Histology Pathways of CNS ( Ascending tracts carrying conscious sensation )
Pain & temp. pathway
This pathway carries pain & temp.
General impulses to the conscious levels of
the cerebral cortex.
- free nerve endings:
For pain
Receptors
- thermoreceptors :
For tempreture.
- These are the small pseudo-
unipolar cells of the dorsal root
ganglia.
Their peripheral process (in the spinal
nerves) receive the impulses from the
receptors
1st order Their axons enter the spinal cord
through:
neuron
lateral division of the dorsal root
and enter the post. column of spinal
cord.
The fibers ascend for one or two
segments in the " Lissauer's tract"
and end in
- the substantia gelatinosa of Rolandi.
- Postro-marginal nucleus
These are the cells of the
- substantia gelatinosa of Rolandi
- Postro-marginal nucleus
Their axons cross to the opposite
side in the ventral white
commissure to the lateral column
2nd order and ascend there as:
neuron the lateral spino-thalamic tract.
They join the ventral spino-
thalamic tract (in the brain stem)
to form the spinal leminiscus and
finally end in the PLVNT of the
thalamus.
The axons of the nerve cells of the
PLVNT project forming the
3rd order thalamo-cortical radiation
neuron that ends in the sensory area ( in the
post-central gyrus) of the cerebral
cortex.
Touch Pathway
Simple (crude) touch
This pathway carries tactile
impulses to the conscious levels
of the cerebral cortex.
Mechanoreceptors:
- Merkel's cells
- Free nerve endings
- Meissner's corpuscles
- Peritrichial nerve endings
- These are the medium-sized
pseudo-unipolar cells of the
dorsal root ganglia.
Their peripheral process (in the
spinal nerves) receive the impulses
from the touch receptors
Their axons enter the spinal cord
through:
Medial division of the dorsal root
and enter the post. column of
spinal cord.
The fibers ascend and gradually
end around
Main sensory nucleus.
These are the cells of the main
sensory nucleus.
Their axons cross to the opposite
side in the ventral white
commissure to the anterior
column and ascend there as:
ventral spino-thalamic tract.
They join the lateral spino-
thalamic tract (in the brain stem)
to form the spinal leminiscus and
finally end in the PLVNT of the
thalamus.
The axons of the nerve cells of
the PLVNT project forming the
thalamo-cortical radiation
that ends in the sensory area ( in
the post-central gyrus) of the cerebral
cortex.
Fine (Complex) touch
Pathway of the conscious proprioceptive sensation
It carries proprioceptive impulses:
- sense of movement
- postion of joints or limbs
- sense of pressure
- teactile localization,discrimination
- muscle spindle.
- Tendon spindle
- Pacinian corpuscle.
- These are the large pseudo-
unipolar cells of the dorsal root
ganglia.
Their peripheral process (in the
spinal nerves) receive the impulses
from the touch receptors
Their axons enter the spinal cord
through:
Medial division of the dorsal root
and enter the post. column of
spinal cord.
The fibers ascend as:
gracile and cuneate tracts
which end in the
gracile and cuneate nuclei.
These are the cells of gracile and
cuneate nuclei in the closed
medulla oblongata.
Their axons pass as
internal arcuate fibers
cross the midline of the medulla,
then bends upwards to ascend as
the medial leminiscus in the brain
stem.
The fibers reach the thalamus where
they finally end around he cells of the
PLVNT.
The axons of the nerve cells of
the PLVNT project forming the
thalamo-cortical radiation
that ends in the sensory area ( in
the post-central gyrus) of the cerebral
cortex.
 ( Descending tracts )

1- Pyramidal tract ( Corticospinal tracts ) :

which carry motor impulses from cerebral cortex directly to the motor nuclei of the cranial and spinal nerves.

2- Extra-pyramidal tracts
Which carry motor impulses to the motor spinal cord nuclei, but they have some stop stations in the brain stem.
…………………………………………………………………………………………………………………………………………………………….

Pyramidal tract ( Corticospinal tracts ) :

- The pyramidal tract involves 2 divisions :
1- The cortico-spinal tract, supplying the motor nuclei of the spinal cord.
Origin 2- The cortico bulber tract, supplying the motor nuclei of cranial nerves.

The tract arises as the axons of the large Betz cells in the 5th layer of the cerebral cortex.

- The axons of Bets cells converge forming the corona radiate.

- The fibers the descend in the genu and ant. 1/2 of the post. limb of the internal
capsule and then descend in the basis pedunculi ( in the midbrain )

- The tracts distributes as follows :

1- The cortico - bulber fibers :
These descend as two separate bundles:
a- medial cortico-bulber fibers
b- lateral cortico-bulber fibers
Pathway
The two bundles distribute their fibers to the :
- motor nuclei of the cranial nerves: 3rd , 4th , 5th , 6th , 7th , 8th , 9th , 10th , 11th ,
12th
- also to the reticular formation.

2- The cortico - spinal tract:

- These fibers continue in the basis pedunuculi to enter the basis pontis (in the
pons) where they split into bundles between the basilar pontine nuclei.
- They continue down to the medulla to form the pyramid.
- In the lower part of the medulla at its junction with the spinal cord, the fibers of the
cortico-spinal tract divide into 3 bundels:

a- The lateral ( crossed-indirect ) cortico-spinal tract :

- 70-90% of the fibers cross to the opposite side and descend in lateral
column …of the spinal cord as lateral cortico-spinal tract.
- The fibers terminate on the motoneurons(i.e. ant. horn cells)of the
opposite side

b- The anterior ( non-crossed-direct ) cortico-spinal tract :

- 20% of the fibers descend uncrossed at the same side in the anterior
…column of the spinal cord as anterior cortico-spinal tract.
N.B. During the descend, these fibers gradually cross to the opposite side, and the crossing in completed at
the upper thoracic levels of the spinal cord.

- The fibers cross in the corresponding segments of the spinal cord to

terminate …around the motoneurons of the contralateral anterior horn cells.

c- The antro-lateral cortico-spinal tract :

- These few fibers 1-2% descend at the same side in the antro-lateral
region of …the lateral cortico-spinal tract coming from the opposite side.

- The fibers terminate on the motoneurons ( i.e. ant. horn cells ) of the
same side
 Cerebro-Vascular diseases
The term cerebrovascular disease refers any abnormality of the brain caused by a pathologic process involving blood vessels. The three basic processes are :

(1) thrombotic occlusion of vessels - Their effects on the brain is the loss of oxygen and metabolic substrates resulting in ischemic injury or infarction of specific regions in brain
(2) embolic occlusion of vessels - A similar pattern of injury occurs when there is complete loss of perfusion.
(3) vascular rupture. Hemorrhage accompanies rupture of vessels, leading to direct tissue damage as well as secondary ischemic injury.

"Stroke" is the clinical designation that applies to all these conditions, particularly when symptoms begin acutely.
- It is convenient to consider cerebrovascular disease as two processes:
1- Hypoxia, ischemia, and infarction resulting from impairment of blood supply and oxygenation of CNS tissue. 2- Hemorrhage resulting from rupture of CNS vessels .

Global cerebral ischemia Focal cerebral ischemia ( Cerebral infarction )

This occurs when there is a generalized reduction of cerebral perfusion below systolic pressures of less than 50mmHg, Cerebral arterial occlusion leads to focal ischemia and-if sustained-to infarction of CNS tissue.
such as: cardiac arrest, shock, severe hypotension. INFARCTION: an area of coagulative necrosis caused by sudden ischemia produced by either arterial
- The clinical outcome varies with the severity of the insult : supply or venous drainge diseases .
• In Mild transient ischemic insults : 1- in situ thrombosis :
1- May only transient confusional state, with eventual complete recovery. - Most thrombotic occlusions causing cerebral infarctions due to atherosclerosis.
2- Some cases, Irreversible damage of CNS tissue. - Atherosclerotic stenoses can develop, accompanied by distal embolization.
• In severe insults :
2- Embolization from a distant source. (more common)
1- widespread neuronal death occurs. individuals who survive in this state often :
- Sources :
- remain severely impaired neurologically and deeply comatose . 1- Cardiac mural thrombi.
- Others with "brain death," including evidence of diffuse cortical injury and brain stem damage. ( with 2- From atheromatous plaques within the carotid arteries.
absence of reflexes ). 3- Paradoxical emboli, particularly in children with cardiac anomalies.
- Morphology : 4- emboli associated with cardiac surgery;
Gross picture 5- emboli of other material (tumor, fat, or air).
- predisposing factors :
- The brain is swollen, with wide gyri and narrowed sulci.
1- myocardial infarct 2- valvular disease 3- atrial fibrillation
- The cut surface shows poor demarcation between gray and white matter.
Microscopic Picture Types of infarction :
Infarcts is divided into two groups based on their macroscopic and radiologic appearance :
The histopathologic changes of irreversible ischemic injury (infarction) are grouped into three categories 1- Nonhemorrhagic infarcts, can be treated with thrombolytic therapies,
1- Early changes 2- Subacute changes 3- Repair 2- Hemorrhagic infarcts, not treated with thrombolytic,
12 to 24 hours after the insult 24 hours to 2 weeks seen after 2 weeks, N.B.The hemorrhage occurs secondary to reperfusion of ischemic tissue,
characterized by : characterized by : characterized by :
Microvacuolization, followed by - Morphology : morphology of nonhemorrhagic infarct changes in time
- Necrosis of tissue, - removal of all necrotic tissue,
cytoplasmic eosinophilia, and later - loss of organized CNS structure, Gross picture
- influx of macrophages,
nuclear pyknosis and karyorrhexis. - gliosis . By48 hours - Tissue becomes pale, soft, and swollen .
- vascular proliferation, - the corticomedullary junction becomes indistinct.
- Similar changes occur later in - gliosis cerebral cortex :
- the brain becomes gelatinous and friable,
astrocytes and oligodendroglia. the neuronal loss & gliosis produce 2 to 10 days - ill-defined boundary between normal and abnormal tissue
destruction of the neocortex, with - edema
- Reaction to tissue damage begins preservation of some layers, a pattern the tissue liquefies, eventually leaving a fluid-filled cavity lined by dark gray
with infiltration by neutrophils . termed : pseudolaminar necrosis. 10 days to 3 weeks tissue, which gradually expands as dead tissue.
Microscopic Picture
- ischemic neuronal change (red neurons)
- cytotoxic and vasogenic edema.
After the first 12 hours - loss of the usual characteristics of white and gray matter structures.
- glial cells swelling,
- myelinated fiber disintegration .
Until 48 hours there is some neutrophilic emigration
Reactions of neurons to injury - Macrophages containing myelin breakdown products
In response to injury, changes can be observed in neurons and their processes (axons and dendrites). 2 to 3 weeks - phagocytosis and liquefaction proceeds,
- astrocytes enlarge, divide, and develop a network of protoplasmic extensions.
Within 12 hours of an irreversible hypoxic/ischemic insult: - Astrocytic nuclear and cytoplasmic enlargement recedes.
- In the wall of the cavity, astrocyte processes form feltwork of
- Acute neuronal injury becomes evident:
glial fibers + admixed with new capillaries + a few perivascular CT fibers
There is shrinkage of the cell body, pyknosis of the nucleus, disappearance of the nucleolus, After several months
and loss of Nissl substance, with intense eosinophilia of the cytoplasm ("red neurons"). - In the cerebral cortex:
- Areas of cerebral ischemia may progress to coagulative necrosis.(infarction) - the cavity is delimited from the meninges and subarachnoid space
- The pia and arachnoid are not affected
- Injured axons undergo swelling and show disruption of axonal transport.
The microscopic picture and evolution of hemorrhagic infarction parallel ischemic infarction, with the addition
Axonal injury also leads to cell body enlargement and rounding, peripheral displacement of the nucleus, enlargement of the
of blood extravasation and resorption.
-

nucleolus, and dispersion of Nissl substance (from the center of the cell to the periphery ("central chromatolysis")

1- ASTROCYTES produce myelin, have a limited repertoire of morphologic changes, apart from
2- Oligo-dendrocytes
They are principle cells responsible for repair & scar formation in the brain by a procees termed GLIOSIS cell death or damage to myelin, as in multiple sclerosis.

