Sunday, March 31, 2013

Antiepileptic and anticonvulsive drugs

Antiepileptic Drugs

Before knowing anit-epileptic drugs, you must know What is epilepsy?
Epilepsy: Epilepsy is a neurological disorder characterized  by short, recurrent electrical malfunctions of the brain which leads to changes in muscle activity, sensation and consciousness. 

Many factors may contribute to the onset of epilepsy

  • Brain damage related to birth 
  • Brain abnormalities present before birth 
  • Brain infections 
  • Brain tumors 
  • Abnormalities in blood vessels of the brain 
  • Head injuries 
  • Drug or alcohol abuse 
  • Lead poisoning 
  • Family history of seizure disorders 
  • Stroke 
  • Low blood sugar 

Common seizure types of Epilepsy
1-Generalized seizures.

  • Absence (petit mal).
  • Tonic/clonic (grand mal). 

2-Partial seizures.

  • Simple partial seizures.
  • Complex partial seizures

NOTE: The type of epileptic seizure determines the drug selected for therapy.

Generalized seizures:
Absence (petit mal): 
These seizures have abrupt onset and cessation, with impaired consciousness, but with normal posture often retained. The EEG shows a typical ‘spike and wave’ pattern.
Tonic/clonic (grand mal)
Consciousness is impaired and the patient usually falls to the  floor. A phase of muscle contraction (‘tonic’) is followed by irregular muscle clonus and then by sleep. Injury may occur.
Partial seizures:
Simple partial seizures: features depend on the part of the brain affected, result from discharge in the precentral gyrus. Consciousness is unimpaired.
Complex partial seizures (temporal lobe epilepsy):
Consciousness is impaired with complex, often repetitive action.

The neuron in brain lesion depolarizes together suddenly, and then product high-frequency, out-break discharge.
The discharge can diffuse to surrounding normal tissue →extensive excitation →the brain function transient aberration.
Therapeutic principle:
Change the permeability of Na+
Ca2+and K+ in nerve cell membrane, degrade excitement stage, extend refractory phase.
Directly or indirectly increase CNS levels of GABA.

Classification of Antiepileptic Drugs
Hydantoins:Sodium Phenytoin
Barbiturates:Phenobarbital, Primidone
Benzodiazepine:  Diazepam, Nitrazepam
Others:  Sodium Valproate

Sodium Phenytoin
Phenytoin is the oldest nonsedative antiseizure drugs, introduced in 1938 following a systematic evaluation of compounds such as phenobarbital that altered electrically induced seizures in laboratory animals. It was known for decades as diphenylhydantoin.

Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption.
(1) Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 hours to 12 hours.
(2) Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended for phenytion. 
In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration.

The elimination of phenytoin is dose-dependent. 

  1. At very low blood levels, phenytoin metabolism follows first-order kinetics.
  2. As blood levels rise with in the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached.
  3. Further increases in dose, even though relatively small, may pruduce very large changes in phenytoin concentrations.

The half-life of phenytoin varies from 12 hours to 36 hours,with an average of 24 hours for most patients, in the low to mid therapeutic range. 
At low blood levels, it takes 5-7 days to reach steady-state blood levels after every dosage change; at higher levels, it may be 4-6 days before blood levels are stable. 

Mechanism of action:

  1. It can block sodium channels (voltage-, frequency-, and time dependent fashion ) and inhibit the generation of action potentials. It can also block L and N type Calcium channels.
  2. It can increase the function of inhibitory transmitter GABA, inhibit nerve terminal to uptake GABA and induce the increasing of GABA receptor, thereby enhance GABA-mediated postsynaptic inhibition.

