Fever

23Nov08
  • Is a pathologic process which is characterized by increase of temperature regardless to environmental temperature change, caused by an action of pyogenic substances.
  • There is no disturbance in temperature regulation

 
 

Pyogenic Substance

  • Exogenous
    • Lipopolysaccharides & Gram Negative Bacteria
  • Endogenous
    • IL-1, IL-G, IL-8, IL-11
    • IFN-a, IFN-g
    • TNF
    • Morfological Inflammatory Protein (MIP)

       
       

       
       

Classification

  • According to temperature elevation
    • Sub febrile (~38 degrees Celsius)
    • Febrile / moderate ( >39 degrees Celsius)
    • Pyretic (39-41 degrees Celsius)
    • Excessively high / hyper pyretic (>41 degrees Celsius)

       
       

  • According to characteristic of time fever
    • Continuous fever
    • Remittent fever
    • Intermittent fever
    • Recurrent fever

 
 

Pathophysiology of Fever

 
 

  1. Infectious agents / toxins / mediators of inflammation (pyrogens)
  2. Stimulate the monocytes/macrophages/endothelial cells
  3. Releasing pyrogenic cytokines – IL-1, TNF, IL-6, IFNS
  4. Stimulate the anterior hypothalamus
  5. Resulting in elevated thermoregulatory set point
  6. Leads to
    1. Increase heat conservation (vasoconstriction)
    2. Increase heat production (involuntary muscle contraction)
  7. Ending in – FEVER

  1. Synergistic Interaction
    1. Pharmacological phenomenon of drug interaction when the drugs increase action of each other.
    2. 2 main types
      1. 1+1=2 : Drug which administrated, all increase the effect of each other and some of its effect is sum up.
      2. 1+1>2 : Drug which enhances/amplifies the effect of each other, usually drugs of CNS
  2. Antagonism
    1. Pharmacological phenomenon of drug interaction when the drugs decrease action of each other
    2. Types:
      1. Chemical antagonism
        1. Chemical neutralization of drug
        2. Formation of insoluble chemical non-active complexes (chelations)
      1. Pharmacokinetic antagonism
        1. Changes in absorption of other drug
        2. Changes in biotransformation of other drug
          1. Increase/activates
          2. Decrease/inhibits
        1. Changes in distribution/redistribution
          1. After injection/administration of drugs, it enters the blood to be transported
          2. Some drugs bind to certain structure of transporters (protein plasma, tissue etc)
          3. Some drugs change the distribution of another drug
        1. Changes in excretion
          1. Some drugs change the output of others
      1. Pharmacodynamic / physiological antagonism
        1. Competitive – both drugs act on one target site of the receptor
        2. Non-competitive – drugs act on different target site but produce opposite effect to each other
        3. Allosteric – drug acts on allosteric centres.

  • Toxic action due to overdose

  1. Too much drugs in body
  2. 2 types
    1. Absolutely overdose – patient took big amount of doses
    2. Insufficiency of biotransformation system
      1. Not enough elimination of drug
      2. Accumulation of drug in body
      3. Resulting from kidney failure
  1. Specific toxic actions of drug
    1. Is associated with
      1. Drug structure
      2. Mechanism of actions
      3. Effects

 

  • Toxin action on route of administrations (input/output)

 

  • Direct toxic action on different organs

 

  • Addiction

  1. Psychotic Addiction
  2. Physical Addiction

 

  • Tolerance

  1. Pharmacological phenomenon associated with decreased effect of drug during administration
  2. Mechanism of tolerance
    1. Decreased absorption of drug due to irritation & atrophy of membranes
      1. Example: skizophrenia _ chlonepramazine
    1. Activation of physiological system that produces opposite action
      1. Example: nitroglycerine –> vasodilation
      2. In physiological response, body produces more Renin –> Angiotensin (vasoconstrictor)
    1. Decreased sensitivity of receptors to drugs
      1. Example: morphine
      2. In case of addictions
    1. Activation of enzymes that causes degradation of drugs
      1. Example: barbiturates activate hepatic enzymes
    1. Antiinfective drug – increased resistance of microorganism
    2. Etiological drug – accommodation to drug

 

  • Withdraw Syndrome

  1. If patient stop using drug, the symptom appears again
  2. Due to
    1. Dose of drug
    2. Strategy of discontinuing
  1. Drug should be discontinued slowly
  2. Administration of steroids

 

  • Accumulation

  1. Material accumulation
    1. Accumulation of drug molecules in the body
    2. Usually by lipophilic drug due to retention in fatty tissue
  1. Physiological accumulation
    1. Drug is eliminated but the effect is accumulated
    2. Example: alcohol
    3. Associated with actions of drug in specific part of CNS
  1. Allergic reactions of drug
    1. Associated with hyperactivity of immune system
    2. Resulting in allergic @ pseudoallergic reaction
    3. Reboud Reaction
      1. Associated with big dose @ fast injection during administration
      2. Example: injection of a therapeutic dosage of antihypertensive drug Clonastine rapidly causes antihypertensive crisis