In response to injury, - line the ventricular system

Astrocytes in 1- The astrocytes undergo hypertrophy and hyperplasia. 3- Ependymal cells - Disruption of ependymal cells is associated with a local proliferation of
Other
Injury & Repair 2- The nucleus enlarges and becomes vesicular, and the nucleolus is prominent. subependymal astrocytes to produce small irregularities on ventricular surfaces
3- The previously scant cytoplasm expands to a bright pink, cells termed as (ependymal granulations)
4- There is minimal extracellular matrix deposition.
healing of cerebral
infarction (Gliosis) - In long-standing gliosis, they have less distinct cytoplasm & appear more fibrillar (fibrillary astrocytes) - function as the phagocytes of the CNS.
- They may be recognizable as activated macrophages in areas of
- Rosenthal fibers are thick, elongated, brightly eosinophilic protein aggregates that can be found in demyelination, organizing infarct, or hemorrhage,
astrocytic processes in 1- chronic gliosis and 2- in some low-grade gliomas. 4- Microglia - microglial nodules :
these are elongated microglia form aggregates at sites of tissue injury,
- Corpora amylacea represent a degenerative change in astrocytes , they are round, faintly basophilic,
- neuronophagia :
periodic acid-Schiff (PAS)- positive, concentrically lamellated aggregates of polyglucosans
Similar collections can be found around portions of dying neurons,

Causes of non-trumatic intraparenchymal hemorrhage
The most causes are :
1- massive hypertension (mentioned in details below )
2- vascular malformations ( artrio-venous malformations ) as :
a- cavernous angiomas b- capillary telangiectasias
The hemorrhage results from rupture of a small intraparenchymal vessel
Intracranial hemorrhage
2- Subdural Hemorrhage (traumatic lesion)
The rapid movement of the brain that occurs in trauma can tear the bridging veins that extend from the cerebral
hemispheres through the subarachnoid and subdural space to empty into dural sinuses. leading to bleeding into the
subdural space.
- In elderly patients with brain atrophy the bridging veins are stretched out and the brain has additional space for
c- venous angiomas movement, accounting for the higher rate of subdural hematomas,
- In Infants also susceptible to subdural hematomas because their bridging veins are thin-walled.
- Clinical manifestations include: -headache or confusion. -slowly progressive neurologic deterioration.

1- Hypertensive cerebral hemorrhage 3- Subarachnoid Hemorrhage

- The most important effects of hypertension on the brain include : Causes of subarachnoid hemorrhage is:
1- massive hypertensive intracerebral hemorrhage, 2- lacunar infarcts, 3- slit hemorrhages, 4- hypertensive encephalopathy 1- rupture of a saccular (berry) aneurysm. (most common) 2-from vascular malformation,
3- trauma 4-rupture of an intracerebral hemorrhage into the ventricular system 5-hematologic disturbances 6-tumor
- Hypertension affects the deep penetrating arteries and arterioles that supply the :
Clinical features and possible outcomes :
1- basal ganglia and 2- hemispheric white matter 3-the brain stem. 1- Rupture can occur in anytime but it's associated with increases of intracranial pressure in about 1/3 of patients.
2-Blood is forced under arterial pressure into the subarachnoid space, with suffering of sudden , severe headache and
- Hypertension causes several changes, including: hyaline arteriolar sclerosis , become weaker and more rapidly lose consciousness.
vulnerable to rupture. 3- Between 25% and 50% of individuals die with the first rupture,
- Chronic hypertension develops micro aneurysms in vessels which may rupture later. 4- Those who survive improve and recover consciousness in minutes BUT Recurring bleeding is common, and The
prognosis worsens with each episode of bleeding.
- Lacunar infarcts (Lacunes):
- An important clinical and pathologic outcome of arteriolar sclerosis Saccular (berry) aneurysm - aneurysms with necks or stems resembling a berry -
- These are small cavitary infarcts a few millimeters wide)
2- After a subarachnoid hemorrhage, there is a risk of
- Found most commonly in deep gray matter (basal ganglia and thalamus), internal capsule, deep white matter, and pons, Cerebral aneurysm :
additional ischemic injury from vasospasm involving other
- Morphology they consist of cavities of tissue loss with scattered lipid-laden macrophages and surrounding gliosis. is a cerebrovascular disorder in which weakness in the wall
vessels.
of a cerebral artery or vein causes a localized dilation of BV
-Slit hemorrhage : 3- In the healing phase of subarachnoid hemorrhage,
- Causes: meningeal fibrosis and scarring occur, sometimes leading to
-occurs due to the effect of the hypertension on the small-caliber penetrating vessels & the development of small hemorrhages - They are sometimes referred to as congenital, obstruction of CSF flow as well as interruption of the normal
- Morphology In time, hemorrhages resorb, leaving a slitlike cavity (slit hemorrhage) surrounded by brownish discoloration - Not present at birth but develop over time pathways of CSF resorption.
because of underlying defects in the vessel media.
- Morphology :
- Acute hypertensive encephalopathy: - disorders of extracellular matrix proteins,
- unruptured saccular aneurysm is a thin-walled
- is a clinicopathologic syndrome characterized by : - there is an increased risk of aneurysms in individuals with
outpouching of an artery.
headaches, confusion, vomiting, and convulsions, sometimes leading to coma. autosomal dominant polycystic kidney disease.
- At the neck of the aneurysm, the muscular wall & intimal
- Rapid therapeutically reduction to the accompanying increased intracranial pressure is required.
- Outcomes : - elastic lamina short and are absent from the aneurysm sac
- Morphology Patients with edematous brain, with or without transtentorial or tonsillar herniation. Petechiae and fibrinoid 1-probability of rupture increases with the size of the - the sac is made up of thickened hyalinized intima.
necrosis of arterioles in the gray & white matter may be seen microscopically lesion - Adventitia covering the sac continuous with the artery
 Seziures
A) First aid management of seizures : Status epilepticus Diagnosis
1- Move person away from danger (fire, water, machinery, furniture)
2- After convulsions cease, turn person into ‘recovery’ position (semi
(semi-prone) Definition : 1- History :
3- Ensure airway is clear but Don't insert anything in mouth ( tongue-biting occurs at seizure onset and cannot be prevented by observers). The diagnosis of a seizure is essentially a clinical one based on taking a history from
m the patient
pa and any witnesses :
• Status epilepticus is seizure activity not resolving spontaneously, or
4- Summon urgent medical attention if convulsions : a- Con8nue for more than 5 mins or
• recurrent seizure with no recovery ry of consciousness in between.
b- Recur without person regaining consciousness
5- Do not leave person alone until fully recovered (drowsiness & confusion can persist for up to 1 hr)
Causes :
B) Lifestyle advice : 1- In patients with pre-existing
existing epilepsy, fall in anti-epileptic
anti drug levels.
• Patients should to avoid activities where they might be at risk for themselves or others if they have a 2- In de novo status epilepticus, exclude precipitants such as :
seizure: - infection (meningitis, encephalitis),
- At home, only shallow baths (or showers) should be taken.
- Prolonged cycle journeys should be discouraged.
- neoplasia
- metabolic derangement (hypoglycaemia, hyponatraemia, hypocalcaemia).
C) Anticonvulsant therapy :
• Indication : Should be considered after more than one unprovoked seizure. Diagnosis , is clinical :
• Mechanism : A wide range of drugs is availa
available. • Prolonged rigidity and/or clonic movements with loss of awareness.
- These agents either : • Cyanosis, pyrexia, acidosis and sweating
1- Increase inhibitory neurotransmission in the brain or • Complications include :
2- Alter neuronal sodium channels to prevent abnormally rapid transmission of impulses. - Aspiration, - Hypotension,
• Guidelines for anticonvulsant therapy :
Start with one first-line drug (see Box 26.46)
- Cardiac arrhythmias - Renal or hepatic failure.
Start at a low dose; gradually increase dose until effective control of seizures is
achieved or side-effects
effects develop (drug levels may be helpful)
Treatment and investigation :
2- Investigations :
Optimise compliance (use minimum number of doses per day) Initial
side-effects develop), start second first-line
If first drug fails (seizures continue or side • Ensure airway is patent; give oxygen to prevent cerebral hypoxia
drug,, followed if possible by gradual withdrawal of first • Check pulse, blood pressure, BM stix® and respiratory rate
If second drug fails, start second
second-line drug in combination with preferred first-line • Secure intravenous acces
drug at maximum tolerated dose (beware interactions) • Send blood for:
If this combination fails replace second
second-line drug with alternative second-line drug - Glucose, urea and electrolytes, calcium and magnesium, liver
If this combination fails function, anti-epileptic
epileptic drug levels
- check compliance and reconsider diagnosis (Are events seizures? - Occult lesion? - Full blood count and clotting screen
- Treatment compliance/alcohol/drugs confounding response?) - Storing a sample for future analysis (e.g. drug misuse)
Consider alternative, non-drugdrug treatments (e.g.epilepsy surgery, vagal nerve stimulation) • If seizures continue for > 5 mins: give diazepam 10 mg IV (or rectally)
or lorazepam 4 mg IV; repeat once only aDer 15 mins
• Correct any metabolic trigger, e.g. hypoglycaemia
hypogly 1- Blood tests
2- ECG (rhythm, conduction abnormalities, QT interval).
are necessary in most patients following an episode of loss of consciousness
Ongoing 3- Electroencephalography
If seizures con.nue a/er 30 mins EEG is most useful to categorize epilepsy and understand its cause, rather than as a means
me of confirming a
• IV infusion (with cardiac monitoring) with one of: doubtful diagnosis of epilepsy.
• EEG abnormalities in epilepsy:
epilepsy
- Phenytoin: 15 mg/kg at 50 mg/min - Focal
ocal cortical spikes (e.g. over a temporal lobe) or
- Fosphenytoin: 15 mg/kg at 100 mg/min - Generalized spike
eneralized spike-andwave activity (in PGE).
- Phenobarbital: 10 mg/kg at 100 mg/min - Epileptic activity is continuous in status epilepticus.
• Cardiac monitor and pulse oximetry • Sleep recordings or 24 h ambulatory EEG: EEG increase sensitivity when routine EEG is normal.
• Inpatient EEG videotelemetry : helpful for diagnosis in attacks of uncertain cause.
- Monitor neurological condition, blood pressure, respiration;
check blood gases 4- Brain imaging : MRI
Indications :
If seizures s.ll con.nue a/er 30–60
30 mins 1- After
fter a first seizure, particularly with partial onset seizures
Withdrawing anticonvulsant therapy 2- Older
lder patients where the chance of a focal brain lesion is greatest.
• Transfer to intensive care
• Indications : After a patient has been seizure
seizure-free for more than 2 years. In pa8ents below the age of 30 with a definite electro-clinical
electro clinical diagnosis of primary generalized
- Start treatment for refractory status with intubation, epilepsy brain imaging is not essential.
• Prognosis : ventilation and general anaesthesia using propofol or
- Childhood-onset
onset epilepsy, particularly classical absence seizures, carries the best prognosis for thiopental
successful drug withdrawal.
- EEG monitor
- Other epilepsy syndromes, such as juvenile myoclonic epilepsy, have a marked tendency to recur after
drug withdrawal.
- Seizures thatat begin in adult life, particularly those with partial features, are also likely to recur, especially Once status controlled
if there is an identified structural lesion. • Commence longer-term
term anticonvulsant medication with one of:
D) Epilepsy surgery : - Sodium valproate 10 mg/kg IV over 3–53 mins, then 800–2000
• Indications : All those who continue to experience seizures despite appro
appropriate drug treatment should mg/day
be considered for surgical treatment. - Phenytoin: give loading dose (if not already used as above) of
• Procedures : 15 mg/kg, infuse at < 50 mg/min, then 300 mg/day
1- Invasive : Surgical resection of epileptogenic brain tissue. - Carbamazepine
ine 400 mg by nasogastric tube,then
tube, 400–1200
2- Less invasive, including: a- Vagal nerve stimulation oor b- Deep brain stimulation mg/day
 Stroke
Management is aimed at :
1- Minimising
inimising the volume of brain that is irreversibly damaged,
2- Preventing complications ,
3- Reducing
educing the patient’s disability and handicap through rehabilitation,
4- Rreducing
reducing the risk of recurrent stroke or other vascular events..