Clinical application

  1. Anti-epileptic: It can be used for partial seizures and tonic/clonic seizures, but not for other generalized seizure types.
  2. Peripheral neuralgia: ischiadic nerve and cranial nerve.
  3. Arrhythmia: membrane-stabilizing action, especially for the cardiac glycoside poisoning, it is the first choice.
Adverse effects
1-Digestive system
anorexia, nausea, vomiting and abdominal pain(recommend to take it after meal). 
2-Gingival hyperplasia
It common occurs in children and teenagers after long term use, the incidence rate is about 20%. Generally, this effect can resolve after drug withdraw 3 to 6 months.
3-Nervous system
diplopia, vertigo, ataxia(usually only at very high concentration). Severe patient occurs language disorder, mental confusion and cataphora
4-Hematological system
Because it can inhibit the absorption of folinic acid and accelerate its metabolism. 
5-Skeletal system
It can enhance vitamin D metabolism, so Phenytoin may increase the risk of hypocalcemia, rickets and osteomalacia  after long-term treatment (pretreat with vitamin D if necessary).
6-Allergic response
rash, thrombocytopenia, agranulocytosist can enhance vitamin D metabolism, so Phenytoin may increase the risk of hypocalcemia, rickets and osteomalacia  after long-term treatment (pretreat with vitamin D if necessary).and aplastic anemia.
Rarely appear male barymastia, female hirsutism and lymphadenectasis

Aside from the bromides, phenobarbital is the oldest of the currently available antiseizure drugs. Although it has long been considered one of the safest of the antiseizure agents, the use of other medical with lesser sedative effects has been urged. 
Mechanism of action:

  • Phenobarbital can inhibit the paradoxical discharge of epilepsy focus selectively, enhance stimulation of surrounding tissues and block discharge diffuse to normal tissues.
  • Phenobarbital facilitate GABA-mediated inhibition of neuronal activity.

Clinical application

  • Phenobarbital is an effective agent for generalized tonic-clonic and partial seizures. 
  • However, its sedative effects and its tendency to disturb behavior in children have reduced its use as a primary agent.

Adverse effects

  • Somnolence, depression
  • Tolerance develops after long-term treatment.

Primidone was first marketed in the early 1950s. It was later reported that Primidone was metabolized to phenobarbital and phenylethylmalonamide (PEMA), All three compounds are active anticonvulsants.


  • Primidone is completely absorbed, usually reaching peak concentration about 3 hours after oral administration. 
  • Primidone is metabolized by oxidation to phenobarbital, which accumulates very slowly, and by scission of the heterocyclic ring to form PEMA. Both Primidone and phenobarbital under go subsequent conjugation and excretion.
  • Primidone has a larger clearance than most other antiseizure drugs(2L/kg/d), corresponding to a half-life of 6-8 hours. PEMA clearance is approximately half that of primidone, but phenobarbital has a very low clearance. The appearance of phenobarbital corresponds to the disappearance of Primidone. Phenobarbital therefore accumulates very slowly but eventually reaches therapeutic concentrations in most patients when therapeutic doses of primidone are administered.

Clinical application

  • It can be used for all types of epilepsy except petit mal. It,s better to use this drug with sodium phenytoin. 
  • With regard to grand mal, the effect of primidone is better than phenobarbital, this drug is useless to petit mal. 

Adverse effects

  • Common: somnolence, vertigo, nausea and vomiting
  • Rare: megaloblastic anemia, leucopenia and thrombocytopenia

Ethosuximide was introduced in 1960 as the third of three marketed succinimides in the USA. Ethosuximide has very little activity against maximal electroshock but considerable efficacy against pentylenetetrazol seizures and was introduced as a “pure petit mal” drug. 

Absorption is complete following administration of the oral dosage forms. 
Peak levels are observed 3-7 hours after oral administration of the capsules. Animal studies indicate that chronic administration of the solution may prove irritating to the gastric mucosa.
Ethosuximide is completely metabolized, principally by hydroxylation, to inactive metablites. 

Half Life
The drug has a very low total body clearance(0.25/kg/d). This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported.

Clinical application
Ethosuximide is effective against absence seizures but not tonic-clonic seizures.

Adverse effects

  • Gastrointestinal tract: anorexia, nausea, vomiting
  • CNS: headache, dizziness and somnolence
  • Rarely appear agranulemia and aplastic anemia

4-Diazepam & Nitrazepam


  • The drug are well absorbed, widely distributed, and extensively metabolized, with many active metabolites.
  • The rate of distribution of benzodiazepines within the body is different from that of other antiseizure drugs. 
  • Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volumes of distribution between 1 L/kg and 3 L/kg.
  • The onset of action is very rapid.
  • Total body clearances of the parent drug and its metabolites are low, corresponding to half-life of 20-40 hours.

Diazepam: given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic-clonic status epileptics. 
The drug is occasionally given orally on a chronic basis, although it is not considered very effective in this application, probably because of the rapid development of tolerance. 
Nitrazepam: is not marketed in the USA but is used in many other countries, especially for infantile spasms and myoclonic seizures. It is less potent than clonazepam, and its clinical advantages over that drug have not been documented.
It’s highly effective in controlling petit mal and myoclonus epilepsy.

