carbamate and Benzodiazepines exert mild inhibitory effects in higher dose it
depress transmission at skeletal neuromuscular junction. Ideal Anesthetics Drugs:
Effects on Respiration and Cardiovascular Function 1. Should induce rapid, smooth loss of consciousness.
- Respiratory depression in patient with pulmonary disease usually can cause death 2. Rapidly reversible upon discontinuation
due to over-dose of sedative-hypnotics. 3. Possess wide margin of safety.
Tolerance
- Decrease responsiveness due to repeated exposure and may need to increased in Balance Anesthesia
dose required to maintain symptomatic improvement or to promote sleep. - Use of combination of intravenous and inhaled drugs.

Choice of Anesthetics Techniques:

- Determine by the type of diagnostic, therapeutic or surgical intervention.
GENERAL ANESTHESIA
Sedative effects: Minor Superficial Surgery / Invasive Diagnostic Procedure:
1. Cannabis - Oral and parenteral sedatives can be used in combination with local anesthetics.
2. Henbane
3. Mandrake More intensive Surgical procedure:
4. Opium poppy - Anesthesia begin without pre-operative benzodiazepines be induced with IV agent
5. Ether and maintained with combination of inhaled or intravenous drugs.

Physical Method: Inhaled Anesthetics:

1. Cold 1. Gaseous
2. Nerve compression 2. Volatile
3. Carotid artery occlusion
4. Cerebral Concussion Volatile Anesthetics:
- Have low vapor pressure and high boiling point
Mechanism of Action: - Liquid at room temperature
- It binds to GABAa
- GABA mediated inhibition and open potassium channels Gaseous Anesthetics
- Have high vapor pressure and low boiling point
5 Primary Effects produced by General Anesthetics: - Gas form at room temperature
1. Unconsciousness o Important determinants of Kinetics of these agents:
2. Amnesia  Uptake from the alveoli into the blood and distribution and
3. Analgesia partitioning into the effect compartments.
4. Inhibition of autonomic reflexes or sensory

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 Pharmacology 1
MAC (Minimal Alveolar Concentration) o Dantrolene
- Anesthetics potency  Low calcium release from sarcoplasmic reticulum.
- Required to prevent a response to a surgical incision. 4. Hepatotoxicity
o Hypovolemic shock and hepatitis esp. for halothane.
Guedel’s Signs
 Stage I - ANALGESIA Intravenous Anesthetics Agents
o Analgesia without amnesia - Used to facilitate rapid induction of anesthesia and have replaced inhalation as the
 Stage II - EXCITEMENT preferred method of anesthesia induction.
o PX is delirious, may vocalize but completely amnesic. Respiration is rapid and Balanced Anesthesia
heart rate and blood pressure is increase - Inhaled anesthetics + sedative-hypnotics + opiods + neuromuscular blocking drugs
 Stage III – SURGICAL ANESTHESIA - Used to avoid or minimize the undesired effects
o Begins with slowing respiration and heart rate extends to complete cessation
of spontaneous respiration(apnea) Propofol
o Described based on ocular movements, eye reflexes, pupil sizes, indicating - Most frequently administered drug for induction of anesthesia
depth of anesthesia - Used during maintenance of anesthesia
 Stage IV – Medullary Depression - Common choice for sedation in anesthesia
o Deep stage of anesthesia - Rapidly metabolized in the liver and poorly soluble in water.
o Severe depression of CNS, vasomotor center in medulla and respiratory
center in brainstem. Ketamine
o Without circulatory and respiratory support, death would rapidly ensure. - Partially water-soluble and highly lipid soluble.
- Dissociative anesthesia-eyes open with slow nystagmic gaze.
Toxicity of Anesthetics Agents: - Inhibition of the NMDA receptor complex
1. Nephrotoxicity
o Enflurane and sevoflurane may generate compounds that are potentially
nephrotoxic
o Nephrotoxic vinyl ether compound / Compound A
Local Anesthetics
2. Hematotoxicity
o Prolonged exposure to nitrous oxide can lower methionine synthase activity - Loss of sensation in a limited region of the body disruption of afferent neural traffic
that can cause MEGALOBLASTIC ANEMIA via inhibition of impulse generation of propagation.
3. Malignant Hyperthermia - Often used with analgesic
o Heritable genetic disorder of skeletal muscle that occurs in individuals - Should not irritate the body and minimal system toxicity
exposed to volatile anesthetics while undergoing general anesthesia - Faster onset of action.
o Succinylcholine - MOA:
 Depolarizing muscle relaxant o Block Sodium Channels
 Trigger malignant hyperthermia - Cocaine
o Consist muscle rigidity, hyperthermia, rapid onset of tachycardia, o First agent that is used as local anesthetics.
hypercapnia, hyperkalemia, metabolic acidosis.
o Rare but important cause of anesthetics morbidity and mortality