1- Supportive care :
• Early admission to a specialised stroke unit facilitates coordinated care from a spe
specialised multidisciplinary team.
• Feeding :
- Dysphagia is common detected by an early bedside test of swallowing.
- This allows hydration,, feeding and medication to be given safely, if necessary by nasogastric tube or IV.
• Neurological deficit :
- The patient’s neurological deficits may worsen during the first few hours or days after their onset.
- Causes :
1- With lacunar infarcts
2- Extension of the area of infarction,
3- Haemorrhage transformation,
4- Development of oedema
It is important to distinguish these patients from those who are deteriorating as a result of
complications such as hypoxia, sepsis, epileptic seizures or metabolic abnormalities that may be
reversed more easily :
- Patients with cerebellar haematomas or infarcts may develop obstructive hydrocephalus
Treated by insertion of a ventricular drain and/or decompressive surgery

- Patients with cerebellar haematomas or infarcts may benefit from :

a- Anti-oedema
oedema agents, such as mannitol or artificial ventilation.
b- Surgical decompression to reduce intracranial pressure

2- Thrombolysis
• Drug: IV recombinant tissue plasminogen activator (rt
(rt-PA).
• Time: within 4.5 hours of symptom onset to carefully selected pa8ents, the haemorrhagic risk is decreases.
• Side effects: Increases the risk of haemorrhagic transforma8on of the cerebral infarct if given > 4.5 h .

3- Aspirin
• In absence of contraindica8ons, aspirin (300 mg daily) should be started immediately aDer an ischaemic stroke
unless rt-PA has been given,
iven, in which case it should be withheld for at least 24 hours.
• Effects of Aspirin : reduces the risk of early recurrence

4- Heparin Anticoagulation with heparin has been widely used to treat acute ischaemic stroke in the past.
• Whilst it reduces the risk of early ischaemic recurrence and venous thromboembolism, :
1- It increases the risk of both: intracranial & extracranial haemorrhage.
2- Routine
outine use of heparin does not result in better long
long-term outcomes,
therefore it should not be used in the routine management of acute stroke.
• Precautions: Intracranial haemorrhage must be excluded on brain imaging before considering anticoagulation.

5- Coagulation abnormalities
• In those with intracerebral haemorrhage,, coagulation abnormalities should be reversed as quickly as possible
to reduce the likelihood of the haematoma enlarging.
• This most commonly arises in those on warfarin therapy.

6- Management of risk factors : The approaches used are summarised in (Figure 27.11 )
- The average risk of a further stroke is : 5–10%
10% within the first week of a stroke or TIA, Fig. 27.11 Strategies for secondary preven8on of stroke. (1) Lower BP with cau8on in pa8ents with postural hypotension, renal impairment
impairm
15% in the first year or bilateral caro8d stenosis. (2) Pravasta8n 40 mg can be used as an alterna8ve to simvasta8n in pa8ents on warfarin or digoxin. (3)
5% per year thereaDer. Warfarin and aspirin can be used in combina8on in pa8ents with prosthe8c heart valves. (4) The combina8on of aspirin and clopidogrel is
• Patients with ischaemic events should receive long term : only indicated in patients
patients with unstable angina who demonstrate ECG or enzyme changes.
1- Antiplatelet drugs and
2- Statins to lower cholesterol.
• Patients in atrial fibrillation :
1- Oral an8coagula8on to achieve an INR of 2–3. risk can be reduced by about 60%
2- The role of newer oral anticoagulants (such as dabigatran) is currently being investigated. The risk of
recurrence after both ischaemic and haemorrhagic strokes can be reduce
reduced by blood pressure reduction,
even for those with relatively normal blood pressures ((Box 27.12).
7- Carotid endarterectomy and angioplasty
- A small propor8on of pa8ents with a caro8d ischaemic stroke or TIA will have a greater than 50%
stenosis of the carotid artery on the side of the brain lesion. Such patients have a greater than
average risk of stroke recurrence.
• Effectiveness : Surgery is most effective in patients with :
1- More severe stenoses (70–99%)
2- Whom performed within the first couple ple of weeks after the TIA or ischaemic stroke.
• Procedure :
1- Carotid angioplasty & stenting
2- Endarterectomy (more effective).
Endarterectomy of asymptomatic carotid stenosis has been shown to reduce the subsequent risk of stroke, but the small
absolute benefit does not justify its routine use.
CNS Tumors :
Gliomas
the most common group of primary brain tumors, they are tumors of the brain parenchyma that histologically resemble different types of glial cells

1- Astrocytomas 2- Oligodendrogliomas 3- Ependymomas

Several different categories of astrocytic tumors are recognized :
- On Macroscopic examination : - On Macroscopic examination :
1- Fibrillary Astrocytoma : They are infiltrative tumors that form : They are solid or papillary masses extending from the floor of the 4th ventricle.
- 80% of adult primary brain tumors, usually found in the cerebral hemispheres. - gelatinous, gray masses,
- may show cysts, focal hemorrhage, and calcification.
Fibrillary astrocytomas show a spectrum of histologic differentiation, based on the
degree of differentiation, they are classified into three groups:
- On microscopic examination:
1-astrocytoma, - On microscopic examination: The tumor is composed of :
2- anaplastic astrocytoma, - cells with regular, round to oval nuclei with abundant granular
3- glioblastoma . the tumor is composed of : chromatin.
- sheets of regular cells
- with spherical nuclei containing finely granular chromatin (similar to - Between the nuclei there is a variably dense fibrillary background.
- MORPHOLOGY : normal oligodendrocytes) surrounded by a clear halo of cytoplasm.

- The macroscopic appearance:

1- a poorly defined, infiltrative tumor that expands and distorts the invaded
brain
2- Some areas are firm and white, others are soft and yellow (the result of
tissue necrosis).
3- The cut surface of the tumor is either firm, or soft and gelatinous; cystic
degeneration may be seen.
4- In glioblastoma, there is a variation in the gross appearance of the
tumor from region to region.

- The microscopic appearance & grading : Tumor cells may form round or elongated structures (rosettes, canals) that
resemble the embryologic ependymal canal, with long, delicate processes extending
1- Astrocytoma: ( well-differentiated ) are characterized by : - The tumor contains a delicate network of anastomosing capillaries. into a lumen (Fig. 23-23B);
- mild to moderate increase in the number of glial cell nuclei - Calcification ranges from microscopic foci to massive depositions. more frequently present are perivascular pseudo-rosettes in which tumor cells
- nuclear pleomorphism, and an intervening feltwork of fine, GFAP- are arranged around vessels with an intervening zone consisting of thin ependymal
positive astrocytic cell processes that give the background a fibrillary - Mitotic activity is usually very difficult to detect. processes directed toward the wall of the vessel.
appearance.
- With increasing cell density, nuclear anaplasia, increased mitotic activity and With increasing cell density, nuclear anaplasia, increased mitotic activity and
- tumor cells can be seen infiltrating normal tissue at some distance from necrosis, the tumor becomes higher grade (anaplastic oligodendroglioma). necrosis, the tumor becomes higher grade (anaplastic ependymomas).
the main lesion.

2- Anaplastic astrocytomas ( moderately differentiated ) : Poorly Differentiated Neoplasms Other parenchyma tumors
- show regions that are more densely cellular and have greater nuclear
pleomorphism; with ncreased mitoses. - Medulloblastoma - Meningioma
The tumor is highly malignant. Meningiomas are benign tumors of adults, usually attached to the dura, arising from
3- glioblastoma ( poorly differentiated ) : the meningothelial cell of the arachnoid.
- On Macroscopic examination :
- The highest grade tumor, - On Macroscopic examination :
- it has a histologic appearance similar to anaplastic astrocytoma with the In children they are located in the midline of the cerebellum; in In adults
additional features of " lateral tumors occur more often. - Meningioma is attached to the dura with compression of underlying brain ,, my
extend to the overlying bone.
- necrosis and endothelial cell proliferation and pseudo- The tumor is often well circumscribed, gray, and friable, and may be seen extending
palisading nuclei.
to the surface of the cerebellar folia and involving the leptomeninges
- On microscopic examination:
- On microscopic examination:
2- Pilocytic Astrocytoma There are many different histologic patterns found in meningiomas, including:
They are extremely cellular, with sheets of anaplastic ("small blue") cells.
They are relatively benign tumors, often cystic, that occur in children and young 1- syncytial, clusters of cells sit in tight groups without visible cell membranes;
adults, and usually located in the cerebellum. Individual tumor cells are small, with little cytoplasm and hyperchromatic nuclei;
mitoses are abundant. 2- fibroblastic, with elongated cells and abundant collagen deposition between
- MORPHOLOGY : them;
- It is often cystic, with a mural nodule in the wall of the cyst; if solid, it
3- transitional, which shares features of the syncytial and fibroblastic types;
is usually well circumscribed.
- The tumor is composed of areas with bipolar cells with long, thin 4- psammomatous, with numerous psammoma bodies (Fig. 23-25B);
"hairlike" processes that are GFAP positive;
- Rosenthal fibers, eosinophilic granular bodies, and microcysts are often
present.
- Molecular genetics :
Certain genetic alterations is associated with the progression of infiltrating
astrocytomas from low to high grade
- Alterations most common in the low-grade astrocytomas are:
- mutations affecting p53
- overexpression of platelet-derived growth factor α (PDGF-A) and its receptor. 5- secretory, with PAS-positive intracytoplasmic droplets and intracellular
- The transition to higher grade astrocytoma is associated with: lumina by electron microscopy;

- disruption of two well-known tumor suppressor genes: RB --- 6- microcystic, with a loose, spongy appearance.
p16/CDKNaA --- tumor suppressor on chr. 19q.
(primary glioblastoma), - Atypical meningiomas
as new onset disease, occurs in older individuals lesions with a higher rate of recurrence, more aggressive local growth,

(secondary glioblastoma). - Anaplastic (malignant) meningiomas

younger patients with a past history of lower-grade astrocytoma. are highly aggressive tumors that resemble a high-grade sarcoma,

the molecular lesions found in the two types of glioblastoma tend to impinge on the
Metastatic Tumors
same pathways. For example: - Metastatic lesions, mostly carcinomas, account for approximately a quarter to half of intracranial tumors in hospital patients.
- The five most common primary sites are: lung, breast, skin (melanoma), kidney, and gastrointestinal tract,
1- Secondary glioblastomas usually have p53 mutations, WHILE
primary astrocytomas more commonly have amplification of MDM2, a gene that
encodes an inhibitor of p53. - MORPHOLOGY :
2- Similarly, while secondary glioblastomas have increased signaling through the
- Intraparenchymal metastases form sharply demarcated masses, often at the junction of gray matter and white matter,
PDGF-A receptor, WHILE primary glioblastomas often have amplified, mutated usually surrounded by a zone of edema.
epidermal growth factor receptor (EGFR) genes, which encode aberrant forms of - The boundary between tumor and brain parenchyma is well defined microscopically as well,
EGFR known as EGFRvIII.
- Nodules of tumor, often with central areas of necrosis, are surrounded by reactive gliosis.
Both types of mutations lead to increased receptor tyrosine kinase activity and the
activation of the RAS and PI-3 kinase pathways, which stimulate the growth and N.B. Meningeal carcinomatosis, with tumor nodules studding the surface of the brain, spinal cord, and intradural nerve roots, is
survival of tumor cells .
associated particularly with carcinoma of the lung and the breast.