5-Sodium Valproate
Sodium Valproate, was found to have antiseizure properties when it was used as a solvent in the search for other drugs effective against seizures. 


  • Valproate is well absorbed following an oral dose, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours.
  • Food may delay absorption, and decreased toxicity may result if the drug is given after meals.

Clearance for valproate is low; its half-time varies from 9 hours to 18 hours. At very high blood levels, the clearance of valproate is dose-dependent. There appear to be offsetting changes in the intrinsic clearance and protein binding at higher doses. Approximately 20% of the drug is excreted as a direct conjugate of valproate.

Clinical application

  • Valproate is very effective against absence seizures. 
  • Valproate is unique in its ability to control certain types of myoclonic seizures; in some cases the effect is very dramatic. The drugs is effective in generalized tonic-clonic seizures, especially those which are primarily generalized.

Closely related to imipramine and other antidepressants, carbamazepine is a tricyclic compound effective in treatment of bipolar depression. It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for epilepsy as well.


  • The rate of absorption of carbamazepine varies widely among patients, although almost complete absorption apparently occurs in all.
  • Peak levels are usually achieved 6-8 hours after administration .

Distribution is slow, and the volume of distribution is rough 1 L/kg.
Carbamazepine has a very systemic clearance of approximately 1 L/kg/d at the start of therapy.

Mechanism of action
 Carbamazepine can block sodium channel, inhibit paradoxical discharge and discharge diffusion. It may relate to the postsynaptic inhibition of GABA.

Clinical application

  • Carbamazepine is considered the drug of choice for generalized tonic-clonic seizures. It can be used with phenytoin in many patients who are different to control.
  • The drug is also very effective in some patients with trigeminal neuralgia.
  • Carbamazepine is also useful in some patients with mania.

Adverse effects

  • CNS: somnolence
  • Gastrointestinal tract: nausea, vomiting and anorexia
  • Rash, thrombocytopenia, aplastic anemia and hepatic lesion.

Principle of Medication 
Grand pit (first choice): Sodium phenytoin or phenobarbital, carbamzepine, Primidone.
Petit mal (first choice): Ethosuximide, clonazepam and sodium valproate.
Status epilepticus: Diazepam or sodium phenytoin (IV), phenobarbital, diazepam, clonazepam.
Psychomotor: Sodium phenytoin or combine with  carbamazepine.

Principle of Medication (I)
The dose can be gradually increased from a low starting dose until reach the best effect.
In the initial stage, the patients should only be treated with a single antiepileptic drug, if the drug is useless, then it can be changed. When drug changing is necessary, it should be gradually withdrawn after the effect of new drug occurs. 
After the symptom is fully controlled, the patients should continuing be treated for 2 or 3 years. Sudden withdrawal of drugs are likely to precipitate relapse. 

Principle of Medication (II)
Enhance therapeutic effect: dosing individually, monitoring drug plasma concentration, examining regularly.  
Evaluating efficacy and safety.
Adjusting drug dosage: the therapeutic index of antiepileptic drug is low→easy to be poisoning Therapeutic dose is get close to toxic dose. 

Anticonvulsant Drugs

  • Convulsions are involuntary skeletal muscular contractions. Convulsions can arise from pathological processes within or outside the brain, toxins, drug overdose, or withdrawal from drug dependence. 
  • Commonly used anticonvulsant drugs are sedative and hypnotic drugs. Magnesium Sulfate is also used on this disease.

Pharmacological Effects
1 If used orally, it will have cathartic effect. 
2 It induces bile secretion as choleretic
3 Effect on neuromuscular system: reduce muscle contraction

Wednesday, March 27, 2013

What is Hypoxia and its Consequences?

This is a general process of oxygen entering into tissue ,and cells.

This process is complex ,troubles in any part will affect the oxygen supply to cell, and lead to hypoxia
Ventilation              Transfer
O2 ——>HbO2  ——> Tissue utilization
      diffusion           Circulatory system

Hypoxia is an extremely important and common cause of cell injury and death.

