Dissociation constants

Fifth Generation:

These are extended spectrum antibiotics.

Ceftaroline, Ceftobiprole

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
 

AUTOCOIDS

An  organic substance, such as a hormone, produced in one part of organism and transported by the blood or lymph to another part of the organism where it exerts a physiologic effect on that part.

TYPES OF AUTACOIDS:
 Amines : Histamine,5-Hydroxytryptamine.
 Lipids    : Prostaglandins, Leukotriens, Platelet activating factor.
 Peptide : Bradykinin , angiotensin. 

Distribution

Three major controlling factors:  

Blood Flow to Tissues:  rarely a limiting factor, except in cases of abscesses and tumors.
Exiting the Vascular System:  Occurs at capillary beds.
- Typical Capillary Beds - drugs pass between cells 
- The Blood-Brain Barrier-  Tight junctions here, so drugs must pass through cells.  Must then be lipid soluble, or have transport system.
- Placenta - Does not constitute an absolute barrier to passage of drugs.  Lipid soluble, nonionized compounds readily pass.  
- Protein Binding:  Albumin is most important plasma protein in this respect.  It always remains in the blood stream, so drugs that are highly protein bound are not free to leave the bloodstream.  Restricts the distribution of drugs, and can be source of drug interactions.

Entering Cells:  some drugs must enter cells to reach sites of action.

Organic Nitrates 
Relax smooth muscle in blood vessel
Produces vasodilatation
– Decreases venous pressure and venous return to the heart  Which decreases the cardiac work load and oxygen demand. 
– May have little effect on the coronary arteries CAD causes stiffening and lack of 
–    responsiveness in the coronary arteries 
– Dilate arterioles, lowering peripheral vascular resistance  Reducing the cardiac workload

Main effect related to drop in blood pressure by
– Vasodilation- pools blood in veins and capillaries, decreasing the volume of blood that the heart has to pump around (the preload)
– relaxation of the vessels which decreases the resistance the heart has to pump against (the afterload) 

Indications
- Myocardial ischemia 
– Prevention
– Treatment 

Nitroglycerin (Nitro-Bid)
• Used
– To relive acute angina pectoris 
– Prevent exercise induced angina 
– Decrease frequency and severity of acute anginal episodes

Type 
• Oral - rapidly metabolized in the liver only small amount reaches circulation 
• Sublingual – Transmucosal tablets and sprays 
• Transdermal  – Ointment s 
– Adhesive discs applied to the skin
• IV preparations 

Sublingual Nitroglycerine 
•  Absorbed directly into the systemic circulation,  Acts within 1-3 minutes , Lasts 30-60 min 

Topical Nitroglycerine 
• Absorbed directly into systemic circulation,   Absorption at a slower rate. ,  Longer duration of action 
Ointment - effective for 4-8 hours 
Transdermal disc - effective for 18-24 hours 

Isosorbide dinitrate 
• Reduces frequency and severity of acute anginal episodes
• Sublingual or chewable acts in 2 min. effects last 2-3 hours
• Orally, systemic effects in about 30 minutes and last about 4 hours after oral administration
    
Tolerance to Long-Acting Nitrates 
• Long-acting dosage forms of nitrates may develop tolerance
– Result in episodes of chest pain
– Short acting nitrates less effective 

Prevention of Tolerance 
• Use long-acting forms for approximately 12-16 hours daily during active periods and omit them during inactive periods or sleep 
• Oral or topical should be given every 6 hours X 3 doses allowing a rest period of 6 hours

Isosorbide dinitrate (Isordil, Sorbitrate) is used to reduce the frequency and severity of acute anginal episodes.
When given sublingually or in chewable tablets, it acts in about 2 minutes, and its effects last 2 to 3 hours. When higher doses are given orally, more drug escapes metabolism in the liver and produces systemic effects in approximately 30 minutes. Therapeutic effects last about 4 hours after oral administration

Isosorbide mononitrate (Ismo, Imdur) is the metabolite and active component of isosorbide dinitrate. It is well absorbed after oral administration and almost 100% bioavailable. Unlike other oral nitrates, this drug is not subject to first-pass hepatic metabolism. Onset of action occurs within 1 hour, peak effects occur between 1 and 4 hours, and the elimination half-life is approximately 5 hours. It is used only for prophylaxis of angina; it does not act rapidly enough to relieve acute attacks.