Peripheral Nerve Sheath Tumors

1- Schwannoma These benign tumors arise from the neural crest–derived Schwann cell and cause symptoms by local
………………………………………………………compression of the involved nerve or adjacent structures (such as brainstem or spinal cord).
They are well-circumscribed, encapsulated masses that are attached to the nerve but can be separated from it .
On microscopic examination tumors show a mixture of two growth patterns :
1- In the Antoni A pattern of growth, elongated cells with cytoplasmic processes are arranged in
Morphology fascicles in areas of moderate to high cellularity and scant stromal matrix;
the “nuclear-free zones” of processes that lie between the regions of nuclear palisading are termed
Verocay bodies.
2- In the Antoni B pattern of growth, the tumor is less densely cellular and consists of a loose
meshwork of cells, microcysts and myxoid stroma.
In both areas the individual cells have an elongated shape and regular oval nuclei.
- A variety of degenerative changes may be found in schwannomas, including :
nuclear pleomorphism, xanthomatous change, and vascular hyalinization.
- Malignant change is extremely rare, but local recurrence can follow incomplete resection.
- Affected individuals often present with tinnitus and hearing loss;
Clinical pictrure - Sensory nerves within the dura are involved, including branches of the trigeminal nerve and dorsal roots.
- When extradural, schwannomas are most commonly found in association with large nerve trunks, where motor
and sensory modalities are intermixed.
2- Neurofibroma Neurofibromas can present as discrete localized masses—most commonly as a
(cutaneous neurofibroma) or in peripheral nerve as a (solitary neurofibroma) or as an infiltrative lesion growing within and
expanding a peripheral nerve (plexiform neurofibroma).
a- Cutaneous Neurofibroma :
- these well-defined but unencapsulated masses are composed of spindle cells.
- they are not invasive,
- The stroma of these tumors is highly collagenized and contains little myxoid material.
- Lesions within peripheral nerves are of identical histologic appearance.
b- Plexiform Neurofibroma :
(These tumors may arise anywhere along a nerve)
The affected nerves are irregularly expanded, and unlike schwannomas, it is not possible to separate the lesion
from the nerve.
On microscopic examination,
- the lesion has a loose, myxoid background with a low cellularity.
- Several cell types are present, including Schwann cells, larger multipolar fibroblastic cells, and
….inflammatory cells, including mast cells.
- Although the myxoid stroma dominates, there are often areas of collagen bundles, which have a “shredded
…carrot” appearance.
- The risk of malignant transformation of these tumors is extremely small,
- In contrast, plexiform tumors may result in significant neurologic deficits when they involve major nerve trunks,
are difficult to remove because of their intraneural spread, and have a significant potential for malignant
transformation.
 Herniation
When the volume of brain tissue increases beyond the limit permitted by compression of veins and displacement of CSF, intracranial
pressure may rise.

Because the cranial vault is subdivided by rigid dural folds (falx and tentorium), a focal expansion of the brain causes it to be displaced in
relation to these partitions. If the expansion is sufficiently severe, herniation will occur ( Fig. ).

Herniations are named by either 1- the part of the brain that is displaced
2- or the structure across which it moves.

The usual consequence of such displacement is compromise of the blood supply to the "pushed" tissue, resulting in :
1- infarction.
2- and often leads to another round of swelling and further herniation .

- occurs when unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulated
Subfalcine gyrus under the edge of falx.
(cingulate) herniation
- associated with compression of branches of the anterior cerebral artery.

- occurs when the medial aspect of the temporal lobe is compressed against the free margin of the
tentorium.
- the third cranial nerve may be compromised, resulting in pupillary dilation and impairment
of ocular movements on the side of the lesion ("blown pupil").

- The posterior cerebral artery may also be compressed, resulting in ischemic injury to the
Transtentorial territory supplied by that vessel, including the primary visual cortex.
(uncinate) herniation
- contralateral cerebral peduncle may also be compressed when the extent of herniation is
large enough,, resulting in hemiparesis ipsilateral to the side of the herniation.

- Progression of transtentorial herniation is often accompanied by hemorrhagic lesions in the

midbrain and pons, termed Duret hemorrhages :
- These linear or flame-shaped lesions usually occur in the midline and paramedian regions,
- believed to be due to tearing of penetrating veins and arteries supplying the upper brain stem.
- The presence of Duret hemorrhages implies a grim prognosis

refers to displacement of the cerebellar tonsils through the foramen magnum.

Tonsillar herniation It is life-threatening, because it causes :

1- brain stem compression
2- compromises vital respiratory & cardiac centers in the medulla.
Parkinsonism
Idiopathic Parkinson’s disease
• There are many causes (Box 26.64) most common is Parkinson’s disease (PD). Clinical Features
• Genetic factors :
- Having a first-degree
degree relative with PD confer
confers a 2–3 ;mes increased risk .
• Prognosis :
- It is a progressive and incurable condition, with a variable prognosis.
- Whilst motor symptoms are the most common presenting features,
non-motor
motor symptoms (particularly cognitive impairment, depression and anxiety)
become increasingly common as the diseas
diseasee progresses, and reduce quality of life
Pathophysiology
The pathological hallmarks of PD are:
1- depletion of the pigmented dopaminergic neurons in the substantia nigra and
2- Presence of α-synuclein
synuclein and other protein inclusions in nigral cells (Lewy bodies).
• It is thought that environmental or genetic factors alter the α-synuclein protein,
renderingng it toxic and leading to Lewy body formation within the nigral cells.
• While interest has primarily focused on the dopamine system, :
neuronal degeneration with inclusion body formation can also affect :
- cholinergic neurons of the nucleus basalis of Meynert (NBM),
- norepinephrine neurons of the locus coeruleus (LC),
- serotonin neurons in the raphe nuclei of the brainstem,
- neurons of the olfactory system,
- cerebral hemispheres, spinal cord, and peripheral autonomic nervous sy system.
This "nondopaminergic"
nondopaminergic" pathology is likely responsible for the
nondopaminergic clinical features listed see Table 371-1.
• Striatum is input region of the basal ganglia.
• GPi and SNr RE output regions the basal ganglia
ganglia.
- The input and output regions are connected via direct and indirect pathways .
- The output of the basal ganglia provides inhibitory tone to thalamic &
brainstem neurons that in turn connect to motor systems in the cerebral
cortex and spinal cord to regulate
late motor function.
• Dopaminergic projections from SNc neurons serve to modulate neuronal firing and to
stabilize the basal ganglia network.
In Parkinson's disease
• dopamine denervation leads to increased firing of neurons in the STN and GPi
resulting in :
1- Excessive inhibition of the thalamus,
2- Reduced activation of cortical motor systems
systems,
Development
evelopment of park
parkinsonian features .
Current
urrent role of surgery in treatment of PD is based upon this model, in which that :
lesions or high-frequency
frequency stimulation of the STN or GPi
might reduce this neuronal overactivity and improve PD features.

Management
1- Drug therapy
Drug treatment for PD remains symptomatic rather than curative, and there is no evidence that any of the currently available drugs are neuroprotective.
Evidence-based
based statements regarding diagnosis and drug management of PD are listed in Box 26.66.
Mechanism of action :
• Levodopa is the precursor to dopamine.
• When administered orally, more than 90% is decarboxylated to dopamine peripherally in : GIT & Blood vessels, and
only a small proportion reaches the brain.
• This peripheral conversion is responsible for the high frequency of adverse
adverse effects, and to avoid this :
LD is combined with a dopa decarboxylase inhibitor (DDI) :
1- Carbidopa ( compination with LD Sinemet® )
2- Benserazide ( compination with LD Madopar®)
Inhibitor
nhibitor does not cross the blood–brain
blood brain barrier, thus avoiding unwanted decarboxylation
decarboxylation-blocking in brain.
Effect :
Levodopa (LD) • Most effective on relieving 1- Akinesia
kinesia 2- Rigidity;
• Less satisfactory on relieving : Tremor
• Failure of akinesia/rigidity to respond • No effect on relieving : 1- many motor (posture, freezing) 2- non-motor
motor symptoms.
to LD 1000 mg/day should prompt
reconsideration of the diagnosis. Adverse effects :
• Most accept that the most effective,
11- Postural hypotension, 2- Nausea
ausea and vomiting, (which
which may be offset by domperidone
domperidone).
best-tolerated and cheapest drug is LD 33- Exacerbate or trigger hallucinations,
44- Abnormal LD-seeking
seeking behaviour (dopamine dysregulation syndrome) in which the patient takes excessive doses of LD.
55- As PD progresses, the response to LD becomes less predictable in many patients , leading to motor fluctuations .
- Due
ue to progressive loss of dopamine storage capacity by dwindling numbers of striatonigral neurons.
- LD-induced
induced involuntary movements (dyskinesia)
(dyskine may occur as :
• a peak-dose phenomenon or
• a biphasic phenomenon (occurring during both the build-up
build up and wearing
wearing-off phases).
- More complex fluctuations present as sudden, unpredictable changes in response, in which periods of
parkinsonism (‘off’ phases) alternate with improved mobility but with dyskinesias (‘on’ phases).
• The non-ergot agonists are preferable to the ergot agonists.
• With the exception of apomorphine,, all the agonists are :
Dopamine agonists - considerably less powerful than LD in relieving parkinsonism,
(Ropinirole monotherapy to delay - have more adverse effects (nausea,
nausea, vomiting, confusion and hallucinations, impulse control disorders)
L-dopa use in the early stages). - more expensive.
• These were the main treatment for PD prior p to the introduction of LD. help tremors
tremors.
• Their role now is limited by :
Anticholinergics 1- Lack
ack of efficacy (apart from an effect on tremor sometimes)
2- Adverse effects : dry mouth, blurred vision, constipation, urinary retention, confusion and hallucinosis.
• Several anticholinergics are available, including : 1- Trihexyphenidyl
rihexyphenidyl (benzhexol) 2- Orphenadrine.
• Monoamine oxidase type B facilitates breakdown of excess dopamine in the synapse.
Inhibitors of • Alternate to Dopamine agonists in treatment of early PDs.
(MAOI)-B • Two inhibitors are used in PD: 1- Selegiline
elegiline 2- Rasagiline. Differential Diagnosis of Parkinsonism
• Catechol-O-methyl-transferase
transferase (along with dopa decarboxylase) is involved in peripheral breakdown of LD. Parkinson's Disease:
Catechol-O-methyl-
• Two inhibitors are available: 1- Entacapone
ntacapone 2- Tolcapone 1- Genetic
transferase (COMT) - Entacapone has a modest effect and is most useful for early wearing-off. 2- Sporadic
inhibitors - It is available either as a single tablet taken with each LD/DDI dose, or as a combination tablet with LD and DDI. Atypical Parkinsonisms:
• lived effect on bradykinesia and is rarely used unless patients are unable to tolerate
This has a mild, usually short-lived 1- Multiple-system atrophy
• Cerebellar type (MSA-c)
Amantadine other drugs.
• Parkinson type (MSA-p)
Weak DA agonists • It is more commonly used as a treatment for LD-induced
LD dyskinesias,, although again benefit is modest and short
short-lived.
2- Progressive supranuclear palsy
2- Surgery 3- Corticobasal ganglionic degeneration
1- Destructive neurosurgery , was commonly used before the introduction of LD. 4- Frontotemporal dementia
Secondary Parkinsonism:
2- Stereotactic surgery has emerged and most commonly involves : Deep Brain Stimulation
S (DBS) : 1- Drug-induced 2-Tumor 3- Infection
- Various targets have been identified, including the thalamus (though this is only effective for tremor), globus pallidus and subthalamic nucleus. 4- Vascular 5-Trauma 6- Liver failure
- DBS is usually reserved for patients with medically refractory tremor or motor fluctuations 7- Normal-pressure hydrocephalus
3- Intracranial delivery
very of fetal grafts or specific growth factors remains experimental. 8- Toxins (e.g.,
.g., carbon monoxide, , MPTP, cyanide)
3- Physiotherapy, occupational therapy and speech therapy : Other Neurodegenerative Disorders:
1- Wilson's disease
• Patients at all stages of PD benefit from physiotherapy, which helps reduce rigidity and corrects abnormal posture.
2- Huntington's disease
• Occupational therapists can n provide equipment to help overcome functional
nctional limitations, such as toilet, and bathing
thing equ
equipment.
3- Neurodegeneration with brain iron accaccumulation
• Speech therapy can help wherehere dys
dysarthria and dysphonia interfere with
ith communication
comm
4- Alzheimer's disease with parkinsonis
nsonis
• As with many complex neurological ld ideally be managed by a multidisciplinary
rological disorders, patients with PD should linary te
team, including PD specialist nurses.
 Neurocutaneous Syndrome
Neurofibromatosis
Neurofibromatosis 1 Neurofibromatosis 2
(von Recklinghausen's syndrome)
Mutaion on chromosome 17 Mutaion on chromosome 22
both types are autosomal dominant inheritance
1- Café-au-lait spots (at least 5 mm)
1- Ear: Bilateral acoustic neuromas
2- Axillary/groin freckles
3- Peripheral neurofibromas 2- Eyes: Posterior subcapsular Cataracts
4- Iris: Lisch nodules in > 90%
5- Macrocephaly, short stature, learning disabilities, feeding problems
Tuberous sclerosis
Autosomal Dominant inheritance the majority of features seen in TS are neuro-cutaneous
Cigarettes and coffee with a rough stupid person with a butterfly on his nose while he is dancing
Cigarettes (ash) - coffee (café-au-lait) - stupid (intellectual and developmental) - dancing (eplipsy)
Cutaneous features :
Depigmented 'ash-leaf' Shagreen patches Adenoma sebaceum Subungual fibromata Café-au-lait spots
spots
which fluoresce under UV Roughened patches of skin butterfly distribution over Fibromata beneath nails may be seen
light over lumbar spine nose