Hypoxia  is a pathological process, in which O2 supply to tissues or organs is inadequate to meet the demand of cells; or the tissue cells can not make use of O2, leading to changes in functions, metabolisms and structures of cells and tissues of the body.
    The absence of O2 in  the tissues
    A deficiency of O2 in blood

Three key points of Concept :
1. Pathological process
2. Causes 
I)Can’t obtain enough oxygen
II)Can’t fully utilize oxygen
3. Changes  

Oxgen  supply  =  CaO2× Q
Oxygen consumption  =(CaO2-CvO2)× Q

Parameters of blood O2
  1. Partial pressure of  O2 (PO2)
     PO2 is the tension caused by O2  physically dissolved in the  blood.

The normal value :
      PaO2 : 100mmHg (13.3kPa )
      PvO2 : 40mmHg (5.33kPa )

PO2(in the air)  :159mmHg
PO2(in alveolar air):104mmHg

Determinants of  PO2 :
O2 pressure in the inhaled air
respiratory function

abnormal right-to-left shunt in  pathological conditions(e.g. ventricular septal defect)

Ventricular septal defect a common congenital heart defect; an abnormal opening in the septum dividing the ventricles allows blood to pass directly from the left to the right ventricle; large openings may cause congestive heart failure .

2. Oxygen capacity (CO2max)
The maximal amount of O2 combined by hemoglobin (Hb) in 100ml blood.
Fully saturated condition:

The level of  Cp-O2max only depends on Hb :
  ① quantity of HB
  ② quality of HB
 The normal value
Cp-O2max  = 1.34 ml/g × 15 g/dl = 20 ml/dl

3. Oxygen content (C-O2)
The actual amount of O2  in blood.
>combined with Hb : 98.5%
>physically dissolved:1.5%(can be  omitted)
The  level of C-O2 depends on:
  ②The level of Hb (quality and quantity)
 The normal value of  C-O2 :
 CaO2 ——19ml/dl
 CvO2 ——14ml/dl

CaO2 - CvO2 
(Arteriovenous Oxygen content difference) 

normal value:
  19ml/dl -14ml/dl = 5ml/dl  
4. Oxygen saturation(SO2)
 The percentage of hemoglobin present as oxyhemoglobin . 

                                                  O2 content
 SO2 can be calculated by :  —–—–—–—–
                                                 O2 capacity
If 100ml blood contains 20ml O2 , the SO2  is 100%
when it contains 15ml O2 , how much is SO2 ?
 The normal value :
The level of  SO2 only depends on PO2
NOTE: When O2 content in arterial blood is 19ml/100ml, the O2 saturation is 95%, When O2 content in venous blood is 14ml/100ml, the O2 saturation is 70%.

Four parameters
1. Partial pressure of O2(PO2)
              PaO2  : 100mmHg , PvO2: 40 mmHg                                       
2. O2 content(C-O2)
              CaO2  : 19ml/dl , CvO2: 14ml/dl
3. O2 capacity(Cp-O2max)=  1.34 ml/g × 15 g/dl
              C-O2max  : 20ml/dl
4. O2 saturation(SO2) 
               SaO2 : 95%, SvO2: 70%

Classification and pathogenesis
 1. Hypotonic hypoxia 
(1) Decreased O2 pressure in the inspired air.
--- atmospheric hypoxia
①In enclosed room
② 3000 meters above sea level 

(2) External respiratory dysfunctions

Peanuts, jelly or any other soft ,sweet food made from fruit juice and sugar boiled together ,used as a topping.
can cause
Paralysis of respiratory muscles, airway obstruction, asthma, emphysema, tuberculosis, pulmonary cancer, inflammation, and edema.

(3) Right-to-left shunt—Venous admixture
Some congenital heart diseases, such as ventricular septal defect, or if the foramen oval fails to close after birth.

◆ Characteristics of blood O2

-O2 content :↓

-O2 capacity:

acute cases:N
chronic cases:↑

-O2 saturation:↓

NOTE: O2 content ↓(both in arterial and venous blood).    
Oxygen capacity is normal in acute cases and is increased in chronic cases.

   Cyanosis refers to a bluish color of the skin, nail beds and mucous membranes when deoxyhemoglobin concentration of blood in capillary is more than 5g per 100ml blood.
NOTE: Cyanosis is the most important clinical sign of hypotonic hypoxia.
The discolor  of the skin, nail beds and mucous membrane.

