CNS Pharmacology

Munir Gharaibeh, MD, PhD, MHPESchool of Medicine

The University of JordanFebruary, 2018

mgharaib@ju.edu.jo

Synaptic TransmissionSynapses: Electrical

ChemicalTransmission:

UnidirectionalDelay Fatigue Selectivity to Drugs Specificity of Transmitter

3

NeurotransmittersChemical substances responsible for

the chemical communication across synapses and other neuro-effector junctions.

Act by causing changes in the ionic conductivity of the membrane and consequent shifts in membrane potentials.

May also be found in plants and microorganisms.February 18 Munir Gharaibeh, MD, PhD, MHPE

4

NeurotransmittersEssential Criteria:Regional distribution and

localization.Synthesis.Storage.Release.Termination of action.Reproducibility of action(Synaptic Mimicry).

February 18 Munir Gharaibeh, MD, PhD, MHPE

5

Neurotransmitters

Methods of Study:Histochemical fluorescence.Immunohistochemical studies.Concentration of agents in sections.MicroiontophoresisPharmacodynamic studies.Receptor studies.

February 18 Munir Gharaibeh, MD, PhD, MHPE

6February 18 Munir Gharaibeh, MD, PhD, MHPE

7February 18 Munir Gharaibeh, MD, PhD, MHPE

8

Neurohormones

Are hormones arising from neurones.

February 18 Munir Gharaibeh, MD, PhD, MHPE

9

Neuromodulators

Substances that can influence neuronal activity differently than neurotransmitters.

They originate from cellular and nonsynaptic sites (e.g. CO2,NH4, steroids, adenosine, PGs), and influence the general level of neuronal excitability without altering the membrane potential.

February 18 Munir Gharaibeh, MD, PhD, MHPE

10

Neuromediators

Substances that participate in the elicitation of postsynaptic response to a neurotransmitter or a modulator( e.g. cAMP, cGMP).

February 18 Munir Gharaibeh, MD, PhD, MHPE

11

Factors Affecting Intensity and Duration of CNS Drugs

Concentration in blood.Blood Brain Barrier(BBB).Receptor binding.Effect on storage of the transmitter.

February 18 Munir Gharaibeh, MD, PhD, MHPE

12

General Anesthesian Definition:

Loss of memory, awareness, and pain sensation, during a medical procedure, together with loss of reflexes, and skeletal muscle relaxation.

February 18 Munir Gharaibeh, MD, PhD, MHPE

13

Features of an Ideal General Anestheticn Rapid loss of awareness and memory.n Rapid emergence or recovery.n Analgesia just to limit reflexes.n Minimal and reversible influence on vital

signs.n Relaxation of skeletal muscles.n Operating room safety.Balanced Anesthesia:n Multi drug approach to manage the

patient’s anesthetic needs.February 18 Munir Gharaibeh, MD, PhD, MHPE

14

Phases of Anesthesia

n Inductionn Maintenancen Emergence = Recovery

February 18 Munir Gharaibeh, MD, PhD, MHPE

15

Stages of Ether Anesthesia. Stage I: “ Analgesia”

Amnesia and euphoria.

. Stage II: “Excitement”Delirium and combative behavior.

. Stage III: “Surgical Anesthesia”Anesthesia, regular respiration and decreasing eye

movements.

. Stage IV: “Medullary Depression”Respiratory and cardiac depression and arrest and

no eye movements. February 18 Munir Gharaibeh, MD, PhD, MHPE

February 18 Munir Gharaibeh, MD, PhD, MHPE 16

17

Preanesthetic Medications" Premedication"

n Opioids: to relieve pain.n Benzodiazepines: to relieve anxiety.n Antimuscarinics: to reduce secretions.n Antihistamines: to prevent allergy.n Antiemetics: to prevent vomiting.

February 18 Munir Gharaibeh, MD, PhD, MHPE

February 18 Munir Gharaibeh, MD, PhD, MHPE 18

19

Intravenous Anesthesian Very lipid soluble drugs.n Have very short t½a.n Slowly metabolized & excreted so,

termination of action depends on: Redistribution (recovery times are similar despite remarkable differences in metabolism)

n Repeated administration leads to delayed awakening.

n Computer assisted i.v. administration (Total Intravenous Anesthesia TIVA).

February 18 Munir Gharaibeh, MD, PhD, MHPE

20

Redistribution of Thiopental after IV bolus administration.

February 18 Munir Gharaibeh, MD, PhD, MHPE

21

Intravenous AnesthesiaGeneral Uses:n Ideally suitable for Induction. n Maintenance of short procedures. n Supplement inhalational anesthesia.

February 18 Munir Gharaibeh, MD, PhD, MHPE

22

Chemical structures of intravenous anesthetics.

February 18 Munir Gharaibeh, MD, PhD, MHPE

23

Ultra Short Acting Barbituratesn Thiopental ------- most popular i.v. agent for

induction

n Methohexital -------- very short acting, less ppt.

n Weak acids, can precipitate . If given in an artery?

n Patients may react to painful stimuli but: – Unaware, Do not remember.– Cardiorespiratory depressants

February 18 Munir Gharaibeh, MD, PhD, MHPE

24

Benzodiazepinesn Diazepam --- viscous formulation so can

precipitate.

n Midazolam --- aqueous , t½ 2hrs.

n Lorazepam --- long t½, viscous.n All do not depress cardiorespiratory

function. n Flumazenil, is the antidote for overdose.

February 18 Munir Gharaibeh, MD, PhD, MHPE

25

Ketaminen Dissociative Anesthesia:

– Profound analgesia, amnesia and superficial sleep.

– Patient appears awake and reactive but does not respond to sensory stimuli.

n Blocks glutamic acid at NMDA receptor n IMn Ambulatory conditions ---used in military

medicine and children. February 18 Munir Gharaibeh, MD, PhD, MHPE

26

Ketamine

n Catatonia( a state of apparent :( دوماجunresponsiveness to external stimuli in a person who is apparently awake, with mild increase in muscle tone, eyes opened and nystagmus.

n Pharyngeal and laryngeal reflexes are maintained causing laryngospasm, cough, salivation and vomiting.

n Maintains cardiovascular function.February 18 Munir Gharaibeh, MD, PhD, MHPE

27

Ketaminen May evoke excitatory and hallucinatory

phenomena during emergence, so needs a quiet recovery room.

n Might also cause shivering, tachycardia, increased intracranial and intraocular pressures.

February 18 Munir Gharaibeh, MD, PhD, MHPE

28

PropofolMost popular IV anesthetic, replaced

thiopental.Not analgesic but lowers dose of opioid

needed.Widely used in ICU patients to produce

prolonged sedationProduces euphoria--- good for induction.n Anti-emetic, better postoperative period.n Pain at site of injection, muscle tremors. n Rapidly metabolized

February 18 Munir Gharaibeh, MD, PhD, MHPE

29

Opioids

Suitable for cardiac surgery.n Not good amnesics.n Supplement others. n Continuous infusion will depress

ventilation.

February 18 Munir Gharaibeh, MD, PhD, MHPE

30

Opioidsn Morphine --- lowers BP,

Bronchospasmn Meperidine ----- Increases HRn Fentanyln Sufentaniln Alfentaniln Remifentanil.

February 18 Munir Gharaibeh, MD, PhD, MHPE

31

Half-life time of common intravenous anesthetics

February 18 Munir Gharaibeh, MD, PhD, MHPE