 

Classifications of drug actions, according to

Action

  1. Excitatory – To stimulate function in case inhibited by disease
  2. Inhibitory – In case of hyperactivity of system/organ due to disease

 

Location of effect

  1. Topical
    1. Places of application
    2. All drug produces topical action
    3. Example: local anaesthetics, ointments, creams, pastes – for inflammation, allergic reactions etc
  2. General/Systemic
    1. After absorption of drug, for system effect, drug produces actions on all body cell
    2. Depends on structure of the drug – the ability of drug to cross biological membranes
    3. Types
      1. Peripheral actions
        1. By drugs that cannot cross the blood-brain barrier
        2. Hydrophilic drug
        3. Cannot dissolve into brain
      1. Central actions
        1. Produces cross-action across biological barrier, enters the CNS
      1. Reflex actions
        1. Acts on reflex pathways, causes change in body function
        2. Acts on receptor of reflex arc
        3. Example: nicotine

Target

  1. Direct
    1. Acts on the target directly
    2. Example : oxytoxin (directly to uterine muscle), cardiatonic (directly to cardiac muscle)
  1. Indirect
    1. Action on different organ is produced by stimulation of another organ
    2. Example: caffein causes increase in urine output (caffein causes increased heart action, causes increased haemodynamic activity, causes increase in kidney activity, causes increased in urine output.)

 

Target II

  1. Selective
    1. Produce action only on specific organ
    2. Example: sabutamol for treating asthma : acts only to the receptor in brochioles
    3. However, in excessive dosage, it produces non-selective action in other parts
  1. Non-selective
    1. Example: epinephrine – stimulates all adrenergenic receptor ( Alpha1, Alpha2, Beta1, Beta2, Beta3)

Pharmacology = Study of action of drugs on living system

Aim:

  1. Experimental aim : to find new drugs, study clinical effects of drugs to patient
  2. To study the actions of drugs on body and the actions of body on drugs

 

Pharmacology

  1. Pharmacodynamics – mechanism of drug action/effect

  2. Pharmacokinetics – Absorption, distribution, biotransformation & excretion of drugs out of the body

Receptors = any biologic molecule to which a drug binds and produces a measurable response.

Examples: enzymes, structural proteins

Most important, richest source of therapeutically exploitable pharmacological receptors : Proteins that are responsible for transducing extracellular signals into intracellular response.

  1. Ligand Gated Ion Channels
  2. G-Protein Coupled Receptors
  3. Enzyme-Linked Receptors
  4. Intracellular Receptors

Ligand Gated Ion Channels

  1. Regulation of the flow of ions across cell membranes
  2. Examples : Cholinergenic nicotinic receptors, GABA
  3. Response = very rapid

    Nicotinic Receptors

  4. Stimulated by acetylcholine
  5. Results in sodium influx, activation of contractions in skeletal muscle

    GABA-receptor

  6. Stimulated by Benzodiazepines, by GABA
  7. Results in increased chloride influx –> hyperpolarization of the cell

 

G-Protein Coupled

  1. Comprised of single peptide that has seven membrane-spanning regions, linked to a G-protein with 3 subunits – alpha (binds GTP) and betagamma
  2. Binding of appropriate ligand to extracellular region – activates G-Protein – GTP replaces GDP on alpha subunit – dissociation of G-Protein – both alpha-GTP and betagamma interact with second messengers
  3. Response last several seconds to minutes
  4. Examples : alpha and beta adrenoreceptors

 

Enzyme-Linked

  1. Have a cytosolic enzyme activity as an integral component of their structure/function.
  2. Binding of a ligand to extracellular domain activates or inhibits cytosolic enzyme activity.
  3. Example : Insulin receptors
  4. Duration of response : minutes to hours

 

Intracellular

  1. Entirely intracellular, ligand must diffuse into the cell to interact with it.
  2. Constrains the physical-chemical properties of the ligand
    • Must have sufficient lipid solubility to be able to move across cell membrane
  3. Example: Steroid receptors
  4. Activated ligand-receptor complex migrated to the nucleus, where it binds to a specific DNA sequences, resulting in regulation of gene expression.
  5. Duration of response: Much longer, hours to days

Interaction of receptors with ligand – formation of chemical bonds (electrostatic & hydrogen)

Bonds

  • Important in determining the selectivity of receptors – the strength of these noncovalent bond is related inversely to the distance between the interacting atoms
  • Successful binding of a drug requires an exact fit of the ligand atoms with the complementary receptor atoms.
  • Usually reversible, except for a handful of drugs that covalently bond to their targets.
  • Factor of the drug molecules that determine which of the myriad binding sites in the cells/tissues can interact with ligand:
      1. Size

      2. Shape

      3. Charge distribution

      4. “Lock & Key”

      5. High degree of specificity




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