Mechanism of Cyanosis
HbO2 (oxygenated Hb) ─bright red
Hb (unoxygenated Hb) ─bluish

Not all the cyanosis means hypoxia

2. Hemic hypoxia (Isotonic hypoxia)
(1) Anemia
The concentration of Hb is less than 9g/100ml。
Patients with severe anemia will have no cyanosis, since their unoxygenated Hb can not reach 5g/100ml

(2) Carbon monoxide  (CO)  poisoning

Mechanism of  CO poisoning
① Hb combine with CO instead of  O2 & produce carboxy-hemoglobin (CO-Hb),the CO-Hb can’t carry O2 any more.
② Hb may combine with both CO and O2 more tightly,so Hb can’t release O2 to tissues.

CO combines with Hb form carboxyhemoglobin (COHb), the color is cherry-red. The cherry-red/pink color will be visible in the skin, nail beds and mucous membrane during CO poisoning. It will have no cyanosis.

(3) Methemoglobinemia
Normal: ferrous state (Fe2+)
oxidized :ferric state (Fe3+)

Hb containing Fe3+ : methemoglobin 

Appearance: Methemoglobin is brown, the patients will appear brown color. 

NOTE: Many chemicals and drugs can oxidize the iron in Hb.(such as: amyl nitrite, aniline, nitrobenzene, acetanilid, phenacetin, and salicylates)
Enterogenous cyanosis

◆ Characteristics of blood O2
     PO2 :N   (isotonic hypoxia)
     O2 content : N or ↓
     O2 capacity : N or ↓
     O2 saturation: N

 3. Circulatory hypoxia
circulatory deficiency
shock, heart failure embolism.

Ischemic hypoxia

Stagnant hypoxia

◆ Characteristics of blood O2
PaO2 :N
C-O2 :N
Cp-O2max :N
SO2 : N

Note: Oxygen supplied for cell in unit time is inadequate.
PO2 in A and O2 content in A are normal; because when blood flow passes through tissues slowly, the PO2 and O2 content in venous blood are decreased. C(a-v) is increased.
C(a-v): ↑ blood flow passes through tissues slowly, the PO2 and O2 content in venous blood are decreased. C(a-v) is increased.

 4. Histogenous hypoxia
Histotoxic hypoxia
(1)  Tissue  poisoning
(2)  cell injured by biological or physical factor
(3)  vitamin deficiency ---vit B1

NOTE:The toxic agent substances include cyanide, arsenic, barbiturates.

◆ Characteristics of blood O2
PaO2 :N
CO2 :N
CO2max :N
SO2 : N

Note: In Histogenous hypoxia;
Cell can’t fully utilize oxygen

The color of skin in hypoxia
1.Anemia —————— pale
2.CO poisoning ———— cherry red
3.Methemoglobinemia—— brown
4.Histotoxic hypoxia—— rose red

Effects on body
Take “Hypotonic hypoxia” for an example
> Functional 
> Metabolic
 mild or chronic hypoxia: compensatory response
 severe or acute hypoxia: organic dysfunction

   1. Respiratory system
PaO2 > 60mmHg:no obvious changes
PaO2 < 60mmHg:compensation

lower segment, Middle, upper segment
remain at  a high level
With the changes in the horizontal axis, vertical axis did not change significantly
The slope is very steep. 

 2. Circulatory system
(1)  In response to hypoxia
I) The heart rate increases (tachycardia),cardiac output increases,due to:
1. Myocardial contractility↑  
2. heart rate↑  
3. venous return↑
II) Peripheral vasodilation occurs.

(2) Pulmonary vasoconstriction
Due to: Sympathetic nerve(+)
        Humoral factors :
       Vasoconstrictive substance ↑↑
       Vasodilative substance↑
significance? --- to maintain the VA/Q

(3) Redistribution of blood flow

 sympathetic nerve(+)---- vasoconstriction
  Local metabolites ----- vasodilation

(4) Capillary proliferation

Capillary hyperplasia

Severe hypoxia ---- decompensation
• Myocardiac systolic and diastolic dysfunction
• Pulmonary hypertension
• Cardiac arrhythmia:
• Venous return↓
Hypoxia  acidosis  hyperkalemia  Arrhythmia

 3.  Hemic system

Hypoxia can stimulate the function of red bone marrow to produce more red blood cells. 

