Metabolism

Hepatic Drug-Metabolizing Enzymes:  most drug metabolism in the liverperformed by the hepatic microsomal enzyme system.

Therapeutic Consequences of Drug Metabolism
- Accelerated Renal Drug Excretion:  The most important consequence of drug metabolism is the promotion of renal drug excretion.  Metabolism makes it possible for the kidney to excrete many drugs that it otherwise could not.

- Drug Inactivation
- Increased Therapeutic Action: Metabolism may increase the effectiveness of some drugs.
- Activation of Prodrugs:  A prodrug is a compound that is inactive when administered and made active by conversion in the body.

- Increased or Decreased Toxicity

Factors that influence rate of metabolism:  

- Age:  Hepatic maturation doesn't occur until about a year old.

- Induction of Drug-Metabolizing Enzymes:  Some drugs can cause the rate of metabolism to increase, leading to the need for an increased dosage.  May also influence the rate of metabolism for other drugs taken at the same time, leading to a need for increased dosages of those drugs as well.

- First-Pass Effect:  Hepatic inactivation of certain oral drugs.  Avoided by parentaral administration of drugs that undergo rapid hepatic metabolism.

- Nutritional Status

- Competition between Drugs

DOPAMINE

It is an immediate metabolic precursor of noradrenaline. It activates D1 receptors in several vascular beds, which causes vasodilatation. It acts on dopaminergic and other adrenergic receptors (α & β1).

Adverse effects of dopamine include nausea, vomiting, ectopic beats, anginal pain, tachycardia, palpitation and widened QRS.
Contraindications are atrial or ventricular tachyarrhythmias, hyperthyroidism and pheochromocytoma.

Amoxicillin

a moderate-spectrum

β-lactam antibiotic used to treat bacterial infections caused by susceptible

Mode of action Amoxicillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria. microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other beta-lactam antibiotics. Amoxicillin is susceptible to degradation by  β-lactamase-producing bacteria, and so is often given clavulanic acid.

Microbiology Amoxicillin is a moderate-spectrum antibiotic active against a wide range of Gram-positive, and a limited range of Gram-negative organisms

Susceptible Gram-positive organisms : Streptococcus spp., Diplococcus pneumoniae, non β-lactamase-producing Staphylococcus spp., and Streptococcus faecalis.

Susceptible Gram-negative organisms  Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, Escherichia coli, Proteus mirabilis and Salmonella spp.

Resistant organisms Penicillinase producing organisms, particularly penicillinase producing Staphylococcus spp. Penicillinase-producing N. gonorrhoeae and H. influenzae are also resistant

All strains of Pseudomonas spp., Klebsiella spp., Enterobacter spp., indole-positive

Proteus spp., Serratia marcescens, and Citrobacter spp. are resistant.

The incidence of β-lactamase-producing resistant organisms, including E. coli, appears to be increasing.

Amoxicillin and Clavulanic acid Amoxicillin is sometimes combined with clavulanic acid, a β-lactamase inhibitor, to increase the spectrum of action against

Gram-negative organisms, and to overcome bacterial antibiotic resistance mediated through β-lactamase production.

Anticonvulsant Drugs

A.    Anticonvulsants: drugs to control seizures or convulsions in susceptible people

B.    Seizures: abnormal neuronal discharges in the nervous system produced by focal or generalized brain disturbances

Manifestations: depend on location of seizure activity (motor cortex → motor convulsions, sensory cortex → abnormal sensations, temporal cortex → emotional disturbances)

Causes: many brain disorders such as head injury (glial scars, pH changes), anoxia (changes in pH or CSF pressure), infections (tissue damage, high T), drug withdrawal (barbiturates, ethanol, etc.), epilepsy (chronic state with repeated seizures)

C.    Epilepsy: most common chronic seizure disorder, characterized by recurrent seizures of a particular pattern,  many types (depending on location of dysfunction)

Characteristics: chronic CNS disorders (years to decades), involve sudden and transitory seizures (abnormal motor, autonomic, sensory, emotional, or cognitive function and abnormal EEG activity)