Neurological features : Also

• Developmental delay • Brain: Gliomatous changes can occur in the brain lesions
• Epilepsy (infantile spasms or partial) • Retinal hamartomas: dense white areas on retina (phakomata)
• Intellectual impairment • Heart: Rhabdomyomas
• Renal angiomyolipomata
Sturge-Weber syndrome
Cutaneous features :
1- Port wine stains (nevus flammeus) along the territory of trigeminal nerve (in V1 cranial nerve distribution)
Neurological features : Skull x-rays:
1- Angiomatous malformations of the brain taken after the age of 2 years, reveal:
2- Seizures ( focal or generalized ) gyriform intracranial calcifications
3- Hemiparesis & Hemisensory disturbance that resemble a tramline
Eye: 1- Hemianopia 2- Ipsilateral Glaucoma
Treatment: 1- Evaluate for glaucoma: reduce IOP 2- Treat Seziures : Anti-convulsives
3- Argon laser therapy is successful in removing the skin lesions

Differential Diagnosis: Other Cutaneous Lesions

Diagnosis Figure Description Association Management
Blue/gray macules on:
Usually fade in first few Rule out child abuse
Mongolian spots 1- presacral back years
2- posterior thighs

Non-toxic neonate in
nd
2 day of life with :
Erythematous papules &
Erythema toxicum vesicles surrounded by
patches of erythema and
eosinophils in skin lesions
Red, sharply demarcated,
raised lesions.
Strawberry -Appearing in first 2 months
Hemangioma - rapidly expanding,
- then involuting by
age 5–9 years
Benign, self-limited
condition
Consider underlying Treat with:
organ involvement with 1- steroids
deep hemangiomas. or
- If it involves the larynx, 2- pulsed laser
it can cause obstruction.
if large or interferes with
- May cause high output
organ function.
cardiac failure when large.
Anti-Depressants
Mechanism of Antidepressant Drugs
The biogenic amine theory, which proposes that depression is due to a deficiency of monoamines, such as norepinephrine and
serotonin, at certain key sites in the brain. Conversely, the theory envisions that mania is caused by an
overproduction of these neurotransmitters.

- The potency of the antidepressant drugs in blocking neurotransmitter uptake often does not correlate with clinically observed antidepressant
effects. This suggests that decreased uptake of neurotransmitter is only an initial effect of the drugs, which may not be directly responsible
for the antidepressant effects.

- It was proposed that presynaptic inhibitory receptor densities in the brain decrease over a 2-to4-week period with antidepressant drug use
This down-regulation of inhibitory receptors permits greater synthesis and release of neurotransmitters into the synaptic cleft and enhanced
signaling in the postsynaptic neurons, leading to a therapeutic response.
Classification of Anti-Depressant Drugs
Selective serotonin Serotonin/Norepinephrine Atypical Anti-depressants Tricyclic Antidepressants Monoamine oxidase
re-uptake inhubitors re-uptake inhibitors inhibitors
Amitriptyline
Citalopram DuloXetine Bupropion Nortriptyline Phenelzine
Escitalopram VenlafaXine Protriptyline Selegiline

Fluxoetine Mirtazapine Amoxapine

Paroxetine Doxepine ( a e)

Sertraline ( t l) Nefazodone Clomipramine Tranylcypromine (o a)

Trazodone Desipramine
Fluvoxamine Imipramine
Trimipramine

Maprotiline

1- Selective Seratonin re-uptake inhibitors 2- Serotonin/Norepinephrine re-uptake inhibitors

Action Action
They specifically inhibit serotonin reuptake, having 300- to 3000-fold greater They selectively inhibit the re-uptake of both serotonin and norepinephrine .
selectivity for the serotonin transporter as compared to the norepinephrine transporter. Effective in treating depression in patients in whom SSRIs are ineffective.
.
The SSRIs block the reuptake of serotonin, leading to increased concentrations of
VenlafaXine: - Low doses
potent inhibitor of serotonin reuptake
the neurotransmitter in the synaptic cleft and, ultimately, to greater postsynaptic ………………… - At medium to higher doses inhibitor of norepinephrine & D. re-uptake
neuronal activity.
DuloXetine : It inhibits serotonin and norepinephrine reuptake at all doses.
N.B. Antidepressants, including SSRIs, typically take at least 2 weeks to produce significant
improvement in mood, and maximum benefit may require up to 12 weeks or more. N.B. Both SNRIs and tricyclic antidepressants, sometimes effective in relieving physical
symptoms of neuropathic pain, such as diabetic peripheral neuropathy.
Side effects Side effects
The SNRIs, unlike the tricyclic antidepressants, have little activity at adrenergic, muscarinic, or histamine
Because they have fewer adverse effects and are relatively safe even in overdose, the SSRIs have largely
receptors and, thus, have fewer of these receptor-mediated adverse effects than the tricyclic antidepressants
replaced tricyclic antidepressants and monoamine oxidase inhibitors as the drugs of choice in treating
depression
1- insomnia
1- Insomnia
2- Nausea & constipation
2- Nausea
3- sexual dysfunction
3- Sexual dysfunction Loss of libido, delayed ejaculation, and anorgasmia
4- headache, dizziness, sedation.
4- Seizures
5- increase in BP and HR.
5- Serotonin syndrome symptoms of hyperthermia, muscle rigidity, sweating
6- Discontinuation syndrome: headache, malaise flu-like symptoms, anxiety.

3- Atypical Anti-depressants 4- Tricyclic Antidepressants

They are mixed group of agents that have actions at several different sites. Action
They selectively inhibit the re-uptake of both serotonin and norepinephrine .
This drug acts as a weak dopamine and norepinephrine reuptake .
Bupropion is unique in that it assists in decreasing the craving and attenuating the
- Mechanism of Action :
Bupropion withdrawal symptoms for nicotine in tobacco users trying to quit smoking. 1- Inhibition of neurotransmitter reuptake:
- sexual dysfunction - dry mouth They are potent inhibitors of the neuronal reuptake of norepinephrine and serotonin into
- sweating - nervousness presynaptic nerve terminals, that causes increased concentrations of monoamines in the
- tremor - seizures synaptic cleft resulting in antidepressant effects.

- This drug enhances serotonin and norepinephrine neurotransmission via N.B. Maprotiline and desipramine are selective inhibitors of norepinephrine reuptake.
mechanisms related to its ability to block presynaptic alpha2 receptors.
Mirtazapine - It is a sedative because of its potent antihistaminic activity, 2- Blocking of receptors:
- TCAs block serotonergic, adrenergic, histaminic, and muscarinic receptors
- It does not cause the antimuscarinic side effects of the tricyclic - However, actions at these receptors are probably responsible for many of the
antidepressants, or interfere with sexual functioning, as do the SSRIs. untoward effects of the TCAs.
- Increased appetite - weight gain N.B. Amoxapine also blocks the D2 receptor.
- They have ability to block postsynaptic 5-HT2A receptors. Side effects
- With chronic use, these agents may desensitize 5-HT1A presynaptic - Blockade of muscarinic receptors leads to :
Nefazodone autoreceptors thereby, increase serotonin release blurred vision, dry mouth, urinary retention, constipation, narrow-angle glaucoma

- They are sedative because of its potent antihistaminic H1 activity, - Block adrenergic receptors leads to :
- These drugs are weak inhibitors of serotonin reuptake. orthostatic hypotension, dizziness, and reflex tachycardia
Trazodone
- Block Histaminic H1 receptors leads to :
- Trazodone priapism,
Sedation especially during the first several weeks of treatment,
- nefazodone hepatotoxicity.
- Others : Weight gain - Sexual dysfunction

5- Monoamine Oxidase Inhibitors

- The MAO inhibitors may irreversibly or reversibly inactivate the enzyme MAO, permitting neurotransmitter molecules to escape degradation therefore, accumulate within the
presynaptic neuron and leak into the synaptic space causing activation of norepinephrine and serotonin receptors, and it may be responsible for the indirect antidepressant
Mechanism action of these drugs.
of Action :
- These drugs inhibit not only MAO in the brain but also MAO in the liver and gut that catalyze oxidative deamination of drugs and potentially toxic substances, such as tyramine,
which is found in certain foods. The MAO inhibitors therefore show a high incidence of drug-drug and drug-food interactions.
Severe side effects due to drug-food and drug-drug Individuals receiving an MAO inhibitor are unable to degrade tyramine obtained from the diet. Tyramine causes the release
Side effects of large amounts of stored catecholamines from nerve terminals, resulting in occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures .
Other possible side effects include drowsiness, orthostatic hypotension, blurred vision, dry mouth, dysuria, and constipation.
Antiepileptic drugs
Types of epilepsy (reading only)
1- Partial Seizures ( Focal Seizures ) 2- Generalized Seizures
- NO loss of conscious Tonic clonic - loss of consciousness - tonic spasm (1 min) clonic jerking
Simple - Clonic jerking of single limb or a muscle group lasting for about 2 min. seizures - Flaccid relaxation - confusion & fatigue - sleep
partial - there maybe some sensory disturbances. Absence - there is brief loss of consciousness lasting only for 10 to 15 sec. with mild or no motor
seizures disturbances.
Complex - there is brief loss of consciousness followed by amnesia.
partial - Purposeless movements & sensory hallucinations. Myoclonic - NO loss of conscious
seizures - Short jerking of the whole body or one of the extremities.
Partial with Partial seizures that is followed immediately by generalized attack due to spread of discharge.
secondarily Atonic
- Sudden loss of posture tone Fall.
seizures seizures

3- Status Epilepticus
Epilepticus - Severe sustained seizures without period or recovery. - It occurs in all types of epilepsy especially if treatment is irregular or suddenly stopped.

Mechanism of action of antiepileptic drugs Drug Choice

- First choice: Carbamazapine & Phenytoin
Tonic clonic
- Alternative : Valproate.
seizures
Drugs that are effective in seizure reduction accomplish this by - Phenobarbital & primidone (Barbiturates)
variety of mechanisms: - First choice: Carbamazapine & Phenytoin
Simple partial - Alternative : Valproate - Lamotrigine , Vigabatrin , Gabapentin ( mono or add on )
1- blockade of voltage-gated channels (Na+ or Ca2+), - Phenobarbital & primidone
2- enhancement of inhibitory GABAergic impulses, - First choice: Ethosuximide
3- interference with excitatory glutamate transmission. Absence seizures - Alternative : Valproat - Lamotrigine - clonazepam
- Acetazolamide.
The antiepilepsy drugs suppress seizures but do not recur or prevent - Mixed :
Absence seizures + Tonic clonic - First choice: Valproate
epilepsy. - Alternative : clonazepam
- Myoclonic seizures

Status Epilepticus Diazepam – clonazepam – Phenytoin – Phenobarbiton - Paraldehyde

Antiepileptic Drugs
Phenytoin Carbamazepine Barbiturates & Benzodiazepines
- Normal concentration of drug : (check Ahmados sedatives & hypnotics papers)
It blocks voltage-gated sodium channels by selectively binding
to the channel in the inactive state thereby inhibiting the
generation of repetitive action potentials in the epileptic focus The primary mechanism of action is the enhancement of
and preventing their spread. Mechanism like phenytoin inhibitory effects of GABA-mediated neurons, via
increase the frequency of chloride channel opening by
- At very high concentrations, binding to the GABAA receptor.
phenytoin can block voltage-dependent calcium channels and
interfere with the release of monoaminergic neurotransmitters. Diazepam, and lorazepam are most often used as an therapy for :
1- myoclonic 2- partial 3- generalized tonic-clonic seizures.