 4.Central nervous system

• Acute  hypoxia  : headache、impaired attention                       
• Chronic  hypoxia : sleepiness, depression
• Severe hypoxia : confusion, coma, convulsion
1. energy deficiency 
2. acidosis 

 5. Cellular alterations
•  Ability to use O2↑:
    number of mitochondia increase
•  Anaerobic glycolysis↑:
    phosphofructokinase activity increase
•  Low metabolic state:
    caused by  acidosis
•  Myoglobin↑

Cellular damage (seen in severe hypoxia) 
(1)Cell membrane 
(3)  Lysosome

Consequences at the cellular level
Lack of ATP may let the sodium pump have no activity, the result is cellular swelling. Hypoxia can increase the cell-membrane permeability, intracellular enzymes enter the ECF.
Myocardial cells contain the enzymes GOT (glutamic-oxaloacetic transaminase), LDH (lactic dehydrogenase), and CPK (creatine phosphokinase), following myocardial infarction the serum levels of these enzymes rise.
GOT and LDH are also abundant in the lungs, liver, pancreas, and kidneys.
Only the heart, brain, and skeletal muscles contain CPK.

Tuesday, March 26, 2013


General Properties of Viruses

What is virus?
The smallest infectious and acellular microbe.
Consisting only one kind of nucleic acid (DNA or RNA), and which obligately replicate inside host cells.

The complete mature viral particles.
(The intact infectious virus particles.)

Distinctive features

  • The simplest: acellular microbes contain either DNA or RNA
  • The smallest: Pas through 0.2μm filters                      
  • Obligatory intracellular parasites.
  • Self-replication

 I. Size, shape and structure
  A. Size 
     The unit of measurement nm

Comparative sizes of virions and bacteria

1. Staphylococcus aureus
2. Rickettsia
3. Chlamydia
4. Poxviruses
5. Bacteriophage of E. coli
6. Influenza virus
7. Adenovirus
8. Encephalitis B virus
9. Poliovirus

B. Shape
Tobacco mosaic virus: rod-shaped

Poxvirus: brick-shaped 


VSV (Vesicular stomatitis virus): bullet-shaped

Bacteriophage T4: tadpole-shaped

Ebola Virus: filamentous shape

Basic structure:
Core: Viral nucleic acid  (DNA or RNA)
Capsid: Protein shell
capsomers (morphological subunit)
polypeptide molecules (chemical subunit)

Core + Capsid → nucleocapsid

Size, shape and structure
Naked virus:
Virion: nucleocapsid.

Enveloped virus:
Virion: nucleocapsid+Envelope
spikes (peplomers);
Others: enzymes, etc.
e.g. Retrovirus has reverse transcriptase

Symmetry of  viral nucleocapsids: Is decided by arrangement of capsomeres
Helical symmetry
(e.g., tobacco mosaic virus)
Icosahedral symmetry
(e.g., adenovirus)
Complex symmetry
(e.g., poxviruses )

Chemical composition
Viral nucleic acid: ssDNA, dsDNA, ssRNA, dsRNA
Viral proteins:
 protection, mediate the attachment of virue to specific receptors on host cell surface
 determine species and organ specificity
 important antigens, superantigen

Unconventional viruses
plant disease
Human Hepatitis D
NOTE: a single circular RNA molecule without a protein coat which mainly cause plant diseases.

Proteinaceous infectious particle
Human diseases:
     e.g., Kuru
Animal diseases:
     Bovine spongiform encephalopathy (BSE)
NOTE: infectious agents composed of a single glycoprotein with MW 27-30 kDa.

II. Replication
In host cell, virus replicates its nucleic acid and synthesizes
its proteins, then assembles them to form progeny viral
particles that are released by budding or cell lysis.

Replication---Normal Replication

  • Adsorption /Attachment
  • Penetration 
  • Uncoating 
  • Biosynthesis
  • Assembly 
  • Release 

i. Adsorption / Attachment
Specific binding of a viral attachment protein (VAP) with a receptor on the surface of host cell;
VAP (on virion ) --- viral surface protein
Spike – enveloped virus
Capsid protein – naked virus
Viral receptor (on host cell)
Glycoprotein, carbohydrate or glycolipid
    e.g., CD4 (HIV), CD46 (measles virus), Sialic acid (influenza virus)

ii. Penetration
A. Endocytosis
Some enveloped viruses
Most naked virus

B. Direct fusion of cell membrane with viral envelope:
Only enveloped viruses

C. Nucleic acid translocation:
Some bacteriophages and naked virus

iii. Uncoating
The process of removing capsid and releasing viral nucleic acid into the cytoplasm;
Acidification of the content of the endosome
Proteases are needed;

iv. Biosynthesis
 Eclipse phase
 Biosynthesis includes:

