• Drugs Agents that act on the brain and spinal cord
• Medical uses
• Psychiatric disorders, suppression of seizures, pain relief, production of anesthesia
• Nonmedical uses
• Stimulant, depressant, euphoriant, and other “ mind-altering ” abilities

• Impedes entry of drugs into the brain
• Passage across the BBB limited to lipid-soluble drugs
• Protein-bound or highly ionized drugs cannot cross
• Mixed blessing of BBB

• PD is a neurodegenerative disorder of the extrapyramidal system associated with disruption of neurotransmission in the striatum
• Characterized by dyskinesias and akinesia
• Proper function of the striatum requires a balance between the neurotransmitters dopamine and acetylcholine (ACh)
• Imbalance between dopamine and ACh results from degeneration of the neurons that supply dopamine to the striatum

• Ideal treatment (reverse neuronal degeneration or prevent further degeneration) does not exist
• Goal is to improve patient’s ability to carry out activities of daily life
• Drug selection and dosages are determined by extent to which PD interferes with work, dressing, eating, bathing, etc.

• Dopaminergic Agents
• Anticholinergic Agents

• By far the most commonly used drugs for PD
• Promote activation of dopamine receptors
• Levodopa (Dopar)

• Prevent activation of cholinergic receptors
• Benztropine (Cogentin)

• Highly effective, but benefits diminish over time
• Most effective in first 2 years – by end of 5 years, symptoms may return to pretreatment level
• Acute loss of effect and on-off phenomenon
• Orally administered, rapid absorption from small intestine
• Food delays absorption
• Neutral amino acids compete with levodopa for intestinal absorption and for transport across blood-brain barrier
• High-protein foods will reduce therapeutic effects

• Advantages
• No adverse effects of its own
• Increases the available levodopa in the CNS and allows for 75% decrease of levodopa dosage; therefore reduces cardiovascular and GI adverse effects
• Effects come mainly from levodopa when given in combination
• Levodopa/ carbidopa ( Sinemet , Paracopa )

• First-line drugs fro PD
• direct activation of dopamine receptors in striatum
• Less effective than levodopa
• not dependent on enzymatic conversion to be ative
• do not compete with dietary proteins
• lower incidence of response failure and less likely to cause dyskinesias

• Devastating illness
• Progressive memory loss
• Impaired thinking
• Neuropsychiatric symptoms
• Inability to perform routine tasks of daily living

• Memory loss
• Confusion
• Feeling disoriented
• Impaired judgment
• Personality changes
• Difficulty with self-care
• Behavior problems (wandering, pacing, agitation, screaming)
• Inability to recognize family members
• Inability to communicate

• Goal of treatment is to improve symptoms and reverse cognitive decline.
•  Available drugs cannot do this.
• Five drugs are approved for AD dementia (none very effective).

• Neuronal receptor Blocker (memantine)
• Cholinesterase Inhibitors (Donepezil, Galantamine, Rivastigmine, Tacrine)

• Indicated for mild to moderate AD
• Prevent breakdown of ACh
• May help to slow progression of disease
• Only three recommended for use – equivalent benefits: Donepezil Galantamine Rivastigmine
• Not recommended – causes liver damage: Tacrine

• First drug in a new class, the NMDA receptor antagonists
• Indicated for moderate to severe AD
• Better tolerated than cholinesterase inhibitors

• Simple Partial
• Complex Partial
• Secondarily Generalized

• Tonic-clonic (grand mal)
• Absence (petit mal)
• Atonic
• Myoclonic
• Status Epilepticus
• Febrile

• Manifest with discrete symptoms that are determined by the brain region involved
• Patient may experience discrete motor symtoms, sensory symptoms, autonomic symptoms, or psychoillusory symptoms
• No loss of consciousness
• 20-60 seconds

• impaired consciousness
• lack of responsiveness
• motionless and stares with a fixed gaze
• followed by a period of automatism
• 45 to 90 seconds

• Begin as simple or complex partial seizures then evolve into generalized tonic-clonic seizure
• consciousness is lost
• 1-2minutes

• seizure activity begins focally in the cerebral cortex and usually undergoes limited spread to adjacent cortical areas

• Neuronal discharge spreads throughout both hemispheres of the cerebral cortex
• major convulsions, followed by synchronous muscle jerks.
• often cause urination, but not defecation
• marked impairment of consciousness and followed by a period of CNS depression (postictal state)
• <90seconds

• loss of consciousness for a brief time (10-30sec)
• mild, symmetric motor activity (eg eye blinking)
• may occur with no motor activity
• occur primarily in children

• characterized by a sudden loss of muscle tone
• occurs mainly in children

• sudden muscle contractions that last for just one second.
• seizure activity may be limited to one limb or may involve the entire body