Side effects Side effects Side effects

- Depression of the CNS occurs particularly in the cerebellum
and vestibular system, causing : - nystagmus , ataxia - Rash - Anorexia
- peripheral neuropathies - osteoporosis. - Nystagmus - anti-diuretic
- confusion & Hallucinations. - Hepatotoxicity. - Ataxia - Hepatitis
- Teratogenic - Bone marrow inhibition (check Ahmados sedatives & hypnotics papers)
- Hormones: release of A.D.H & insulin (hyperglycemia)
- Hirsutism. - Teratogenic.
Fosphenytoin Oxcarbazepine
It is a prodrug and is rapidly converted to phenytoin in It is a prodrug that is rapidly reduced to the 10-monohydroxy
the blood, providing high levels of phenytoin within min. (MHD) MHD blocks sodium channels preventing the spread of
the abnormal discharge producing anticonvulsant activity.

Phernytoin , Carbamazepine & Barbiturates 1-Hepatic microsomal enzyme inducer (drug interactions) 2-Treat Tonic clonic & partial seizures 3-wosens Absence

Ethosuximide Divalproex Acetazolamide

It blocks T-type calcium channels so, reduces Divalproex sodium is a combination of: It's carbonic anhydrase inhibitor Increase CO2
propagation of abnormal electrical activity in the brain sodium valproate + valproic acid & Acidosis decrease CNS excitability
and is reduced to valproate when it reaches the gastrointestinal tract.
It is effective in treating only primary generalized
absence seizures. Usefula in Absence seizures
- Proposed mechanisms of action include:
1-sodium channel blockade,
Side effects 2- blockade of GABA transaminase, Side effects
- CNS Drowsiness , Lethargy , behavioral changes 3- action at the T-type calcium channels. - Hypokalemia - alkaline urine
- GIT upset - Sedation - acidosis
These many mechanisms provide a broad spectrum of activity
- Allergy against seizures.

Trimethadione Side effects

- GI distress,
- hepatotoxicity due to formation of toxic metabolite,
Mechanism like Ethosuximide - pancreatitis
Side effects - alopecia,
- tremor,
- CNS Drowsiness , Lethargy , behavioral changes - Photosensitivity
- GIT upset - Hepatic microsomal enzyme inhibitor.
- Allergy
- Hepatotoxicity – Nephrotoxicity – Bone marrow depression

New Anti-Epileptic Drugs

Lamotrigine
The drug blocks :
1- sodium channels
2- voltage dependent
calcium channels.
Topiramate
1- It blocks sodium channels;
2- The primary mechanism of
action is the enhancement of
inhibitory effects of GABA-
mediated neurons
3- antagonize the excitatory
transmitters e.g: glutamate .
Felbamate
1- It blocks sodium channels;
2- The primary mechanism of
action is the enhancement of
inhibitory effects of GABA-
mediated neurons
3- antagonize the excitatory
transmitters e.g: glutamate
Gabapentin Tiagabin Vigabatrin
Tiagabine blocks GABA uptake
Gabapentin is an analog of GABA. It's irreversible inhibitor of
into presynaptic neurons,
GABA transaminase
permitting more GABA to be
It increases the release of resulting in increase the GABA
available for receptor binding
GABA
thus, enhanced inhibitory
activity.

Side effect : Side effect : Side effect : Side effect : Side effect : Side effect :
Rash - Dermatits Sedation - confusion Fatal aplastic anemia Sedation - ataxia tiredness, dizziness, GIT upset. Depression - Psychosis
 Parasympatholytics(Anti-Cholinergicagents )
- The cholinergic antagonists bind tocholinoceptors, but they do not trigger the usual receptor-mediated
receptor
intracellular effects.

- The effects of parasympathetic innervation are thus interrupted, and the actions of sympathetic
stimulation are left unopposed.

1- Anti-muscarinic
muscarinic agents
- They block muscarinic receptors , causing inhibition of all muscarinic functions.
- In addition, these drugs block the few exceptional sympathetic neurons that are cholinergic, such
su as those innervating
salivary and sweat glands.

* Actions and Uses :

1- Eye :
Atropine -
-
persistent mydriasis
unresponsiveness to light.
- Competitive antagonist of muscarinic - cycloplegia (inability to focus for near vision).
receptors.
- Atropine acts both centrally and peripherally.
- In patients with glaucoma, intraocular pressure may rise dangerously

- Its general actions last about 4 hours except • Refraction Exam.

when placed topically in the eye, where the
action may last for days.
• Acute iridocyclitis.
• Acute uveitis .

2- GIT :
Pharmacokinetics - Gastric motility is reduced.
- hydrochloric acid production is not significantly affected. Thus,
the drug is not effective in promoting healing of peptic ulcer.
- It's a tertiary aminebelladonna
belladonna
alkaloid(lipid soluble).
• Anti-spasmodic.

- Well absorbed orally, mucous

membranes and parenterally. 3- Urinary Bladder :
- Relaxation of the wall (reduce hypermotility states of the urinary
- widely distributed & passes BBB. bladder)
- Constriction of sphincters.
- partially metabolized in live 70%.
• enuresis (involuntary voiding of urine) among children.
- Excreted in urine partially • Urinary urgency.
unchanged 30%.
N.B.(acidification
(acidification of urine increases its urinary 4- Heart :
excretion). - At low doses, (bradycardia) due to:
a- central activation of vagal efferent outflow.
b- blockade of the M1 receptors on the inhibitory presynaptic
neurons, thus permitting increased acetylcholine release

- At High doses -1 gm- , ( tachycardia ) due to :

a- the M2 receptors on the sinoatrial node are blocked.

- Blood Vessels not affected so no effect on arterial blood pressure,

but at toxic levels,atropinewill
will dilate the cutaneousvasculature.

• Sinus bradycardia after myocardial infarction.

 Side Effects 5- Bronchi :
- parasympatholytic manifestations :
- It decreases the bronchial secretion.
1- mydriasis. - Bronchodilatation.
2- cytopelgia
3- Photophobia.
4- Blurring vision.(due to of 1,2,3) • Pre-anesthetic.
5- Glaucoma. • Bronchial asthma.
6- Sandy Eyes, due to decr. lacrimation.
7- Dry, red and hot skin.
8- Dry mouth. 6- CNS :
9- Tachycardia.( SAN receptors )
10- Distention of urinary bladder & - Stimulant.
retention of urine.
11- Constipation ( due to decr. motility)
12- Allergy. • Tremor of parkinsonism.
13- CNS effects:
a- Restlessness.
• Drug-induced parkinsonism.
b- Confusion. • Motion sickness.
c- Hallucination.
d- Delirium. 7- Glands :

- It decreases salivary and sweat glands secretion, producing a drying

Contraindications effect on the oral mucous membranes (xerostomia).
- lacrimal glands are also affected.
1- Fever. - [Note: Inhibition of secretions by sweat glands can cause elevated
2- glycoma. body temperature.]
3- Bronchial asthma.
4- Tachycardia. • Antisecretory agent.
5- Constipation and paralytic ileus. • Hyperhidrosis.
6- Benign prostatic hyperplasia. • Preanaesthetic medication.
7- allergy to atropine.

8- Antidote for cholinergic agonists:

N.B.Confirm atropine poisoning by putting a
drop of patient's urine into eye of cat which is
natural hypersensitivity.
- Atropine is used for the treatment of overdoses of cholinesterase
inhibitor insecticides.
- drug also blocks the effects of excess acetylcholine resulting from
acetylcholinesterase inhibitors, such as physostigmine.

- Pharmacology is similar to atropine BUT:

1- Stronger on eye and secretions ANDWeaker on GIT & heart ( notachyca.)

Scoplamine 2- Greater action on the CNS ( more penetration for BBB ) :

a- Mainly depressant leading to sedation and hypnosis.

- Another tertiary amine belladonna alkaloid.
b- Euophoria.
- longer duration of action.
c- Inhibition of vomiting center
• Used as Anti-motion sickness.

* Pharmacokinetics and adverse effects: d- Inhibition of basal ganglia .

are similar to those of atropine • Used as anti-Parkinsonian.

e- Stimulation of respiratory center.

f- Stimulation of cardiac inhibitory center.

g- In large doses:
It leads to Excitation ( central anticholinergic syndrome).

• Used also in treatment of "blocking of short term memory" in some

anesthetic procedures.
- The amnesic action of scopolamine makes it an important adjunct
drug in anesthetic procedures.
 Inhaled in treatment :
Ipratropium • Bronchial asthma
• Chronic obstructive pulmonary disease. COPD
- a quaternary derivative of atropine.

N.B.
Because of its positive charge, it does not enter the systemic
circulation or the CNS, isolating its effects to the pulmonary system.

Tropicamide * These agents are used as ophthalmic solutions (topical) :

- tropicamideproduces mydriasis for 6 hours
& - andcyclopentolatefor 24 hours.

Cyclopentolate * duration of action is shorter than that of atropine.

- Lipid soluble , so CNS entery.

Benztropine - Used in:

trihexyphenidyl • Parkinsonism.
• Drug induced extrapyramidal dysfunction.

2- Ganglion Blockers

- Anti-nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia.

- Some also block the ion channels of the autonomic ganglia.
- These drugs show no selectivity toward the parasympathetic or sympathetic ganglia.
- not effective as neuromuscular antagonists.
- Thus, these drugs block the entire output of the autonomic nervous system at the nicotinic
receptor.
- The responses observed are complex and unpredictable.
- It is rarely used therapeutically. However, ganglionic blockers often serve as tools in
experimental pharmacology.

Nicotine
- A component of cigarette smoke.
- nicotine is a poison with many
undesirable actions.
- It is without therapeutic benefit .
- Nicotine is highly lipid soluble and
readily crosses the blood-brain barrier.
Trimethaphan
Mecamylamine
• Source/Lippincott .
- Mechanism of action
- Depending on the dose, nicotine depolarizes autonomic ganglia,
resulting first in stimulation and then in paralysis of all ganglia
* In low doses,
nicotinecauses ganglionic stimulation by depolarization.
nicotinecauses
* At high doses,
nicotine
nicotinecauses ganglionic blockade.
The stimulatory effects are complex due to effects on both sympathetic and
parasympathetic ganglia.
- CNS :
1- Cigarette smoking or administration of low doses of nicotine produces: some
1
degree of euphoria and arousal as well as relaxation.It improves attention, learning,
problem solving, and reaction time.
2- High doses of nicotine result in central respiratory paralysis and severe
2
hypotension caused by medullary paralysis,
paralysis, Nicotine is an
appetite suppressant.
- Peripheral effects:
- increases blood pressure and heart rate. Thus, use of tobacco is particularly
harmful in hypertensive patients.
- nicotine-induced
induced vasoconstriction can decrease coronary blood flow, adversely
adver
affecting a patient with angina.
- Stimulation of parasympathetic ganglia also increases motor activity of the bowel.
- At higher doses, blood pressure falls, and activity ceases in both the
gastrointestinal tract and bladder musculature as a result
resul of a nicotine-induced block
of parasympathetic ganglia.
( Summary Behind the page )
- Adverse Effects
- intestinal cramps,
- diarrhea,
- increased heart rate and blood pressure.
- cigarette smoking increases the rate of metabolism for a number of drugs.
The CNS effects of nicotine include irritability and tremors.
- Bad oral absorption.
- Short acting.
- Competitive nicotinic ganglion blockers.
• Used as emergency lowering of blood pressure e.g. pulmonary
edema, dissecting aortic aneurysm .
- Good oral absorption.
- Long Duration of action : 10 hours.
- Competitive nicotinic ganglion blocker.
• Used as emergency lowering of blood pressure
 Sedatives and Hypnotic Drugs
A sedative is a substance that induces sedation by reducing irritability or excitement.

I- Benzodiazepines
clonazepam Diazepam Flurazepam Lorazepam Quazepam Oxazepam
Temazepam AlpraZolam TriaZolam EstaZolam Chlordiazepoxide chlorazepate
Benzodiazepines are the most widely used anxiolytic drugs, They have largely replaced other drugs in the treatment of anxiety, because they
are safer and more effective.