Etiology: hyperexcitable neurons; often originate at a site of damage (epileptogenic focus), often found at scar tissue from tumors, strokes, or trauma; abnormal discharge spreads to normal brain regions = seizure

Idiopathic (70%; may have genetic abnormalities) and symptomatic epilepsy (30%; obvious CNS trauma, neoplasm, infection, developmental abnormalities or drugs)

Neuropathophysiology: anticonvulsants act at each stage but most drugs not effective for all types of epilepsy (need specific drugs for specific types)

Seizure mechanism: enhanced excitation (glutamate) or ↓ inhibition (GABA) of epileptic focus → fire more quickly → ↑ release of K and glutamate → ↑ depolarization of surrounding neurons (=neuronal synchronization) → propagation (normal neurons activated)

TRICYCLIC ANTIDEPRESSANTS

e.g. amitriptyline, imipramine, nortriptyline

Belong to first generation antidepressants

ACTION:

Inhibit 5-HT(5-hydroxytryptamine) and norepinephrine reuptake

slow clearance of norepinephrine & 5-HT from the synapse 

enhance norepinephrine & 5-HT neuro-transmission

MODE OF ACTIONMODE OF ACTION

TCAs also block
– muscarinic acetylcholine receptors
– histamine receptors 
– 5-HT receptors
– α1 adrenoceptors

Onset of antidepressant activity takes 2-3 weeks

PHARMACOKINETICS

-  Readily absorbed from the gastro-intestinal tract 
- Bind strongly to plasma albumin
- Has a large volume of distribution(as a result of binding to extravascular tissues)
- Undergo liver CYP metabolism into biologically active metabolites
- These metabolites are inactivated via glucuronidation and excreted in urine

ADVERSE DRUG REACTIONS

Antimuscarinic - dry mouth, blurred vision, constipation and urinary retention
Antihistamine – drowsiness
adrenoceptor blockage(+/- central effect) postural hypotension
Reduce seizure threshold
Testicular enlargement, gynaecomastia, galactorrhoea
AV-conduction blocks and cardiac arrhythmias

TOXICITY

- Fatal in toxicity

- Most important toxic effect is, slowing of depolarisation of the cardiac action potential by blocking fast sodium channels ("quinidine-like" effect) 

- delays propagation of depolarisation through both myocardium and conducting tissue

- prolongation of the QRS complex and the PR/QT intervals

- predisposition to cardiac arrhythmias

DRUG INTERACTIONS

Pharmacodynamic:
– ↑ sedation with antihistamines, alcohol
– ↑ antimuscarinic effects with anticholinergics– ↑ antimuscarinic effects with anticholinergics
– Hypertension and arrhythmias with MAOIs- should be given at least 14 days apart

Pharmacokinetic (via altering CYP metabolism)
– ↓ plasma concentration of TCA by- carbamazepine, rifampicin
– ↑ plasma concentration of TCA by- cimetidine, calcium channel blockers,fluoxetine

OTHER CLINICAL USES OF AMITRIPTYLINE

- Treatment of nocturnal enuresis in children
- Treatment of neuropathic pain
- Migraine prophylaxis

Osmotic diuretics

An osmotic diuretic is a type of diuretic that inhibits reabsorption of water and sodium. They are pharmacologically inert substances that are given intravenously. They increase the osmolarity of blood and renal filtrate.

Mechanism(s) of Action

1.    Reduce tissue fluid (edema) 
2.    Reflex cardiovascular effect by osmotic retention of fluid within vascular space which increases blood volume (contraindicated with Congestive heart failure) 
3.    Diuretic effect

o    Makes H2O reabsorption far more difficult for tubular segments insufficient Na & H2O capacity in distal segments
o    Increased intramedullary blood flow (washout)
o    Incomplete sodium recapture (asc. loop). this is indirect inhibition of Na reabsorption (Na stays in tubule because water stays) 
o    Net diuretic effect: 
    Tubular concentration of sodium decreases 
    Total amount of sodium lost amount increases 
    GFR unchanged or slightly increased

Toxicity

Circulatory overload, dilutional hyponatremia,  Hyperkalemia, edema, skin necrosis

Agents
Mannitol