Excretion
Routes of drug excretion
The most important route of drug elimination from the body is via the kidney

Renal Drug Excretion

- Glomerular Filtration

- Passive Tubular Reabsorption: drugs that are lipid soluble undergo passive reabsorption from the tubule back into the blood.

- Active Tubular Secretion

Factors that Modify Renal Drug Excretion

- pH Dependent Ionization:  manipulating urinary pH to promote the ionization of a drug can decrease passive reabsorption and hasten excretion.

- Competition for Active Tubular Transport

- Age:  Infants have a limited capscity to excrete drugs.

Nonrenal Routes of Drug Excretion
Breast Milk
Bile, Lungs, Sweat and Saliva

The kidney is the major organ of excretion. The lungs become very important for volatile substances or volatile metabolites.

Drugs which are eliminated by the kidney are eliminated by:

a) Filtration - no drug is reabsorbed or secreted.

b) Filtration and some of the drug is reabsorbed.

c) Filtration and some secretion.

d) Secretion

By use of the technique of clearance studies, one can determine the process by which the  kidney handles the drug.

Renal plasma clearance = U x V ml/min U  / Cp = conc. of drug in urine

Cp = conc. of drug in plasma

V = urine flow in ml/min

Renal clearance ratio = renal plasma clearance of drug (ml/min) / GFR (ml/min)

Total Body Clearance = renal + non-renal

Agonist, Antagonist, and Partial Agonists

Agonists:  molecules that activate receptors.  A drug that mimics the body's own regulatory processes.
Antagonists:  produce their effects by preventing receptors activation by endogenous regulatory molecules and drugs.  Block activation of receptors by agonists.
Noncompetive Antagonist:  Bind irreversibly to receptors, and reduce the maximal response that an agonist can elicit.
Competitive Antagonist:  Bind reversibly to receptors, competing with agonists for binding sites.
Partial Agonists:  Have moderate intrinsic activity, the maximal effect that a partial agonist can produce is lower than that of a full agonist.  Act as antagonists as well as agonists.
 

VITAMIN -K

• Group of lipophilic, hydrophobic vitamins.
• Needed for the post-translational modification of coagulation proteins.
• Phylloquinone (vitamin K1) is the major dietary form of vitamin K.

• Vitamin K2 (menaquinone, menatetrenone) is produced by bacteria in the intestines.

Antipsychotic Drugs

A.    Neuroleptics: antipsychotics; refers to ability of drugs to suppress motor activity and emotional expression (e.g., chlorpromazine shuffle)
Uses: primarily to treat symptoms of schizophrenia (thought disorder); also for psychoses (include drug-induced from amphetamine and cocaine), agitated states

Psychosis: variety of mental disorders (e.g., impaired perceptions, cognition, inappropriate or ↓ affect or mood)

Examples: dementias (Alzheimer’s), bipolar affective disorder (manic-depressive)

B.    Schizophrenia: 1% world-wide incidence (independent of time, culture, geography, politics); early onset (adolescence/young adulthood), life-long and progressive; treatment effective in ~ 50% (relieve symptoms but don’t cure)

Symptoms: antipsychotics control positive symptoms better than negative

a.    Positive: exaggerated/distorted normal function; commonly have hallucinations (auditory) and delusions (grandeur; paranoid delusions particularly prevalent; the most prevalent delusion is that thoughts are broadcast to world or thoughts/feelings are imposed by an external force)

b.    Negative: loss of normal function; see social withdrawal, blunted affect (emotions), ↓ speech and thought, loss of energy, inability to experience pleasure

Etiology: pathogenesis unkown but see biochemical (↑ dopamine receptors), structural (enlarged cerebral ventricles, cortical atrophy, ↓ volume of basal ganglia), functional (↓ cerebral blood flow, ↓ glucose utilization in prefrontal cortex), and genetic abnormalities (genetic predisposition, may involve multiple genes; important)

 Dopamine hypothesis: schizo symptoms due to abnormal ↑ in dopamine receptor activity; evidenced by 

i.    Correlation between potency and dopamine receptor antagonist binding: high correlation between therapeutic potency and their affinity for binding to D2 receptor, low correlation between potency and binding to D1 receptor)

ii.    Drugs that ↑ dopamine transmission can enhance schizophrenia or produce schizophrenic symptoms:

A)    L-DOPA: ↑ dopamine synthesis
B)    Chronic amphetamine use: releases dopamine
C)    Apomorphine: dopamine agonist

iii.    Dopamine receptors ↑ in brains of schizophrenics: postmortem brains, positron emission tomography

Dopamine pathways: don’t need to know details below; know that overactivity of dopamine neurons in mesolimbic and mesolimbocortical pathways → schizo symptoms

i.    Dorsal mesostriatal (nigrostriatal): substantia nigra to striatum; controls motor function
ii.    Ventral mesostriatal (mesolimbic): ventral tegmentum to nucleus accumbens; controls behavior/emotion; abnormally active in schizophrenia
iii.    Mesolimbocortical: ventral tegmentum to cortex and limbic structures; controls behavior and emotion; activity may be ↑ in schizophrenia
iv.    Tuberohypophyseal: hypothalamus to pituitary; inhibits prolactin secretion; important pathway to understand side effects