  •  Viral genome replication
  •  Viral protein synthesis
The replication strategy depends on the nature of viral genome.
dsDNA;   ssDNA;   dsRNA;   +ssRNA;   -ssRNA; retrovirus
+ssRNA with DNA intermediate in life cycle (HIV);
dsDNA with RNA intermediate (HBV);


+ssRNA virus (Poliovirus, HAV)
 Viral genomic RNA serve as mRNA;
 Enzymes for replication are made after infection, not carried in virion;
 (Extracted) Viral genomic RNA is infectious

-ssRNA virus e.g., influenza virus
 Virion carries RDRP;
 First step: Transcription of viral genome;
 Extracted -ssRNA not infectious;

v. Assembly
Naked virus:    capsid + viral genome → nucleocapsid (virion, complete structure)
Enveloped virus: capsid + viral genome → nucleocapsid (incomplete structure)
a. DNA viruses (except poxvirus): cell nucleus;
b. RNA viruses and poxvirus: cell cytoplasm;
a. assemble as empty shell (procapsid), then viral genome fill in.    
b. Viral capsomeres array around the viral genome to form helical

vi. Release
The process of progeny viruses getting out of host cell.

Naked viruses:released by cell lysis.
Enveloped viruses:usually released by budding.
During budding enveloped viruses acquire their envelope.
Defective measles virus: release from cell to cell via cell bridges.

enveloped virus replication (1)

enveloped virus replication (2a)
enveloped virus replication (2b)

enveloped virus replication (3)

enveloped virus replication (4)

 Abnormal replication
Two aspect factors:
Defective viruses
Host cells
non-permissive cells → Abortive infection

Defective viruses
are genetically deficient and incapable of producing infectious progeny virions.
Helper virus
can supplement the genetic deficiency and make defective viruses replicate progeny virions when they simultaneously infect host cell with defective viruses.
e.g., HDV & HBV

  • Defective viruses lack gene(s) necessary for a complete infectious cycle;
  • helper viruses provide missing functions;

  • 100:1 (defective to infectious particles)
  • DIP (defective interfering particle) : When the defective viruses can not replicate, but can interfere other congeneric mature virion entering the cells, we call them defective interfering particles (DIP).

Abortive infection:
Virus infection which does not produce infectious progeny because the host cell cannot provide the enzyme, energy or materials required for the viral replication.
non-permissive cells
The host cells that cannot provide the conditions for viral replication.
permissive cells
The host cells that can provide the conditions for viral replication.

 III. Viral interference:
   When two viruses infect simultaneously one host cell, One type of virus
    may inhibit replication of another type of virus.
Range of interference occurrence

  •  between the different species of viruses;
  •  between the same species of viruses;
  •  between the inactivated viruses and live viruses.

Main mechanisms of viral interference:
a. One type of virus inhibit or prevent subsequent adsorption and penetration
    of another virus by blocking or destroying receptors on host cell.
b. The competition of two viruses for replication materials, e.g., receptor
    polymerase, translation initiation factors, etc.
c. One type of virus may induce the infected cell to produce interferon that
    can prevent viral replication.
The mechanism of IFN function 

Significance of viral interference:
    a. Stop viral replication and lead to patient recovery.
    b. Inactivated virus or live attenuated virus can be used as vaccine to
        interfere with the infection of the virulent virus.
 May decrease the function of vaccine when bivalent/trivalent vaccine is used.

Just for your practice see the answers at the end.
Fill in the blank
1-The surrounding protein coat of a virus is called the _______   and it is composed of protein subunits called _________.      
2-Viruses that are only covered with a protein coat outside viral genome are called ______ viruses, while those that have an additional lipid-containing membrane covering are called ________ viruses.
3. The general steps of the viral replication cycle include ( in the order of their occurrence) ___________________, ___________, ____________, __________, _________________.

1-Capsid. Capsomeres.
2-Naked, Enveloped.
3-Attachment, Penetration, Uncoating, Biosynthesis, Assembly and release.