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 Pharmacology 1
2 Chemical Classification:
1. Amides
Opioid Agonist and Antagonist
2. Esters
Amides Local Anesthetics: Morphine
a. Lidocaine - Prototype opioid agonist
i. Prototype of anesthetics agents. - Standard against which all drugs that have strong analgesic action are compared.
b. Mepivacaine - Full agonist at the M-opioid receptor.
c. Bupivacaine
d. Ropivacaine Opium Poppy
e. Articaine - Source of crude opium
Morpheus
Esters Local Anesthetics: - Greek Gods for dreams
a. Cocaine
b. Procaine Papaver somniferum Linne. Family Papaveraceae & P. album
c. Tetracaine - Source of morphine and poppy.
d. Benzocaine
Opioid
- Compounds that work opioid receptors
Local Anesthetic route of Administration: - Converted to polar metabolite (glucoronides)
1. Infiltration o CYP450
o Intravascular Opiate
 Bier Block - Naturally occurring alkaloids:
o Extravascular  Morphine
 SQ Intradermal  Codeine
2. Peripheral Nerve Block  Thebaine
o Minor / Major  Papaverine
3. Central Neuro Axis Block Narcotic
o Spinal / subarachnoid Anesthesia - Sleep-inducing medications
o Epidural Anesthesia
o Lumbar area Opioid Drugs
 For Painless birth - Full agonists, partial agonists, antagonists
4. Topical
o EMLA (Eutectic Mixture Of Local Anesthesia) Opioids receptor:
 Containing 2.5% lidocaine and 2.5% prilocaine - Delta
- Kappa

Endogenous opioid peptides

o Endorphins

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o Pentapeptide enkephelins-methionine-enkephalins(meth-kephalins) and Central Nervous System Effects:
leucine-enkephalins-leu-enkephalins 1. Analgesia
o Dynorphins  Both sensory and affective components
Opioid Analgesics 2. Euphoria
- Well-absorbed when given SQ, IM, PO  IV
- Have a high first pass effects  Pleasant floating sensation with lessened anxiety and distress
PO  Dysphoria
- Needs to be much higher than parenteral  Unpleasant state characterized by restlessness and malaise
- Codeine and Oxycodone 3. Sedation
 Drowsiness and clouding of mentation are common effects of opioids
Other route of administration:  Little or no amnesia
- Oral mucosa via lozenges 4. Respiratory Depression
- Transdermal route via patches  Cause of death secondary to tolerance and depressed the response
o Potent analgesics over days of carbon dioxide.
5. Cough Suppression
High concentration of opioids are more likely highly perfused in the tissue and the main  Codeine
reservoir is the skeletal muscles.  For pathologic cough
6. Miosis
Opioid Agonist  Pinpoint pupil = opioid overdose
- Metabotropic; Voltage-gated inhibitory  Naloxone – antidote for morphine overdose
- MOA 7. Truncal Rigidity
o Produce analgesia by binding to specific G-CHON coupled receptor located in 8. Nausea and Vomiting
brain and spinal cord involved in transmission and modulation of pain. 9. Temperature
10. Sleep architecture
Opioid Receptor
- Peripheral sensory nerve endings and afferent end -sensory Peripheral Effect:
o Presynaptic- Calcium close 1. Emesis
o Postsynaptic- Potassium open 2. GIT
 Causes hyperpolarization o Constipation
3. Paregoric
Withdrawal / Abstinence Syndrome 4. Uterus
- When a drug is stopped or an antagonist is administered o Fentanyl and Meperidine inhibit the uterine contractility
Tolerance and independence o Epidural anesthesia – 2nd stage labor
- Frequently repeated therapeutic doses of morphine 5. Pruritus
- Gradual loss in effectiveness o Morphine and Codeine
 Produce flushing and warming of skin
 Sweating, utecaria, itching
 Peripheral histamine release

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 Pharmacology 1
Clinical Uses: - Upon discontinuing methadone, the
1. Analgesia addict experiences a mild but
2. Acute Pulmonary Edema endurable withdrawal syndrome
3. Cough Phenylpiperidines Fentanyl
4. Diarrhea - 100x more potent than morphine
5. Chronic Heart Failure
6. For Terminal Illness
Mild to Moderate Agonist
Adverse Effects with Acute Use Adverse Effect with Chronic Use Codeine Oxycodone
1. Respiratory depression 1. Hypogonadism - The prototype - 2x more potent than morphine
2. Nausea and vomiting 2. Immunosuppression Dihydrocodeine Propoxyphene
3. Pruritus 3. Increase feeding - Chemically related to methadone,
4. Urticaria 4. Increase growth hormone secretion low analgesia activity
5. Constipation 5. Withdrawal effect Hydrocodone Diphenoxylate
6. Urinary retention 6. Tolerance and dependence - Its metabolite DIFENOXIN used for
7. Delirium 7. Abuse or addiction analgesia but for the treatment of
8. Sedation 8. Hyperalgesia Diarrhea
9. Myoclonus 9. Impairment while driving Loperamide
10. Seizures - Used to control diarrhea

Strong Agonist
Morphine
- Prototype
Hydromorphone
Phenanthrenes - 8-10x more potent than morphine
Oxymorphone
Heroine (diamorphine, diacetylmorphine)
- 3x more potent than morphine
- Can cross blood brain barriers

Methadone
- Potent M-receptor agonist
- Well absorbed in the GIT
Phenylheptylamines - Used in the treatment of opioid
abuse

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