 Antipsychotic drugs: non-compliance is major reason for therapeutic failure

1.    Goals: prevent symptoms, improve quality of life, minimize side effects
2.    Prototypical drugs: chlorpromazine (phenothiazine derivative) and haloperidol (butyrophenone derivative)
a.    Provide symptomatic relief in 70%; delayed onset of action (4-8 weeks) and don’t know why (maybe from ↓ firing of dopamine neurons that project to meso-limbic and cortical regions)
3.    Older drugs: equally efficacious in treating schizophrenia; no abuse potential, little physical dependence; dysphoria in normal individuals; high therapeutic indexes (20-1000)

Classification: 

i.    Phenothiazines: 1st effective antipsychotics; chlorpromazine and thioridazine
ii.    Thioxanthines: less potent; thithixene
iii.    Butyrophenones: most widely used; haloperidol

 Side effects: many (so known as dirty drugs); block several NT receptors (adrenergic, cholindergic, histamine, dopamine, serotonin)  and D2 receptors in other pathways

i.    Autonomic: block muscarinic receptor (dry mouth, urinary retention, memory impairment), α-adrenoceptor (postural hypotension, reflex tachycardia)
Neuroleptic malignant syndrome: collapse of ANS; fever, diaphoresis, CV instability; incidence 1-2% of patients (fatal in 10%); need immediate treatment (bromocriptine- dopamine agonist)

ii.    Central: block DA receptor (striatum; have parkinsonian effects like bradykinesia/tremor/muscle rigidity, dystonias like neck/facial spasms, and akathisia—subject to motor restlessness), dopamine receptor (pituitary; have ↑ prolactin release, breast enlargement, galactorrhea, amenorrhea), histamine receptor (sedation)

DA receptor upregulation (supersensitivity): occurs after several months/years; see tardive dyskinesias (involuntary orofacial movements)

Drug interactions: induces hepatic metabolizing enzymes (↑ drug metabolism), potentiate CNS depressant effects (analgesics, general anesthetics, CNS depressants), D2 antagonists block therapeutic effects of L-DOPA used to treat Parkinson’s

Toxicity: high therapeutic indexes; acute toxicity seen only at very high doses (hypotension, hyper/hypothermia, seizures, coma, ventricular tachycardia)

Mechanism of action: D2 receptor antagonists, efficacy ↑ with ↑ potency at D2 receptor

Newer drugs: include clozapine (dibenzodiazepine; has preferential affinity for D4 receptors, low affinity for D2 receptors), risperidone (benzisoxazole), olanzapine (thienobenzodiazepine)

Advantages over older drugs: low incidence of agranulocytosis (leucopenia; exception is clozapine), very low incidence of motor disturbances (extrapyramidal signs; may be due to low affinity for D2 receptors), no prolactin elevation

Side effects: DA receptor upregulation (supersensitivity) occurs after several months/years; may → tardive diskinesias
 

Ciprofloxacin : Ciprofloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase

Ciprofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and  Gram-negative bacteria.

Enterobacteriaceae, Vibrio,  Hemophilus influenzae, Neisseria gonorrhoeae

 Neisseria menigitidis,  Moraxella catarrhalis,  Brucella, Campylobacter,

 Mycobacterium intracellulare, Legionella sp., Pseudomonas aeruginosa,

Bacillus anthracis - that causes anthrax

Weak activity against: Streptococcus pneumoniae,

No activity against:  Bacteroides,  Enterococcus faecium, Ureaplasma urealyticum  and others

It is contraindicated in children, pregnancy, and epilepsy.

Ciprofloxacin can cause photosensitivity reactions and can elevate plasma

theophylline levels to toxic values. It can also cause  constipation and sensitivity to caffeine.

Dosage in respiratory infections is 500-1500 mg a day in 2 doses.

COAGULANTS

An agent that produces coagulation (Coagulation is a complex process by which blood forms clots).

ANTICOAGULANTS

An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting.

Anticoagulants:

Calcium Chelators (sodium citrate, EDTA)

Heparin

Dalteparin Sodium (Fragmin) -Low molecular-weight heparin

Enoxaparin - Low molecular-weight heparin

Tinzaparin Sodium  - Low molecular-weight heparin

Warfarin

Lepirudin - recombinant form of the natural anticoagulant hirudin: potent and specific Thrombin inhibitor

Bivalirudin - analog of hirudin: potent and specific Thrombin inhibitor

Procoagulants:

Desmopressin acetate

Antiplatelet Drugs:

Acetylsalicylic Acid, Ticlopidine, Sulfinpyrazone, Abciximab , Clopidogrel bisulfate

Fibrinolytic Drugs:

Tissue Plasminogen Activator (t-PA, Activase), Streptokinase (Streptase),

Anistreplase, Urokinase

Antagonists:

Protamine sulfate, Aminocaproic acid

Pharmacological agents used to treat blood coagulation disorders fall in to three major categories:

1. Anticoagulants: Substances that prevent the synthesis of a fibrin network which inhibits coagulation and the formation of arterial thrombi and thromboembolic clots.

2. Antiplatelet agents: Substances that reduce the adhesion and aggregation of platelets.

3. Fibrinolytic agents: Substances that promote the destruction of already formed blood clots or thrombi by disrupting the fibrin mesh.