Mechanism of action Actions

- The targets for benzodiazepine actions are the gamma- The benzodiazepines have neither antipsychotic activity nor analgesic
aminobutyric acid (GABAA) receptors. action, and they do not affect the autonomic nervous system.

[Note: GABA is the major inhibitory neurotransmitter in the central
nervous system (CNS).]
These receptors are primarily composed of alpha, beta and gamma
subunit families of which a combination of five or more span the
postsynaptic membrane.
1- Reduction of anxiety
At low doses, the benzodiazepines are anxiolytic.
They are thought to reduce anxiety by selectively enhancing
GABAergic transmission in neurons having the alpha2 subunit in their
GABAA receptors thereby inhibiting neuronal circuits in the limbic
system of the brain.
2- Sedative and hypnotic actions

- used to treat anxiety have some sedative properties,

- and some can produce hypnosis (artificially produced sleep) at
higher doses.

Their effects have been shown to be mediated by the alpha1-GABAA

receptors.

3- Anterograde amnesia
The temporary impairment of memory with use of the
benzodiazepines is also mediated by the alpha1-GABAA receptors.
4- Anticonvulsant

- Binding of GABA to its receptor triggers an opening of a chloride

- Several of the benzodiazepines have anticonvulsant activity
channel, which leads to an increase in chloride conductance (see - and some are used to treat epilepsy (status epilepticus) and other
Figure 9.3). seizure disorders.

- Benzodiazepines increase the frequency of channel openings
produced by GABA.
The influx of chloride ions causes a small hyperpolarization that
moves the postsynaptic potential away from its firing threshold and
making it more difficult to depolarize thus, inhibits the formation
of action potentials therefore, reduces neural excitability.
Binding of a benzodiazepine to its receptor site will increase the
affinity of GABA for the GABA-binding site (and vice versa) without
actually changing the total number of sites.
This effect is partially, although not completely, mediated by alpha1-
GABAA receptors.
5- Muscle relaxant:
At high doses, the benzodiazepines relax the spasticity of skeletal
muscle, probably by:
increasing presynaptic inhibition in the spinal cord, where
the apha2-GABAA receptors are largely located.
Baclofen is a muscle relaxant that is believed to affect GABAb
receptors at the level of the spinal cord.

Therapeutic uses
- The individual benzodiazepines show small differences in their relative anxiolytic, anticonvulsant, and sedative properties.
- the duration of action varies widely among this group, and pharmacokinetic considerations are often important in choosing one
benzodiazepine over another.
• Effective for the treatment of the anxiety symptoms secondary to:
- panic disorder,
- generalized anxiety disorder,
1- Anxiety disorders - social anxiety disorder,
- performance anxiety,
- posttraumatic stress disorder,
- obsessive-compulsive disorder,
- and the extreme anxiety sometimes encountered with specific phobias, such as fear of flying.
- the anxiety that accompanies some forms of depression and schizophrenia.
 Diazepam is useful in the treatment of
2- Muscular disorders - skeletal muscle spasms, such as occur in muscle strain,
- and spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy.
- The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant
3- Amnesia procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty.

- They also cause a form of conscious sedation, allowing the person to be receptive to instructions during
these procedures.

- Clonazepam is occasionally used in the treatment of certain types of epilepsy,

- diazepam and lorazepam are the drugs of choice in terminating grand mal epileptic seizures and
4- Seizures status epilepticus.
- chlordiazepoxide, clorazepate , diazepam, and oxazepam are useful in the acute treatment
of alcohol withdrawal and reducing the risk of withdrawal-related seizures.

Commonly prescribed benzodiazepines for sleep disorders ( e.g. insomnia ) include :

5- Sleep disorders - long-acting flurazepam,
- intermediate-acting temazepam,
- and short-acting triazolam.
They tend to decrease the latency to sleep onset and increase Stage II of non-rapid eye movement
(REM) sleep.
Both REM sleep and slow-wave sleep are decreased.

Pharmacokinetics Adverse Effects

1- Absorption and distribution:
- The benzodiazepines are lipophilic, and they are rapidly and
completely absorbed after oral administration and distribute
throughout the body.
- All the benzodiazepines cross the placental barrier and may
depress the CNS of the newborn if given before birth.
- Nursing infants may also become exposed to the drugs in
breast milk.
1- Drowsiness and confusion
These effects are the two most common side effects of the benzodiazepines.
Ataxia occurs at high doses and precludes activities that require
fine motor coordination, such as driving an automobile.
Cognitive impairment (decreased long-term recall and acquisition of
new knowledge) can occur with use of benzodiazepines.

2- Duration of actions 2- Precautions

The half-lives of the benzodiazepines are very important clinically,
because the duration of action may determine the therapeutic - Benzodiazepines should be used cautiously in treating patients
usefulness. with liver disease.

The benzodiazepines can be roughly divided into : - They should be avoided in patients with acute narrow-angle
short , intermediate , and long-acting groups glaucoma.
look(see Figure 9.4)p.108, lippincott.
- Alcohol and other CNS depressants enhance the sedative-hypnotic
The longer-acting agents form active metabolites with long half-lives. effects of the benzodiazepines.
3- Fate
metabolism excretion
Most benzodiazepines are The drugs' effects are terminated not
metabolized by the hepatic only by excretion but also by
microsomal system to redistribution.
compounds that are also
active. The benzodiazepines are excreted in
the urine as glucuronides or oxidized
metabolites.

Dependence Tolerance

Psychological and physical dependence on benzodiazepines can The antianxiety effects of the benzodiazepines are less
develop if high doses of the drugs are given over a prolonged period. subject to tolerance than the sedative and hypnotic effects.

Abrupt discontinuation of the benzodiazepines results in withdrawal - Tolerance that occurs when used for more than one to two
symptoms that may occur slowly and last number of days ( due to weeks.
long-half lives), including : - It has been shown that tolerance is associated with a decrease in
confusion, anxiety, agitation, restlessness, insomnia, GABA receptor density
tension, and rarely, seizures.
- Cross-tolerance exists among this group of agents with ethanol.
Benzodiazepines with a short elimination half-life, such as triazolam,
induce more abrupt and severe withdrawal reactions than those seen
with drugs that are slowly eliminated, such as flurazepam.
 II- Barbiturates
Amobarbital Phenobarbital Pentobarbital
Today, they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance, drug-
metabolizing enzymes, physical dependence, and are associated with very severe withdrawal symptoms
Mechanism of action
1- The sedtive-hypnotic action of the barbiturates is due to their
interaction with GABAA receptors, which enhances GABAergic
transmission.
The binding site is distinct from that of the benzodiazepines.
Barbiturates potentiate GABA action on chloride entry into the
neuron by prolonging the duration of the chloride channel openings.
2- In addition, barbiturates can block excitatory glutamate receptors
3- Anesthetic concentrations of pentobarbital also block high-
frequency sodium channels.
All of these molecular actions lead to decreased neuronal activity.
Therapeutic uses
1- Anesthesia
The ultrashort-acting barbiturates, such as thiopental, are used
intravenously to induce anesthesia.
2- Anticonvulsant
Phenobarbital is used in long-term management of:
- tonic-clonic seizures,
- status epilepticus,
- eclampsia.
- young children with recurrent febrile seizures.
• phenobarbital can depress cognitive performance in children,
and the drug should be used cautiously.
3- anxiety
- mild sedative to relieve: anxiety, nervous tension & insomnia.
- When used as hypnotics, they suppress REM sleep more than other
stages.
However, most have been replaced by the benzodiazepines.
Pharmacokinetics
1- Absorption
absorbed orally
2- Distribution
- distributed widely throughout the body
- All barbiturates redistribute in the body from the brain to the
splanchnic areas, to skeletal muscle, and finally, to adipose tissue.
This movement is important in causing the short duration of action of
thiopental and similar short-acting derivatives.
- They readily cross the placenta and can depress the fetus.
3- Metabolism & Excretion
Barbiturates are metabolized in the liver, and inactive
metabolites are excreted in the urine.
Secobarbital Thiopental
Actions
Barbiturates are classified according to their duration of action
(Figure 9.7)p. 111.
For example,
- Thiopental,which acts within seconds and has a duration of action of
about 30 minutes, is used in the intravenous induction of anesthesia.
- By contrast, Phenobarbital, which has a duration of action greater than
a day, is useful in the treatment of seizures.
- Pentobarbital, secobarbital, and amobarbital are short-acting
barbiturates, which are effective as sedative and hypnotic (but not
antianxiety) agents.
1- Depression of CNS
- At low doses,
the barbiturates produce sedation (calming effect, reducing
excitement).
- At higher doses,
the drugs cause hypnosis, followed by anesthesia (loss of
feeling or sensation), and finally, coma and death.
Thus, any degree of depression of the CNS is possible, depending on the dose.
- Barbiturates do not raise the pain threshold and have no analgesic
properties. They may even exacerbate pain.
- Chronic use leads to tolerance.
2- Respiratory depression
Barbiturates suppress the hypoxic and chemoreceptor response to
CO2, and overdosage is followed by respiratory depression and
death.
3- Enzyme induction:
Barbiturates induce P450 microsomal enzymes in the liver.
Therefore, chronic barbiturate administration diminishes the action
of many drugs that are dependent on P450 metabolism to reduce
their concentration.
Adverse Effects
1- CNS
- drowsiness, impaired concentration, mental& physical sluggishness
2- Drug hangover
Hypnotic doses of barbiturates produce a feeling of tiredness well
after the patient wakes.
- nausea and dizziness occur.
3- Precautions
- Barbiturates induce the P450 system and, therefore, may decrease
the duration of action of drugs that are metabolized by these hepatic
enzymes.
- Barbiturates increase porphyrin synthesis, and are contraindicated
in patients with acute intermittent porphyria.
4- Physical dependence:
Abrupt withdrawal may cause tremors, anxiety, weakness,
restlessness, nausea and vomiting, seizures, delirium, and cardiac
arrest.
5- Poisoning
drug overdoses Severe depression of respiration is coupled with
central cardiovascular depression, and results in a shock-like
condition with shallow, infrequent breathing
 Drugs of abuse
Tetrahydrocannabinol -THC- ( Cannabis )
The main psychoactive alkaloid contained in marijuana
N.B. Hashish , Marijuana & bhang obtained from cannabis plant
- THC can produce : - Adverse effects :

- euphoria, followed by drowsiness and relaxation. - increased heart rate,

- affecting short-term memory and mental activity. - decreased blood pressure,
- decreasing muscle strength - Red eye
- impairs highly skilled motor activity, such as that required to drive a car.
- At high doses, a toxic psychosis develops.
• Its wide range of effects include:
- appetite stimulation,
- Tolerance and mild physical dependence occur with
- xerostomia,
continued, frequent use of the drug.
- visual hallucinations,
- delusions,
- enhancement of sensory activity.

Appearance: Dried plant material, in different shades of

……………………green and brown
Delivery: Commonly smoked, occasionally ingested

Lysergic acid diethylamide -LSD- ( Hallucinogens )

Actions Treatment
The drug shows serotonin (5-HT) agonist activity at : - Haloperidol
and other neuroleptics can block the hallucinatory action of LSD
- presynaptic 5-HT1 receptors in the midbrain,
and quickly abort the syndrome.
- also 5-HT2 receptors.
- BZDz.
- Acute effects (with low doses)of LSD induce : - Antipsychotic.
1- hallucinations – delusions – illusions
2- brilliant colors.
3- Ephoria & sensory changes.

Nicotine ( CNS stimulants )

- Adverse effects
Nicotine is a selective agonist of the nicotinic acetylcholine
receptor (nAChR) that is normally activated by acetylcholine, - intestinal cramps,
nAChRs are expressed on dopamine neurons. - diarrhea,
- increased heart rate and blood pressure.
- cigarette smoking increases the rate of metabolism for a
Acute effects : number of drugs.
some degree of euphoria and arousal as well as relaxation.It - Treatment
improves attention, learning, problem solving, and reaction time.
- Psychotherapy
- nicotine replacement by : - nicotine gum
Risk of chronic abuse :
- transdermal nicotine patch
- cancer - lung diseases - ischemic heart diseases.
- Bupropion :
Withdrawal syndrome : • is an atypical antidepressant and smoking cessation aid
Insomnia – anxiety – increase appetite – decrease concentration – • Bupropion reduces the severity of nicotine cravings and
headache – aggressiveness withdrawal symptoms.