• a seizure that persists for 30 minutes or longer

• Fever associated seizures
• common comg children ages 6mo-5yrs
• manifest as generalized tonic-clonic convulsions of short duration

• Partial and tonic-clonic seizures
• Mechanism of action: selective inhibition of sodium channels
• Varied oral absorption
• Half-life: 8 to 60 hours

alter synaptic transmission

Drugs that alter synaptic transmission can produce effects that are much more selectie than those produced by drugs that alter axonal conduction

• slowing heart rate
• increased gastric secretion
• emptying of bladder
• emptying of bowel
• focusing the eye for near vision
• constricting the pupil
• contracting bronchial smooth muscle

• Regulating the cardiovascular system
• regulating body temp
• implementing the fight-or-flight reaction

Cholinergic

Adrenergic

• Acetylcholine
• norepinephrine
• epinephrine

1. synapses between preganglionic neurons and postganglionic neurons
2. the junctions between postganglionic neurons and their effector organs

• PNS neurotransmitter
• released by all pre/postganglionic neurons of the parasympathetic nervous system and all pre/post ganglionic neurons of the sympathetic nervous system and all motor neurons to skeletal muscles

• PNS neurotransmitter
• released by practially all postganglionic neurons of the sympathetic nervous system (eceptions: postganglionic symp neurons that go to sweat glands)

• Nicotinic_M
• Nicotinic_N
• Muscarinic
  

• Alpha₁
• Alpha₂
• Beta₁
• Beta₂
• Dopamine
  

• produce their effects by preventing receptor activation by endogenous regulatory molecules and drugs

• heart
• exocrine glands
• smooth muscles
• eye

produces bradycardia

• Lung and GI tract
• contraction
• Bladder
• --> bladder emptying
• Vascular Smooth Muscle
• relaxation
• hypotension

1. pupillary constriction
2. accomodation

• urinary retention
• GERD
• GI paralysis

• competetive blockade at muscarinic receptors
• all responses to atropine result from preventing receptor activation by endogenous ACh
• atropine has no direct effects of its own.

• Anticholinergic drugimilar to atropine, but with two exceptions:
• therapeutic doses of atropine produce mild CNS excitation, therapeutic doses of scopalamine produce sedation
• scopolamine suppresses emesis and motion sickness, atropine does not
• Use in motion sickness

located in the eyes, blood vessels, male sex organs, prostatic capsule and bladder.

• vasoconstriction
• ejaculation
• bladder contraction
• pupil dilation

• located on nerve terminals and not on the organs inervated by the autonomic nervous system.
• function is to regulate transmitter release
• Reduction of SNS
• relief of severe pain

located in heart and kidney

activation:

• increases heart rate, force of contraciton and velocity of impulse conduction
• release of renin in the blood (elevates BP)

activation

• lungs: bronchodilation
• uterine relaxation
• heart, lungs, skeletal muscles: vasodilation
• increases blood levels of glucose

located in vasculature of the kidney

dilates renal blood vessels (enhances renal perfusion)

• drugs that block beta1 AND beta2 receptors
• produce a broader spectrum of adverse affects than selective beta blockers

Treatment of:

• angina pectoris
• hypertension
• cardiac dysrhythmias
• MI
• Heart Failure
• Hyperthyroidism
• Migraine
• Stage Fright
• Pheochromocytoma
• Glacoma

• Bradycardia
• Reduced Cardiac Output
• Precipitation of Heart Failure
• AV heart block
• rebound cardiac excitation
• bronchoconstrictio

• delay absorption of local anesthetic
• control superficial bleeding
• elevate blood pressure
• mydriasis during ophthalmologic procedures
• overcome AV block
• restore cardiac fxn in arrest
• bronchial dilation in asthma
• treatment of choice for anaphylactic shock

• Characterized by fluctuating muscle weakness and predisposition to rapid fatigue
• Common symptoms:
• ptosis, dysphagia, weakness of skeletal muscles
• Autoimmune process in which antibodies attack nicotinicm receptors on skeletal muscle

• characterized by extreme muscle weakness or frank paralysis and signs of excessive muscarinic stimulation
• too much ACh
• treatment with respiratory support and atropine

• Very short acting cholinesterase inhibitor (causes increase of ACh)
• used to distinguish Myasthenic crisis from cholinergic crisis
• if patient gets better... then Myasthenic crisis
• if patient gets worse... then Cholinergic crisis

• Muscle relaxation during surgery
• facilitation of mechanical ventilation
• adjunct to ECT
• endotracheal intubation
• diagnosis of myasthenia gravis

• dry mouth
• blurred vision
• photophobia
• urinary retention
• constipation
• tachycardia
• anhidrosis
• orthostatichyptension