Barbiturates & Benzodiazepines ( CNS depressant )

Acute effects : - Treatment
Euphoria – relieve anxiety - insomnia
Risk of chronic abuse : Replace the short acting agent by a longer acting one (less sever
Anterograde – retrograde memory loss withdrawal :

Withdrawal syndrome : - Phenobarbital for pentobarbital

Insomnia – anxiety – tremor – delirium – hallucinations – - Diazepam for alprazopam triazolam
convulsions
Opioids ( CNS depressant )
- Treatment
Acute effects :
1- Methadone : (longer-acting, less withdrawal symptoms)
Euphoria – Drowsiness & hyperactivity Replacement of heroin or morphine by methadone followed by its
Risk of chronic abuse : gradual withdrawal
Fatal overdose – homicide – suicide – increase risk of infection 2- Clonidine:
Withdrawal syndrome : To inhibit sympathetic discharge
Insomnia – anxiety – tremor – SPATHATIC OVER ACTIVITY. 3- treatment of the sympathetic withdrawal symptoms e.g. anxiolytics
, antiemetics , anti-spasmodics.
 1- Oxycodone (opioids)
Dr.Ahmados
- It is a semisynthetic derivative of morphine.
• Appearance: Pills
• Delivery: oral ingestion
• Effects: relaxed, calm, lower rate of respiration

- Abuse of the sustained-release preparation (ingestion of crushed tablets) has been implicated in many deaths.

2- Heroin (opioids)
• Heroin is converted to morphine in the body
• Appearance: Powder, or black tar-like substance, colors can range from white to brown to black
• Delivery: injected or smoked
• Effect: sleepiness, slow resiration, loss of appetite or other desires, constipation, loss of memory

Cocaine ( CNS stimulants )

• Appearance: powder or in solid pieces
• Delivery: injected, intranasal or smoked
• Effects:
Cocaine is highly addictive drug due to it's short duration of action (1,5 h), so need to get the drug each 15 min. to get the euphoria and avoid the
physical withdrawal symptoms.
- Risks during acute administration:
1- euphoria I.V : intense & risk of infection,, Intranasal: less euphoria & nasal septal perforation ,, Smoking: intense euphoria
2- increases mental awareness
3- and produces a feeling of well-being Withdrawal symptoms :
Fatigue – sleep – depression – overeating
- Overdose toxicity (due to potentate the actions of catecholamines) :
1- tremors and convulsions,
Treatment
2- Arrythmia – increase BP – myocardial infarction – cerebral aciddents
Treated by : Anti-depressants – antipsycotics
- Risk with chronic use: produce hallucinations and delusions

Amphetamine & Methamphetamine ( CNS stimulants )

• Appearance: Pill
• Delivery: oral ingestion
• Effect:
Amphetamine Similar to the Cocaine but: longer acting – less addictive with more psychosis.
Methamphetamine is a CNS stimulants as amphetamine with hallucinogenic properties.
The effects of amphetamine on the CNS and peripheral nervous system are indirect; depending on an elevation of the level of catecholamine
neurotransmitters in synaptic spaces. by releasing intracellular stores of catecholamines.
Ecstasy
• Known as: MDMA, the love or hug drug
• Appearance: Almost always a pill or capsule
• Delivery: Oral ingestion, snorting
• Effect: Euphoria, alert, affectionate, increases metabolism, enhances emotions and perception, Hyperthermia, sweating, dehydration, jaw
clenching, depression, short-term memory loss.

MDMA causes 5-HT release into the synaptic cleft, inhibits its synthesis, and blocks its reuptake resulting in increase 5-HT concentration in the
synaptic cleft and a depletion of intracellular 5-HT stores.

Gamma-hydroxybutyric acid (GHB)

• Appearance: liquid, clear, odorless, nearly tastless
• Delivery: Oral ingestion, or mixed with other beverage
Notes: Commonly used as a date rape drug, is used in sexual assaults.
• Effect: sleepy, calm, mildly euphoric effects can last up to 4 hours and can result in unconsciousness, ………….Hallucinations, bradycardia,
hypotension

Low doses of the drug stimulate dopamine synthesis but inhibit its release, causing dopamine to concentrate in the nerve terminal

• Treatment :
- Bradycardia unresponsive to stimulation should be treated with atropine.
- Pentobarbital has been used successfully in the treatment of severe GHB withdrawal.
Ketamine
• Appearance: liquid, powder, pill or capsule
• Delivery: injection, snorted, oral ingestion
• Effect: Can cause hallucinations in large doses, duration of effect can last up to 2 hours
It also stimulates the central sympathetic outflow, resulting in increased blood pressure and cardiac output.

It is a short-acting, nonbarbiturate anesthetic,

Sudafed
• Alias: pseudoehedrine
• Appearance: pills
• Delivery: Oral ingestion
• Effects: effects the central nervous system, similar to but less intense than amphetamines

Often abused in its original form, but also used for the manufacture of methamphetamine
 Neuromuscular Blocking Drugs ( Post synaptic neuromuscular blockers )
These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end plate of skeletal muscle. These neuromuscular blockers are structural analogs of acetylcholine,
and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the receptors on the end plate of the neuromuscular junction.
Dr.Ahmados Nondepolarizing (competitive) blockers
tubocurarine is considered to be the prototype agent in this class, it has been largely replaced by
other agents due to side effects
1- At low doses:
- Nondepolarizing neuromuscular blocking drugs interact with the nicotinic
receptors to prevent the binding of acetylcholine thus prevent depolarization
of the muscle cell membrane and inhibit muscular contraction.
- Because these agents compete with acetylcholine at the receptor without
Mechanism of
stimulating the receptor, they are called competitive blockers.
action:
N.B. Their action can be overcome by increasing the concentration of
acetylcholine in the synaptic gap for example, by administration of
cholinesterase inhibitors, such as neostigmine, pyridostigmine, or
edrophonium.
2- At high doses:
Nondepolarizing blockers can block the ion channels of the end plate. This leads
to further weakening of neuromuscular transmission, and it reduces the ability
of acetylcholinesterase inhibitors to reverse the actions of nondepolarizing
muscle relaxants.
Not all muscles are equally sensitive to blockade by competitive blockers.
- Small, rapidly contracting muscles of the face and eye are most susceptible
and are paralyzed first, followed by the fingers.
Actions: - Thereafter, the limbs, neck, and trunk muscles are paralyzed.
- Then the intercostal muscles are affected, and lastly, the diaphragm muscles
are paralyzed.
- Those agents (for example, tubocurarine, mivacurium, and atracurium),
which release histamine, can produce a fall in blood pressure, flushing, and
bronchoconstriction.
1- These blockers are used therapeutically as adjuvant drugs in anesthesia
during surgery to relax skeletal muscle.
Therapeutic
uses: 2- These agents are also used to facilitate intubation as well as during
orthopedic surgery.
Depolarizing agents
The depolarizing neuromuscular blocking drug succinylcholine attaches to
the nicotinic receptor and acts like acetylcholine to depolarize the junction.
Unlike acetylcholine, which is instantly destroyed by acetylcholinesterase,
the depolarizing agent persists at high concentrations in the synaptic cleft,
remaining attached to the receptor for a relatively longer time and
providing a constant stimulation of the receptor.
The depolarizing agent first causes the opening of the sodium channel
associated with the nicotinic receptors which results in depolarization of
the receptor (Phase I) This leads to a transient twitching of the muscle
(fasciculations).
Continued binding of the depolarizing agent renders the receptor incapable
of transmitting further impulses. With time, continuous depolarization gives
way to gradual repolarization as the sodium channel closes or is blocked
This causes a resistance to depolarization (Phase II) and a flaccid paralysis.
- The sequence of paralysis may be slightly different, but as with the
competitive blockers, the respiratory muscles are paralyzed last.
- Succinylcholine initially produces short-lasting muscle fasciculations,
followed within a few minutes by paralysis.
- The drug does not produce a ganglionic block except at high doses, but it
does have weak histamine-releasing action.
- However, succinylcholine that gets to the neuromusclular junction is not
metabolized by acetylcholinesterase, allowing the agent to bind to nicotinic
receptors, and redistribution to plasma is necessary for metabolism
(therapeutic benefits last only for a few minutes).]
- Because of its rapid onset and short duration of action, succinylcholine is
useful when rapid endotracheal intubation is required during the induction
of anesthesia
(a rapid action is essential if aspiration of gastric contents is to be avoided
during intubation).
- It is also employed during electroconvulsive shock treatment.
 All are injected intravenously, because their uptake via oral absorption is
Route of admin. minimal BECAUSE:
These agents possess two or more quaternary amines in their bulky ring
structure, making them orally ineffective.
They penetrate membranes very poorly and do not enter cells or cross the - Normally, the duration of action of succinylcholine is extremely short,
Distribution blood-brain barrier.
because this drug is rapidly broken down by plasma cholinesterase.
- tubocurarine, pancuronium, mivacurium, metocurine, doxacurium

are not metabolized; their actions are terminated by redistribution and are - Succinylcholine is injected intravenously. Its brief duration of action
excreted in the urine unchanged. (several minutes) results from:
- Atracurium : 1-redistribution
Pharmaco- is degraded spontaneously in the plasma and by ester hydrolysis. 2-and rapid hydrolysis by plasma cholinesterase.
kinetics:
N.B. Atracurium has been replaced by its isomer, cisatracurium BECAUSE
Metabolism & Atracurium releases histamine and is metabolized to laudanosine, which can It therefore is usually given by continuous infusion.
Excretion provoke seizures.

- isatracurium,

has the same pharmacokinetic properties as atracurium, is less likely to have

these effects.

- vecuronium, rocuronium (The aminosteroid drugs)

are deacetylated in the liver, and their clearance may be prolonged in

patients with hepatic disease.

These drugs are also excreted unchanged in the bile.

1- Histamine release and promote ganglion blocker. Adverse effects:

tubocurarin
Adverse 2- Decrease blood pressure.
effects: a.Hyperthermia:
pancuronium Increased heart rate. When halothane is used as an anesthetic, administration of succinylcholine has
- Drugs: neostigmine, physostigmine, pyridostigmine, and edrophonium
occasionally caused malignant hyperthermia (with muscular rigidity and
can overcome the action of nondepolarizing neuromuscular blockers, hyperpyrexia) in genetically susceptible people (see Figure 5.10).
This is treated by rapidly cooling the patient and by administration of dantrolene, which
- but with increased dosage, cholinesterase inhibitors can cause a
Cholinesterase blocks release of Ca2+ from the sarcoplasmic reticulum of muscle cells, thus reducing heat
depolarizing block as a result of elevated acetylcholine concentrations
inhibitors: production and relaxing muscle tone.
at the end-plate membrane.
- If the neuromuscular blocker has entered the ion channel, cholinesterase b.Apnea:
inhibitors are not as effective in overcoming blockade.
Drug Administration of succinylcholine to a patient who is genetically deficient in plasma
Drugs: halothane act to enhance neuromuscular blockade by cholinesterase or has an atypical form of the enzyme can lead to prolonged apnea
interactions: Halogenated
exerting a stabilizing action at the neuromuscular junction. due to paralysis of the diaphragm.
hydrocarbon
anesthetics: These agents sensitize the neuromusclular junction to the effects of
neuromuscular blockers. c.Hyperkalemia:
Drugs: gentamicin or tobramycin inhibit acetylcholine release from Succinylcholine increases potassium release from intracellular stores.
Aminoglycoside
cholinergic nerves by competing with calcium ions.
antibiotics:
They synergize with tubocurarine and other competitive blockers, This may be particularly dangerous in:
enhancing the blockade. 1- burn patients or
These agents may increase the neuromuscular block of tubocurarine 2- patients with massive tissue damage
Ca–channel bloc. and other competitive blockers as well as depolarizing blockers. in which postassium is been rapidly lost from within cells.